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Cardiovascular Frcem Success
Cardiovascular Frcem Success
Cardiovascular Frcem Success
a) 10 mL
b) 100 mL
c) 500 mL
d) 70 mL
e) 25 mL
Something wrong?
Answer
The stroke volume is the volume of blood ejected per beat. It is usually about 70 mL/beat at rest.
Notes
Total blood volume, cardiac output and stroke volume
The total blood volume in the circulatory system of a healthy adult is about 5 L.
The stroke volume is the volume of blood ejected per beat. It is usually about 70 mL/beat at
rest. The heart rate is the number of beats per minute. It is usually about 70 beats/minute
at rest.
The cardiac output is the volume of blood pumped out of heart via the aorta per minute.
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Cardiac output (CO) = Stroke volume x Heart rate = 70 mL/beat x 70 beats/min = 4900
During systole, the pressure in the left ventricle increases and blood is ejected into the aorta. The rise in pressure
stretches the elastic walls of the aorta and large arteries and drives blood flow. Systolic pressure is the maximum
arterial pressure during systole. During diastole, arterial blood flow is partly maintained by elastic recoil of the walls
of large arteries. The minimum pressure reached before the next systole is the diastolic pressure. The difference
between the systolic and diastolic pressure is the pulse pressure.
The mean arterial pressure (MAP) cannot be calculated by averaging these pressures, because for about 60% of
the time, the heart is in diastole. It is instead estimated as the diastolic + one-third of the pulse pressure, e.g. = 80
+ 1/3(110 – 80) = 90 mmHg where BP 110/80 mmHg.
The mean arterial pressure (MAP) at the start of the arterioles is about 65 mmHg. The pressure on the arterial side
of capillaries is about 25 mmHg, and on the venous side is about 15 mmHg. Venules converge into veins and finally
the vena cava. The pressure in the vena cava at the level of the heart (the central venous pressure) is usually close
to 0 mmHg.
What is the normal total volume of blood in the circulatory system of a healthy adult male:
a) 10 L
b) 8 L
c) 5 L
d) 2.5 L
e) 1 L
Something wrong?
Answer
The total blood volume in the circulatory system of a healthy adult is about 5 L.
Notes
Total blood volume, cardiac output and stroke volume
The total blood volume in the circulatory system of a healthy adult is about 5 L.
The stroke volume is the volume of blood ejected per beat. It is usually about 70 mL/beat at rest.
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The heart rate is the number of beats per minute. It is usually about 70 beats/minute at rest.
The cardiac output is the volume of blood pumped out of heart via the aorta per
minute.
Cardiac output (CO) = Stroke volume x Heart rate = 70 mL/beat x 70 beats/min = 4900
During systole, the pressure in the left ventricle increases and blood is ejected into the aorta. The rise in pressure
stretches the elastic walls of the aorta and large arteries and drives blood flow. Systolic pressure is the maximum
arterial pressure during systole. During diastole, arterial blood flow is partly maintained by elastic recoil of the walls
of large arteries. The minimum pressure reached before the next systole is the diastolic pressure. The difference
between the systolic and diastolic pressure is the pulse pressure.
The mean arterial pressure (MAP) cannot be calculated by averaging these pressures, because for about 60% of
the time, the heart is in diastole. It is instead estimated as the diastolic + one-third of the pulse pressure, e.g. = 80
+ 1/3(110 – 80) = 90 mmHg where BP 110/80 mmHg.
The mean arterial pressure (MAP) at the start of the arterioles is about 65 mmHg. The pressure on the arterial side
of capillaries is about 25 mmHg, and on the venous side is about 15 mmHg. Venules converge into veins and finally
the vena cava. The pressure in the vena cava at the level of the heart (the central venous pressure) is usually close
to 0 mmHg.
a) Blood-brain barrier
b) Renal glomeruli
c) Reticuloendothelial system
d) Endocrine glands
e) Intestinal villi
Something wrong?
Answer
Continuous capillaries, found in the skin, lungs, muscles and CNS, are the most selective with low permeability, as
junctions between the endothelial cells are very tight, restricting the flow of molecules with MW > 10,000.
Notes
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Capillaries and the smallest venules are formed from a single layer of endothelial cells supported on the outside by a
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basal lamina containing collagen. The luminal surface is covered by the glycoprotein network called the glycocalyx.
Capillary permeability
Capillaries throughout the body vary in their permeability based on the size of their pores. There are three basic types:
Continuous capillaries, found in the skin, lungs, muscles and CNS, are the most selective with low permeability,
as junctions between the endothelial cells are very tight, restricting the flow of molecules with MW >
10,000. Fenestrated capillaries, found in renal glomeruli, endocrine glands and intestinal villi, are more
permeable with less tight junctions, and the endothelial cells are also punctured by pores which allow large
amounts of fluids or metabolites to pass.
Discontinuous capillaries, found in the reticuloendothelial system (bone marrow, liver and spleen), have large
gaps between endothelial cells and are permeable to red blood cells.
Water, gases and other substances cross the capillary wall mainly by diffusion down their concentration gradients.
Non-polar lipophilic substances e.g. CO2 and O2 can cross the endothelial lipid bilayer membrane easily. The
membrane is however more impermeable to hydrophilic molecules such as glucose and polar molecules and ions.
Such substances mainly cross the wall of continuous capillaries through the gaps between endothelial cells, slowed
down by tight junctions between cells and by the glycocalyx so that diffusion is much slower than for lipophilic
substances.
This small pore system also prevents the diffusion of substances greater than 10,000 Da such as plasma proteins.
Plasma proteins can cross the capillary wall, but extremely slowly; this may involve large pores through endothelial
cells, such as in fenestrated capillaries or large spaces between endothelial cells, such as in discontinuous
capillaries.
Regarding the valves in the cardiac cycle, which of the following statements is CORRECT:
Answer
Atrial systole Open (atrial pressure > ventricular Closed (arterial pressure > ventricular
pressure) pressure)
Isovolumetric Closed (ventricular pressure > atrial Closed (arterial pressure > ventricular
contraction pressure) pressure)
Ventricular ejection Closed (ventricular pressure > atrial Open (ventricular pressure > arterial
pressure) pressure)
Isovolumetric Closed (ventricular pressure > atrial Closed (arterial pressure > ventricular
relaxation pressure) pressure)
Ventricular filling Open (atrial pressure > ventricular Closed (arterial pressure > ventricular
pressure) pressure)
Notes
The cardiac cycle describes the events that occur during one beat of the heart.
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At the start of the cardiac cycle, towards the end of diastole, the whole of the heart is relaxed. The atrioventricular
(AV) valves are open because the atrial pressure is still slightly greater than the ventricular pressure. The semilunar
valves are closed, as the pressure in the pulmonary artery and aorta is greater than the ventricular pressures. The
cycle starts when the sinoatrial node (SAN) initiates atrial systole.
Atrial depolarisation causes the P wave on the ECG and initiates atrial contraction (atrial repolarisation is too
diffuse to be seen on the ECG).
As the atria contract, the atrial pressure increases which forces more blood flow across the open AV valves, leading
to rapid flow of blood into the ventricles. There are no valves between the veins and atria and atrial systole causes
a small pressure rise in the great veins (the a wave on the JVP waveform).
At rest, atrial contraction only contributes the last 15 – 20% of the final ventricular volume, as most of the
ventricular filling has occurred passively in diastole due to venous pressure. The proportion of atrial contribution
increases with heart rate as diastole shortens and there is less time for passive ventricular filling.
The end-diastolic volume (EDV) is usually about 120 – 140 mL, and the end-diastolic pressure is less than 10
mmHg (and higher in the left ventricle than the right due to the thicker and therefore stiffer left ventricle).
In ventricular hypertrophy, filling of the ‘stiff’ ventricle by atrial systole causes a fourth heart sound, which is not
audible in normal adults.
Ventricular depolarisation causes the QRS complex on the ECG, and triggers excitation-contraction coupling and
myocyte contraction.
The ventricular pressure rises sharply during contraction and the AV valves close as soon as this is greater than
the atrial pressure (causing the first heart sound). Because the mitral valve closes before the tricuspid valve, the first
heart sound may be split.
For a short period, as the forces are developing, both the AV and the semilunar valves are closed as the ventricular
pressure is still less than that in the pulmonary artery and aorta, and no ejection occurs. This is isovolumetric
contraction.
The increasing pressure makes the AV valves bulge into the atria, causing a small atrial pressure wave (the c wave of
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When the ventricular pressure exceeds that in the pulmonary artery and the aorta, the semilunar valves open and
blood is ejected, initially rapidly (rapid ejection phase) and then more slowly (reduced ejection phase).
Atrial pressure initially decreases as the atrial base is pulled downward during ejection, expanding the atrial chamber
(the x descent of the JVP waveform). Atrial filling begins in the rapid ejection phase and continues during the
reduced ejection phase and atrial pressure begins to rise (the v wave of the JVP waveform).
During the second half of ejection, the ventricles stop actively contracting, the ventricular pressure starts to
decrease and the muscle starts to repolarise; this causes the T wave on the ECG, which marks the end of both
ventricular contraction and rapid ventricular ejection.
The ventricular pressure during the reduced ejection phase begins to decrease. Aortic pressure also decreases
because of the runoff of blood from large arteries into smaller arteries. The ventricular pressure falls slightly
below that in the aorta, but initially blood continues to flow out of the ventricle because of momentum;
eventually the ventricular pressure falls sufficiently and the semilunar valves close.
Closure of the semilunar valves causes a small increase in aortic pressure (the dicrotic notch on the arterial
waveform), and the second heart sound. Inspiration delays closure of the pulmonary valve and thus causes splitting of
the second heart sound.
The amount of blood ejected is the stroke volume (SV), and is usually about 70 mL (therefore about 50 mL is left;
this is the end-systolic volume). The proportion of EDV that is ejected (i.e. the SV/EDV) is the ejection fraction and
this is normally about 0.6.
Immediately after the closure of the semilunar valves, the ventricles rapidly relax and ventricular pressure
decreases rapidly but the AV valves remain closed as initially the ventricular pressure is still greater than atrial
pressure. This is isovolumetric relaxation.
Atrial pressure continues to rise because of venous return, with the v wave of the JVP waveform peaking during
this phase. As the ventricles continue to relax, the ventricular pressure falls below that of the atrial pressure and
the AV valves open.
When the AV valves open, the atrial pressure falls (the y descent of the JVP waveform) and the ventricles refill,
initially rapidly (the rapid filling phase) and then more slowly as the ventricles expand, become less complicant, and
ventricular pressures rise (the reduced filling phase). Rapid flow of blood from the atria into the ventricles causes
the third heart sound, which is normal in children but, in adults, is associated with disease such as ventricular
dilation.
Diastole is usually twice the length of systole at rest, but decreases with increased heart rate. During systole,
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contraction of the ventricles compresses the coronary arteries and suppresses blood flow. This is particularly
evident
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in the left ventricle, where during systole the ventricular pressure is the same as or greater than that in the arteries
and as a result more than 85% of left ventricular perfusion occurs during diastole. This becomes a problem if the
heart rate is increased as the diastolic interval is shorter and can result in ischaemia.
Atrial systole Open (atrial pressure > ventricular Closed (arterial pressure > ventricular
pressure) pressure)
Isovolumetric Closed (ventricular pressure > atrial Closed (arterial pressure > ventricular
contraction pressure) pressure)
Ventricular ejection Closed (ventricular pressure > atrial Open (ventricular pressure > arterial
pressure) pressure)
Isovolumetric Closed (ventricular pressure > atrial Closed (arterial pressure > ventricular
relaxation pressure) pressure)
Ventricular filling Open (atrial pressure > ventricular Closed (arterial pressure > ventricular
pressure) pressure)
c wave Isovolumetric Occurs due to the bulging of the tricuspid valve into the right atrium
contraction during right isovolumetric ventricular contraction
(early systole)
x descent Rapid ventricular Occurs due to a combination of right atrial relaxation, the downward
ejection (mid systole) displacement of the tricuspid valve during right ventricular contraction,
and the ejection of blood from both the ventricles
v wave Ventricular ejection Occurs due to right atrial filling from venous return
and isovolumetric
relaxation (late
systole)
y descent Ventricular filling Occurs due to opening of the tricuspid valve and the subsequent rapid
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(early diastole) inflow of blood from the right atrium to the right ventricle
First Start of systole Caused by closure of the atrioventricular (mitral & tricuspid) valves
heart
sound
Second heart End of systole Caused by closure of the semilunar (aortic and pulmonary) valves
sound
Third heart Early diastole Caused by rapid flow of blood from the atria into the ventricles during the
sound ventricular filling phase
Fourth heart Late diastole Caused by filling of an abnormally stiff ventricle in atrial systole
sound
ECG Event
Which of the following type of blood vessel contributes the most to total peripheral
resistance:
a) Capillaries
b) Large arteries
c) Smaller arteries and arterioles
d) Capillaries and small venules
e) Large veins
Something wrong?
Answer
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The major regulator of vascular resistance in the body is regulation of vessel radius. In humans, there is very little
pressure change as blood flows from the aorta to the large arteries, but the small arteries and arterioles are the
site of about 70% of the pressure drop, and are the main regulators of total peripheral resistance. Smaller arteries
and arterioles contain relatively more muscle and are resistance vessels, responsible for controlling tissue blood
flow through constriction.
Notes
The vascular system consists of arteries and arterioles that take blood from the heart to the tissues, thin-walled
capillaries and post-capillary venules that allow the diffusion of gases and metabolites, and venules and veins that
return blood to the heart. The blood pressure, vessel diameter and wall thickness vary throughout the circulation.
Varying amounts of smooth muscle are contained within the vessel walls, allowing them to constrict and alter their
resistance to flow.
Large arteries are elastic and partially damp out oscillations in pressure produced by pumping of the heart; stiff
arteries (e.g. age, atherosclerosis) result in larger oscillations. The major arteries are conductance vessels and divide
repeatedly into smaller muscular arterioles. Smaller arteries and arterioles contain relatively more muscle and are
resistance vessels, responsible for controlling tissue blood flow through constriction.
The arterioles divide into dense networks of capillaries and these rejoin into small and then larger venules.
Capillaries and small venules are exchange vessels which have no smooth muscle and which provide the exchange
surface between blood and tissues.
Veins
Veins have a larger diameter than equivalent arteries and provide less resistance. They have thin distensible walls
and contain about 70% of the total blood volume at any one time. Large veins are capacitance vessels and act as a
blood volume reservoir; when required they can constrict and increase the effective blood volume. Large veins in
the limbs contain one-way valves, and when muscle activity intermittently compresses these veins, they act as a
pump and assist venous return to the heart.
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By Kelvinsong (Own work) [CC BY-SA 3.0 (], via Wikimedia Commons
Answer
The pulmonary circulation is not controlled by either autonomic nerves or metabolic products, and the most
important mechanism regulating flow is hypoxic pulmonary vasoconstriction, in which small arteries constrict in
response to hypoxia (in contrast to elsewhere in the body). If an area of lung is poorly ventilated and the alveolar
partial pressure of oxygen is low, pulmonary blood vessels are constricted and blood is diverted to areas of the
lung that are better ventilated, thus maintaining optimal ventilation-perfusion matching. This effect is accentuated
by high alveolar PCO2. The response is unhelpful in the presence of global lung hypoxia, at altitude or in
respiratory failure, where it may contribute to the development of pulmonary hypertension and right-sided heart
failure (cor pulmonale).
Notes
Skeletal muscle circulation
The skeletal muscle circulation normally receives about 15 – 20% of the cardiac output, but this may rise to > 80%
during exercise. Skeletal muscle provides a major contribution to the total peripheral resistance and sympathetic
regulation of muscle blood flow is important in the baroreceptor reflex. At rest most capillaries are not perfused as
their arterioles are constricted. Capillaries are recruited during exercise by metabolic hyperaemia, caused by release
of
+
K and CO2 from the muscle and adenosine. This overrides sympathetic vasoconstriction in working muscle; the latter
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reduces flow in non-working muscle conserving cardiac output.
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Pulmonary circulation
The pulmonary circulation is not controlled by either autonomic nerves or metabolic products, and the most
important mechanism regulating flow is hypoxic pulmonary vasoconstriction, in which small arteries constrict in
response to hypoxia (in contrast to elsewhere in the body).
If an area of lung is poorly ventilated and the alveolar partial pressure of oxygen is low, pulmonary blood vessels
are constricted and blood is diverted to areas of the lung that are better ventilated, thus maintaining optimal
ventilation- perfusion matching. This effect is accentuated by high alveolar PCO 2.
The response is unhelpful in the presence of global lung hypoxia, at altitude or in respiratory failure, where it may
contribute to the development of pulmonary hypertension and right-sided heart failure (cor pulmonale).
Cutaneous circulation
The main function of the cutaneous circulation is thermoregulation. Arteriovenous anastomoses (AVAs) directly
linked arterioles and venules, allowing a high blood flow into the venous plexus and thus radiation of heat. AVAs
are mostly found in the hands, feet and areas of the face.
Temperature is sensed by peripheral thermoreceptors and the hypothalamus coordinates the response.
Increased temperatures reduce sympathetic adrenergic stimulation, causing vasodilation and allowing more blood
to flow to the skin and radiate its heat to the environment, whereas activation of sympathetic cholinergic fibres
promotes sweating and the release of bradykinin, which also causes vasodilation.
Cerebral circulation
The brain receives around 15% of the total cardiac output and has a high capillary density.
The endothelial cells of the capillaries of the blood-brain barrier have very tight junctions, and contain membrane
transporters that control the movement of substances, such as ions, glucose and amino acids, and tightly regulate
the composition of cerebrospinal fluid. This is continuous except where substances need to be absorbed or released
e.g. pituitary gland, choroid plexus.
The autoregulation of cerebral blood flow can maintain a constant flow for blood pressures between 50 and 170
+
mmHg. CO2 and K are particularly important metabolic regulators in the brain, with increasing concentration
causing vasodilation and a functional hyperaemia.
Hyperventilation reduces blood PCO2 and can cause fainting due to cerebral vasoconstriction.
Coronary circulation
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The heart has a high metabolic demand and its high capillary density allow it to extract an unusually large fraction
(about 70%) of oxygen from the blood.
In exercise, the reduced diastolic interval and increased oxygen consumption demand a greatly increased blood
+
flow which is achieved by metabolic hyperaemia mediated by adenosine, K and hypoxia. This overrides the
vasoconstriction mediated by sympathetic nerves acting at alpha-adrenergic receptors and is assisted by circulating
adrenaline which causes vasodilation by acting on beta-adrenergic receptors.
Blood flows from the left atrium into the left ventricle via:
Answer
Blood flows from the right atrium into the right ventricle via the tricuspid atrioventricular valve and from the left
atrium into the left ventricle via the mitral atrioventricular valve. Blood is ejected from the right ventricle through
the pulmonary semilunar valve into the pulmonary artery and from the left ventricle via the aortic semilunar valve
into the aorta.
Notes
The heart consists of four chambers – two thin-walled atria and two muscular ventricles. The atria are separated
from the ventricles by a band of fibrous connective tissue called the annulus fibrosus, which provides a skeleton for
the attachment of muscle and cardiac valves, and prevents electrical conduction between the atria and ventricles
(except at the atrioventricular node).
Basic anatomy
The walls of the heart are formed from myocardium, and the left side has more muscle than the right (as the
systemic circulation has greater resistance to flow, the left ventricle requires more force).
The inner surface of the heart is covered by the endocardium which provides an anti-thrombogenic surface. The
outer surface is covered by epicardium, a layer of mesothelial cells. The whole heart is enclosed in a thin fibrous
sheath, the pericardium.
Valves
Blood flows from the right atrium into the right ventricle via the tricuspid atrioventricular valve and from the left
atrium into the left ventricle via the mitral atrioventricular valve. Blood is ejected from the right ventricle through
the
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pulmonary semilunar valve into the pulmonary artery and from the left ventricle via the aortic semilunar valve into
the aorta.
By National Heart Lung and Blood Institute (NIH) (National Heart Lung and Blood Institute (NIH)) [Public domain], via Wikimedia Common
The afferent component of the baroreceptor reflex is carried in which of the following:
Answer
Arterial baroreceptors are located in the carotid sinus and aortic arch, and detect the mean arterial pressure (MAP).
A decrease in MAP (such as in postural hypotension, or haemorrhage) reduces arterial stretch and decreases
baroreceptor activity, resulting in decreased firing in afferent nerves travelling via the glossopharyngeal nerve
(carotid sinus) and vagus nerve (aortic arch) to the medulla where the activity of the autonomic nervous system is
coordinated.
Notes
Mean arterial pressure (MAP) = Cardiac output (CO) x Total peripheral resistance (TPR).
Cardiac output is itself dependent on the central venous pressure (CVP), which in turn is highly dependent on the
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blood volume. Alterations of any of these variables may change
On standing from a prone position, gravity causes blood to pool in veins in the legs. Central venous pressure (CVP)
falls, causing a fall in stroke volume and cardiac output (due to Starling’s law) and thus a fall in blood pressure.
Normally this fall in BP is rapidly corrected by the baroreceptor reflex which causes venoconstriction (partially
restoring CVP), and an increase in heart rate and contractility, so restoring cardiac output and blood pressure.
Impaired autonomic nervous activity in the elderly accounts for the greater likelihood of postural hypotension. Any
symptoms of dizziness, blurred vision or syncope is due to a transient fall in cerebral perfusion that occurs before
cardiac output and MAP can be corrected.
Baroreceptor reflex
Arterial baroreceptors are located in the carotid sinus and aortic arch, and detect the mean arterial pressure (MAP).
A decrease in MAP (such as in postural hypotension, or haemorrhage) reduces arterial stretch and decreases
baroreceptor activity, resulting in decreased firing in afferent nerves travelling via the glossopharyngeal nerve
(carotid sinus) and vagus nerve (aortic arch) to the medulla where the activity of the autonomic nervous system is
coordinated.
Sympathetic nerve activity consequently increases, causing an increase in heart rate and cardiac contractility,
peripheral vasoconstriction with an increase in TPR, and venoconstriction with an increase in CVP and thus an
increase in cardiac output and blood pressure. Parasympathetic activity (vagal tone) decreases, contributing to the
rise in heart rate. MAP therefore returns to normal. An increase in MAP has the opposite effect.
The baroreceptors are most sensitive between 80 and 150 mmHg and their sensitivity is increased by a large pulse
pressure. They also show adaptation; if a new pressure is maintained for a few hours, activity slowly moves
towards normal. The baroreceptor reflex is important for buffering short-term changes in MAP e.g. with postural
changes, or when muscle blood flow increases rapidly in exercise.
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a) Ca2+ influx accounts for about 70% of the rise in intracellular [Ca2+].
b) In relaxation, most Ca2+ is actively pumped out of the myocyte.
c) Ca2+ is transported out of the cell predominantly by Ca2+ ATPase.
d) The Treppe effect refers to an increase in contractility secondary to an increase in heart rate.
e) Digoxin has a negative inotropic effect.
Something wrong?
Answer
2+
Although Ca entry during the action potential (AP) is essential for contraction, it only accounts for about 25% of
2+ 2+
the rise in intracellular Ca . The rest is released from Ca stores in the sarcoplasmic reticulum (SR). In
2+ 2+ 2+
relaxation, about 80% of Ca is rapidly pumped back into the SR (sequestered) by Ca ATPase pumps. The Ca
+ 2+
that entered the cell during the AP is transported out of the cell primarily by the Na /Ca exchanger in the
2+
membrane. When more action potentials occur per unit time, more Ca enters the cell during the AP plateau,
2+ 2+ 2+
more Ca is stored in the SR, more Ca is released from the SR and thus more Ca is left inside the cell and
greater tension is produced during contraction.
2+
Increased heart rate increases the force of contraction in a stepwise fashion as intracellular [Ca ] increases
cumulatively over several beats; this is the Treppe effect. Cardiac glycosides such as digoxin have a positive
inotropic effect.
Notes
2+
Cardiac muscle contracts when intracellular Ca rises (> 100
2+
Although Ca entry during the action potential (AP) is essential for contraction, it only accounts for about 25% of the
2+ 2+
rise in intracellular Ca . The rest is released from Ca stores in the sarcoplasmic reticulum (SR).
APs travel down invaginations of the sarcolemma called T-tubules, which are close to, but do not touch, the
2+ 2+ 2+
terminal cisternae of the SR. During the AP plateau, Ca enters the cell and activates Ca sensitive Ca release
2+ 2+
channels in the sarcoplasmic reticulum allowing stored Ca to flood into the cytosol; this is called Ca -induced
2+ 2+ 2+
Ca release. The amount of Ca released is dependent on how much is stored, and on the size of the initial Ca
influx during the AP.
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2+ 2+
In relaxation, about 80% of Ca is rapidly pumped back into the SR (sequestered) by Ca ATPase pumps. The
2+ + 2+
Ca that entered the cell during the AP is transported out of the cell primarily by the Na /Ca exchanger in the
membrane
2+ + +
which pumps one Ca ion out in exchange for three Na ions in, using the Na electrochemical gradient as an
energy source. This is relatively slow and continues during diastole.
2+
Treppe effect: When more action potentials occur per unit time, more Ca enters the cell during the AP plateau,
2+ 2+ 2+
more Ca is stored in the SR, more Ca is released from the SR and thus more Ca is left inside the cell and
greater tension is produced during contraction. Increased heart rate increases the force of contraction in a
stepwise fashion as
2+
intracellular [Ca ] increases cumulatively over several beats.
Inotropic agents
2+
Factors that affect intracellular [Ca ] and hence cardiac contractility are called inotropes.
2+ +
Cardiac glycosides (e.g. digoxin) slow the removal of Ca from the cell by inhibiting the membrane Na pump which
+ 2+ 2+
generates the Na gradient required for driving the export of Ca ; consequently the removal of Ca from the
2+
myocyte is slowed and more Ca is available for the next contraction.
+ 2+
Acidosis is negatively inotropic, largely because H competes for Ca binding sites.
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Answer
2+
Nitric oxide (NO) production by the endothelium is increased by factors that elevate intracellular Ca , including
local mediators such as bradykinin, histamine and serotonin, and some neurotransmitters (e.g. substance P). Increased
flow (shear stress) also stimulates NO production and additionally activates prostacyclin synthesis. The basal
production of NO continuously modulates vascular resistance. Nitric oxide also inhibits platelet activation and
thrombosis.
Notes
The endothelium
The endothelium plays a vital role in regulation of vascular tone (as well as regulation of haemostasis, angiogenesis and
inflammatory response).
In response to substances in the blood, endothelial damage or changes in blood flow, it can synthesise several
important substances; nitric oxide and prostacyclin are important vasodilators and endothelin-1 and thromboxane
A2 are potent vasoconstrictors.
2+
Nitric oxide (NO) production by the endothelium is increased by factors that elevate intracellular Ca , including
local mediators such as bradykinin, histamine and serotonin, and some neurotransmitters (e.g. substance P). Increased
flow (shear stress) also stimulates NO production and additionally activates prostacyclin synthesis. The basal
production of NO continuously modulates vascular resistance. Nitric oxide also inhibits platelet activation and
thrombosis.
Endothelin-1 (ET-1) is an extremely potent vasoconstrictor peptide which is released from the endothelium in the
presence of many other vasoconstrictors, including angiotensin II, antidiuretic hormone (ADH) and noradrenaline,
and may be increased in disease and hypoxia.
The eicosanoids prostacyclin (PGI2) and thromboxane A2 (TXA2) are synthesised by the cyclooxygenase pathway from
arachidonic acid, which is made from membrane phospholipids by phospholipase A2.
Vasoconstriction
2+
Most vasoconstrictors bind to G-protein coupled receptors which mediate elevation in intracellular [Ca ], leading
to vascular smooth muscle contraction. Important vasoconstrictors include endothelin-1, angiotensin II and
noradrenaline.
2+ 2+
The increase in intracellular [Ca ] is brought about by release of Ca from the sarcoplasmic reticulum and by
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2+ 2+
depolarisation and entry of Ca via L-type voltage-gated Ca channels. Most types of vascular smooth muscle do not
2+
generate action potentials, but instead depolarisation is graded, allowing graded entry of Ca .
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Vasodilation
2+ 2+
Vasodilation occurs by decreasing intracellular [Ca ] by sequestration by the sarcoplasmic reticulum Ca
2+ + 2+
ATPase and by removal from the cell by a plasma membrane Ca ATPase and Na /Ca exchange.
Most endogenous vasodilators cause relaxation by increasing cyclic guanosine monophosphate (cGMP) (e.g. nitric
oxide) or cyclic adenosine monophosphate (cAMP) (e.g. prostacyclin, beta-adrenergic receptor agonists), which
2+
activate protein kinases causing substrate level phosphorylation. L-type Ca channel blocker drugs are clinically
effective vasodilators.
Thromboxane A2 Prostacyclin
Angiotensin II Beta-agonists
Endothelin-1 release from endothelium is stimulated by all of the following EXCEPT for:
a) Angiotensin II
b) Antidiuretic hormone
c) Noradrenaline
d) Hypoxia
e) Nitric oxide
Something wrong?
Answer
Endothelin-1 (ET-1) is an extremely potent vasoconstrictor peptide which is released from the endothelium in the
presence of many other vasoconstrictors, including angiotensin II, antidiuretic hormone (ADH) and noradrenaline,
and may be increased in disease and hypoxia.
Notes
The endothelium
The endothelium plays a vital role in regulation of vascular tone (as well as regulation of haemostasis, angiogenesis and
inflammatory response).
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In response to substances in the blood, endothelial damage or changes in blood flow, it can synthesise several
important substances; nitric oxide and prostacyclin are important vasodilators and endothelin-1 and thromboxane
A2 are potent vasoconstrictors.
2+
Nitric oxide (NO) production by the endothelium is increased by factors that elevate intracellular Ca , including
local mediators such as bradykinin, histamine and serotonin, and some neurotransmitters (e.g. substance P). Increased
flow (shear stress) also stimulates NO production and additionally activates prostacyclin synthesis. The basal
production of NO continuously modulates vascular resistance. Nitric oxide also inhibits platelet activation and
thrombosis.
Endothelin-1 (ET-1) is an extremely potent vasoconstrictor peptide which is released from the endothelium in the
presence of many other vasoconstrictors, including angiotensin II, antidiuretic hormone (ADH) and noradrenaline,
and may be increased in disease and hypoxia.
The eicosanoids prostacyclin (PGI2) and thromboxane A2 (TXA2) are synthesised by the cyclooxygenase pathway from
arachidonic acid, which is made from membrane phospholipids by phospholipase A2.
Vasoconstriction
2+
Most vasoconstrictors bind to G-protein coupled receptors which mediate elevation in intracellular [Ca ], leading
to vascular smooth muscle contraction. Important vasoconstrictors include endothelin-1, angiotensin II and
noradrenaline.
2+ 2+
The increase in intracellular [Ca ] is brought about by release of Ca from the sarcoplasmic reticulum and by
2+ 2+
depolarisation and entry of Ca via L-type voltage-gated Ca channels. Most types of vascular smooth muscle do not
2+
generate action potentials, but instead depolarisation is graded, allowing graded entry of Ca .
Vasodilation
2+ 2+
Vasodilation occurs by decreasing intracellular [Ca ] by sequestration by the sarcoplasmic reticulum Ca
2+ + 2+
ATPase and by removal from the cell by a plasma membrane Ca ATPase and Na /Ca exchange.
Most endogenous vasodilators cause relaxation by increasing cyclic guanosine monophosphate (cGMP) (e.g. nitric
oxide) or cyclic adenosine monophosphate (cAMP) (e.g. prostacyclin, beta-adrenergic receptor agonists), which
2+
activate protein kinases causing substrate level phosphorylation. L-type Ca channel blocker drugs are clinically
effective vasodilators.
Thromboxane A2 Prostacyclin
Angiotensin II Beta-agonists
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a) The a wave
b) The c wave
c) The v wave
d) The x descent
e) The y descent
Something wrong?
Answer
c wave Isovolumetric Occurs due to the bulging of the tricuspid valve into the right atrium
contraction during right isovolumetric ventricular contraction
(early systole)
x descent Rapid ventricular Occurs due to a combination of right atrial relaxation, the downward
ejection (mid systole) displacement of the tricuspid valve during right ventricular contraction,
and the ejection of blood from both the ventricles
v wave Ventricular ejection Occurs due to right atrial filling from venous return
and isovolumetric
relaxation (late
systole)
y descent Ventricular filling Occurs due to opening of the tricuspid valve and the subsequent rapid
(early diastole) inflow of blood from the right atrium to the right ventricle
Notes
The cardiac cycle describes the events that occur during one beat of the heart.
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At the start of the cardiac cycle, towards the end of diastole, the whole of the heart is relaxed. The atrioventricular
(AV) valves are open because the atrial pressure is still slightly greater than the ventricular pressure. The semilunar
valves are closed, as the pressure in the pulmonary artery and aorta is greater than the ventricular pressures. The
cycle starts when the sinoatrial node (SAN) initiates atrial systole.
Atrial depolarisation causes the P wave on the ECG and initiates atrial contraction (atrial repolarisation is too
diffuse to be seen on the ECG).
As the atria contract, the atrial pressure increases which forces more blood flow across the open AV valves, leading
to rapid flow of blood into the ventricles. There are no valves between the veins and atria and atrial systole causes
a small pressure rise in the great veins (the a wave on the JVP waveform).
At rest, atrial contraction only contributes the last 15 – 20% of the final ventricular volume, as most of the
ventricular filling has occurred passively in diastole due to venous pressure. The proportion of atrial contribution
increases with heart rate as diastole shortens and there is less time for passive ventricular filling.
The end-diastolic volume (EDV) is usually about 120 – 140 mL, and the end-diastolic pressure is less than 10
mmHg (and higher in the left ventricle than the right due to the thicker and therefore stiffer left ventricle).
In ventricular hypertrophy, filling of the ‘stiff’ ventricle by atrial systole causes a fourth heart sound, which is not
audible in normal adults.
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Ventricular depolarisation causes the QRS complex on the ECG, and triggers excitation-contraction coupling and
myocyte contraction.
The ventricular pressure rises sharply during contraction and the AV valves close as soon as this is greater than
the atrial pressure (causing the first heart sound). Because the mitral valve closes before the tricuspid valve, the first
heart sound may be split.
For a short period, as the forces are developing, both the AV and the semilunar valves are closed as the ventricular
pressure is still less than that in the pulmonary artery and aorta, and no ejection occurs. This is isovolumetric
contraction.
The increasing pressure makes the AV valves bulge into the atria, causing a small atrial pressure wave (the c wave of
the JVP waveform).
When the ventricular pressure exceeds that in the pulmonary artery and the aorta, the semilunar valves open and
blood is ejected, initially rapidly (rapid ejection phase) and then more slowly (reduced ejection phase).
Atrial pressure initially decreases as the atrial base is pulled downward during ejection, expanding the atrial chamber
(the x descent of the JVP waveform). Atrial filling begins in the rapid ejection phase and continues during the
reduced ejection phase and atrial pressure begins to rise (the v wave of the JVP waveform).
During the second half of ejection, the ventricles stop actively contracting, the ventricular pressure starts to
decrease and the muscle starts to repolarise; this causes the T wave on the ECG, which marks the end of both
ventricular contraction and rapid ventricular ejection.
The ventricular pressure during the reduced ejection phase begins to decrease. Aortic pressure also decreases
because of the runoff of blood from large arteries into smaller arteries. The ventricular pressure falls slightly
below that in the aorta, but initially blood continues to flow out of the ventricle because of momentum;
eventually the ventricular pressure falls sufficiently and the semilunar valves close.
Closure of the semilunar valves causes a small increase in aortic pressure (the dicrotic notch on the arterial
waveform), and the second heart sound. Inspiration delays closure of the pulmonary valve and thus causes splitting of
the second heart sound.
The amount of blood ejected is the stroke volume (SV), and is usually about 70 mL (therefore about 50 mL is left;
this is the end-systolic volume). The proportion of EDV that is ejected (i.e. the SV/EDV) is the ejection fraction and
this is normally about 0.6.
Immediately after the closure of the semilunar valves, the ventricles rapidly relax and ventricular pressure
decreases rapidly but the AV valves remain closed as initially the ventricular pressure is still greater than atrial
pressure. This is isovolumetric relaxation.
Atrial pressure continues to rise because of venous return, with the v wave of the JVP waveform peaking during this
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phase. As the ventricles continue to relax, the ventricular pressure falls below that of the atrial pressure and the AV
valves open.
When the AV valves open, the atrial pressure falls (the y descent of the JVP waveform) and the ventricles refill,
initially rapidly (the rapid filling phase) and then more slowly as the ventricles expand, become less complicant, and
ventricular pressures rise (the reduced filling phase). Rapid flow of blood from the atria into the ventricles causes
the third heart sound, which is normal in children but, in adults, is associated with disease such as ventricular
dilation.
Diastole is usually twice the length of systole at rest, but decreases with increased heart rate. During systole,
contraction of the ventricles compresses the coronary arteries and suppresses blood flow. This is particularly evident
in the left ventricle, where during systole the ventricular pressure is the same as or greater than that in the arteries
and as a result more than 85% of left ventricular perfusion occurs during diastole. This becomes a problem if the
heart rate is increased as the diastolic interval is shorter and can result in ischaemia.
Atrial systole Open (atrial pressure > ventricular Closed (arterial pressure > ventricular
pressure) pressure)
Isovolumetric Closed (ventricular pressure > atrial Closed (arterial pressure > ventricular
contraction pressure) pressure)
Ventricular ejection Closed (ventricular pressure > atrial Open (ventricular pressure > arterial
pressure) pressure)
Isovolumetric Closed (ventricular pressure > atrial Closed (arterial pressure > ventricular
relaxation pressure) pressure)
Ventricular filling Open (atrial pressure > ventricular Closed (arterial pressure > ventricular
pressure) pressure)
c wave Isovolumetric Occurs due to the bulging of the tricuspid valve into the right atrium
contraction during right isovolumetric ventricular contraction
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(early systole)
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x descent Rapid ventricular Occurs due to a combination of right atrial relaxation, the downward
ejection (mid systole) displacement of the tricuspid valve during right ventricular contraction,
and the ejection of blood from both the ventricles
v wave Ventricular ejection Occurs due to right atrial filling from venous return
and isovolumetric
relaxation (late
systole)
y descent Ventricular filling Occurs due to opening of the tricuspid valve and the subsequent rapid
(early diastole) inflow of blood from the right atrium to the right ventricle
First Start of systole Caused by closure of the atrioventricular (mitral & tricuspid) valves
heart
sound
Second heart End of systole Caused by closure of the semilunar (aortic and pulmonary) valves
sound
Third heart Early diastole Caused by rapid flow of blood from the atria into the ventricles during the
sound ventricular filling phase
Fourth heart Late diastole Caused by filling of an abnormally stiff ventricle in atrial systole
sound
ECG Event
Noradrenaline exhibits its positive inotropic effect by which of the following mechanisms:
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b) Binds to beta1-receptors and increases the size of the action potential arriving at the cardiac myocyte
c) Slows the removal of Ca2+ from the cell by inhibiting the membrane Na+/Ca2+ exchanger
d) Slows the removal of Ca2+ from the cell by inhibiting the membrane Na+ pump
e) Binds to beta1-receptors and causes increased Ca2+ entry via L-type channels during the action potential
Something wrong?
Answer
Noradrenaline (the sympathetic neurotransmitter) is a positive inotrope; it binds to β1-adrenoceptors on the
2+ 2+
membrane and causes increased Ca entry via L-type channels during the AP and thus increases Ca release
from
2+ 2+
the SR. Noradrenaline also increases Ca sequestration into the SR and thus more Ca is available for the next
contraction.
Notes
2+
Cardiac muscle contracts when intracellular Ca rises (> 100
2+
Although Ca entry during the action potential (AP) is essential for contraction, it only accounts for about 25% of the
2+ 2+
rise in intracellular Ca . The rest is released from Ca stores in the sarcoplasmic reticulum (SR).
APs travel down invaginations of the sarcolemma called T-tubules, which are close to, but do not touch, the
2+ 2+ 2+
terminal cisternae of the SR. During the AP plateau, Ca enters the cell and activates Ca sensitive Ca release
2+ 2+
channels in the sarcoplasmic reticulum allowing stored Ca to flood into the cytosol; this is called Ca -induced
2+ 2+ 2+
Ca release. The amount of Ca released is dependent on how much is stored, and on the size of the initial Ca
influx during the AP.
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2+ 2+
In relaxation, about 80% of Ca is rapidly pumped back into the SR (sequestered) by Ca ATPase pumps. The
2+ + 2+
Ca that entered the cell during the AP is transported out of the cell primarily by the Na /Ca exchanger in the
membrane
2+ + +
which pumps one Ca ion out in exchange for three Na ions in, using the Na electrochemical gradient as an
energy source. This is relatively slow and continues during diastole.
2+
Treppe effect: When more action potentials occur per unit time, more Ca enters the cell during the AP plateau,
2+ 2+ 2+
more Ca is stored in the SR, more Ca is released from the SR and thus more Ca is left inside the cell and
greater tension is produced during contraction. Increased heart rate increases the force of contraction in a
stepwise fashion as
2+
intracellular [Ca ] increases cumulatively over several beats.
Inotropic agents
2+
Factors that affect intracellular [Ca ] and hence cardiac contractility are called inotropes.
2+ +
Cardiac glycosides (e.g. digoxin) slow the removal of Ca from the cell by inhibiting the membrane Na pump which
+ 2+ 2+
generates the Na gradient required for driving the export of Ca ; consequently the removal of Ca from the
2+
myocyte is slowed and more Ca is available for the next contraction.
+ 2+
Acidosis is negatively inotropic, largely because H competes for Ca binding sites.
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Answer
Oedema is swelling of the tissues due to excess fluid in the interstitial space overwhelming the lymphatic system or due
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to obstruction or dysfunction of the lymphatic system.
A reduction in plasma protein e.g. in starvation or a loss of endothelial integrity e.g. in inflammation or ischaemia
will reduce the oncotic pressure gradient and enhance filtration and loss of fluid into the tissues. An increase in
venous pressure e.g. in congestive heart failure or venous insufficiency will increase capillary hydrostatic pressure
with a similar effect.
Increased capillary Caused by increased venous pressures e.g. by gravitational forces, volume expanded
hydrostatic states, in heart failure or with venous obstruction
pressure
Decreased Caused by decreased protein concentration in blood e.g. nephrotic syndrome, protein
plasma oncotic malnutrition, liver failure
pressure
Lymphatic Caused by, for example, filariasis or following lymph node dissection, surgery or radiation
obstruction therapy
Notes
Lymphatics
Normally, filtration of fluid out of the capillaries is slightly greater than absorption of fluid into the capillaries.
Fluid filtered by the microcirculation (about 8 L per day) is returned to the circulation by the lymphatic system.
Lymphatic capillaries are blind-ended tubes walled with endothelial cells which allow the entry of fluid, protein
and bacteria, but prevent their exit. Lymphatic capillaries drain into collecting lymphatics and then into larger
lymphatic vessels, both containing smooth muscle and unidirectional valves.
From here, lymph is propelled by smooth muscle constriction and compression of the vessels by body movements
into afferent lymphatics and then the lymph nodes, where bacteria and other foreign materials are removed by
phagocytes. Most fluid is reabsorbed here by capillaries, with the remainder returning via efferent lymphatics and
the thoracic duct into the subclavian veins.
The lymphatic system plays a major role in the body’s immune defence and is also important for absorption and
transport of fats.
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Oedema
Oedema is swelling of the tissues due to excess fluid in the interstitial space overwhelming the lymphatic system or
due to obstruction or dysfunction of the lymphatic system.
A reduction in plasma protein e.g. in starvation or a loss of endothelial integrity e.g. in inflammation or ischaemia
will reduce the oncotic pressure gradient and enhance filtration and loss of fluid into the tissues. An increase in
venous pressure e.g. in congestive heart failure or venous insufficiency will increase capillary hydrostatic pressure
with a similar effect.
Increased capillary Caused by increased venous pressures e.g. by gravitational forces, volume expanded
hydrostatic states, in heart failure or with venous obstruction
pressure
Decreased Caused by decreased protein concentration in blood e.g. nephrotic syndrome, protein
plasma oncotic malnutrition, liver failure
pressure
Lymphatic Caused by, for example, filariasis or following lymph node dissection, surgery or radiation
obstruction therapy
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a) Blood volume
b) Cardiac output
c) Central venous pressure
d) Stroke volume
e) Mean arterial pressure
Something wrong?
Answer
Arterial baroreceptors are located in the carotid sinus and aortic arch, and detect the mean arterial pressure (MAP).
Notes
Mean arterial pressure (MAP) = Cardiac output (CO) x Total peripheral resistance (TPR).
Cardiac output is itself dependent on the central venous pressure (CVP), which in turn is highly dependent on the
blood volume. Alterations of any of these variables may change MAP.
Postural hypotension
On standing from a prone position, gravity causes blood to pool in veins in the legs. Central venous pressure (CVP)
falls, causing a fall in stroke volume and cardiac output (due to Starling’s law) and thus a fall in blood pressure.
Normally this fall in BP is rapidly corrected by the baroreceptor reflex which causes venoconstriction (partially
restoring CVP), and an increase in heart rate and contractility, so restoring cardiac output and blood pressure.
Impaired autonomic nervous activity in the elderly accounts for the greater likelihood of postural hypotension. Any
symptoms of dizziness, blurred vision or syncope is due to a transient fall in cerebral perfusion that occurs before
cardiac output and MAP can be corrected.
Baroreceptor reflex
Arterial baroreceptors are located in the carotid sinus and aortic arch, and detect the mean arterial pressure (MAP).
A decrease in MAP (such as in postural hypotension, or haemorrhage) reduces arterial stretch and decreases
baroreceptor activity, resulting in decreased firing in afferent nerves travelling via the glossopharyngeal nerve
(carotid sinus) and vagus nerve (aortic arch) to the medulla where the activity of the autonomic nervous system is
coordinated.
Sympathetic nerve activity consequently increases, causing an increase in heart rate and cardiac contractility,
peripheral vasoconstriction with an increase in TPR, and venoconstriction with an increase in CVP and thus an
increase in cardiac output and blood pressure. Parasympathetic activity (vagal tone) decreases, contributing to the
rise in heart rate. MAP therefore returns to normal. An increase in MAP has the opposite effect.
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The baroreceptors are most sensitive between 80 and 150 mmHg and their sensitivity is increased by a large pulse
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pressure. They also show adaptation; if a new pressure is maintained for a few hours, activity slowly moves towards
normal. The baroreceptor reflex is important for buffering short-term changes in MAP e.g. with postural changes, or
when muscle blood flow increases rapidly in exercise.
Which of the following provides strong adhesions between adjacent cardiac myocytes:
a) Gap junctions
b) Tight junctions
c) Desmosomes
d) Connexons
e) Annulus fibrosus
Something wrong?
Answer
The synchronicity between myocytes occurs because all the adjacent cells are connected by intercalated discs. The
intercalated discs provide both a structural attachment by ‘glueing’ cells together at desmosomes and an electrical
contact made up of proteins called connexons, called a gap junction, which essentially creates a low-resistance
pathway between cells. Gap junctions allow action potentials to spread rapidly from one cell to another and allows
the myocardium to act as a functional syncytium.
Notes
Myocytes
The myocardium is composed of cardiac muscle cells called myocytes. The cells are striated due to the
arrangement of the thick and thin filaments which make up the bulk of the muscle, although they are less
organised than in skeletal
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muscle. The myocytes are small and branched, with a single nucleus and are rich in mitochondria. The normal
pumping action of the heart is dependent on the synchronised contraction of all cardiac cells.
Intercalated discs
The synchronicity between myocytes occurs because all the adjacent cells are connected by intercalated discs. The
intercalated discs provide both a structural attachment by ‘glueing’ cells together at desmosomes and an electrical
contact made up of proteins called connexons, called a gap junction, which essentially creates a low-resistance
pathway between cells. Gap junctions allow action potentials to spread rapidly from one cell to another and allows
the myocardium to act as a functional syncytium.
Cardiac pacemaker
Cardiac myocyte contraction is not dependent on an external nerve supply but instead the heart generates its own
rhythm, demonstrating inherent rhythmicity.
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The heartbeat is initiated by spontaneous depolarisation of the sinoatrial node (SAN), a region of specialised
myocytes in the right atrium, close to the coronary sinus. The rate is modulated by the autonomic nervous system.
Action potentials in the SAN activate adjacent atrial myocytes and a wave of depolarisation and contraction
therefore spreads through atrial muscle. This is prevented from reaching the ventricles directly by the annulus
fibrosis.
This impulse is channelled through the atrioventricular node (AVN), located between the right atrium and ventricle
near the atrial septum. The AVN contains small cells and thus conducts slowly and delays the impulse for about 120
ms, allowing time for atrial contraction to complete ventricular filling.
Once complete, the impulse is then transmitted by specialised, wide, fast conducting myocytes in the bundle of His
and Purkinje fibres, by which it is distributed over the inner surface of both ventricles. From here a wave of
depolarisation and contraction moves from myocyte to myocyte across the endocardium until the whole ventricular
mass is activated.
Electrocardiogram (ECG)
The wave of depolarisation through the heart causes local currents in surrounding fluid which are detected at the
body surface as small changes in voltage. This forms the basis of the ECG. The classical ECG records voltage
between the left and right arm (lead I), the right arm and left leg (lead II) and the left arm and left leg (lead III).
This is represented by Einthoven’s triangle. The size of the voltage at any time depends on the quantity of muscle
depolarisation and the direction in which the wave of depolarisation is travelling. Thus lead II normally shows the
largest deflection during ventricular depolarisation, as the muscle mass is greatest and depolarisation travels from
apex to base, more or less parallel to a line from the left hip to the right shoulder.
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By Npatchett (Own work) [CC BY-SA 4.0 (], via Wikimedia Commons
Answer
The microcirculation consists of the smallest terminal arterioles and the exchange vessels – the capillaries and
small postcapillary venules. Water tends to flow from a low to a high osmotic pressure, but from a high to a low
hydrostatic pressure. The net flow of water across the capillary wall is therefore determined by the balance
between the hydrostatic pressure which tends to drive water out of the capillaries (as capillary hydrostatic pressure
> interstitial hydrostatic pressure) and the oncotic pressure which tends to draw water into the capillaries from the
interstitial space (as interstitial oncotic pressure < capillary oncotic pressure). Flow of fluid across capillary walls is
described by Starling’s equation. Normally overall the hydrostatic pressure along the length of the capillary is
greater than plasma oncotic pressure and thus there is a small net filtration of fluid from the capillary into the
interstitial space.
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Notes
Overview of microcirculation
The microcirculation consists of the smallest terminal arterioles and the exchange vessels – the capillaries and small
postcapillary venules.
Blood flow into the microcirculation is regulated by the vasoconstriction of small arterioles, activated by the
sympathetic nervous system through numerous nerve endings in their walls. Each small arteriole feeds many
capillaries via several terminal arterioles. Terminal arterioles are not innervated and vasoconstriction is instead
mediated by local metabolites, allowing perfusion to be matched to metabolism.
Starling equation
The capillary wall is very permeable to water. Water tends to flow from a low to a high osmotic pressure, but from
a high to a low hydrostatic pressure. The net flow of water across the capillary wall is therefore determined by the
balance between the hydrostatic pressure which tends to drive water out of the capillaries and the oncotic pressure
which tends to draw water into the capillaries from the interstitial space.
Starling’s equation tells us that the net flow of water across the capillary wall is proportional to (Pc – Pi) – (πp –
πi), where (Pc – Pi) is the difference in hydrostatic pressure between the capillary and interstitial space and (πp –
πi) is the difference in osmotic pressure between plasma and interstitial fluid. A positive value means there is a net
fluid movement out of the capillary (filtration), a negative value means there is a net fluid movement into the
capillary (absorption).
Oncotic pressure:
Across capillary walls, unlike proteins, most ions and small molecules diffuse easily and thus the crystalloid osmotic
pressure they exert is roughly the same on either side of the capillary wall; for this reason, the osmotic force across
the capillary wall is largely determined by protein concentration in the blood. Plasma protein concentration is
normally much higher than interstitial protein concentration because very little protein is filtered; plasma colloidal
osmotic pressure is therefore higher than interstitial colloidal osmotic pressure and tends to draw fluid
intravascularly.
Hydrostatic pressure:
Capillary hydrostatic pressure normally varies from about 35 mmHg at the arteriolar end to about 15 mmHg at the
venous end, whereas the interstitial hydrostatic pressure is normally close to 0 mmHg (or is slightly negative). The
greater hydrostatic pressure inside the capillary tends to drive filtration of water out of the capillary into the
tissues.
Net filtration:
Normally overall the hydrostatic pressure along the length of the capillary is greater than plasma oncotic pressure
and thus there is a small net filtration of fluid from the capillary into the interstitial space; of about 4000 L of
plasma entering the capillaries daily as the blood recirculates, a net filtration of 8 L occurs. Although arteriolar
constriction will reduce capillary hydrostatic pressure and therefore lead to the reabsorption of fluid, this will
normally be transient due to the concentration of interstitial fluid, i.e. the increased interstitial oncotic pressure.
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Increased capillary Caused by increased venous pressures e.g. by gravitational forces, volume expanded
hydrostatic states, in heart failure or with venous obstruction
pressure
Decreased Caused by decreased protein concentration in blood e.g. nephrotic syndrome, protein
capillary oncotic malnutrition, liver failure
pressure
Lymphatic Caused by, for example, filariasis or following lymph node dissection, surgery or radiation
obstruction therapy
Regarding the heart sounds in the cardiac cycle, which of the following statements is
INCORRECT:
Answer
First Start of systole Caused by closure of the atrioventricular (mitral & tricuspid) valves
heart
sound
Second heart End of systole Caused by closure of the semilunar (aortic and pulmonary) valves
sound
Third heart Early diastole Caused by rapid flow of blood from the atria into the ventricles during the
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sound ventricular filling phase
Fourth heart Late diastole Caused by filling of an abnormally stiff ventricle in atrial systole
sound
Notes
The cardiac cycle describes the events that occur during one beat of the heart.
At the start of the cardiac cycle, towards the end of diastole, the whole of the heart is relaxed. The atrioventricular
(AV) valves are open because the atrial pressure is still slightly greater than the ventricular pressure. The semilunar
valves are closed, as the pressure in the pulmonary artery and aorta is greater than the ventricular pressures. The
cycle starts when the sinoatrial node (SAN) initiates atrial systole.
Atrial depolarisation causes the P wave on the ECG and initiates atrial contraction (atrial repolarisation is too
diffuse to be seen on the ECG).
As the atria contract, the atrial pressure increases which forces more blood flow across the open AV valves, leading
to rapid flow of blood into the ventricles. There are no valves between the veins and atria and atrial systole causes
a small
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pressure rise in the great veins (the a wave on the JVP waveform).
At rest, atrial contraction only contributes the last 15 – 20% of the final ventricular volume, as most of the
ventricular filling has occurred passively in diastole due to venous pressure. The proportion of atrial contribution
increases with heart rate as diastole shortens and there is less time for passive ventricular filling.
The end-diastolic volume (EDV) is usually about 120 – 140 mL, and the end-diastolic pressure is less than 10
mmHg (and higher in the left ventricle than the right due to the thicker and therefore stiffer left ventricle).
In ventricular hypertrophy, filling of the ‘stiff’ ventricle by atrial systole causes a fourth heart sound, which is not
audible in normal adults.
Ventricular depolarisation causes the QRS complex on the ECG, and triggers excitation-contraction coupling and
myocyte contraction.
The ventricular pressure rises sharply during contraction and the AV valves close as soon as this is greater than
the atrial pressure (causing the first heart sound). Because the mitral valve closes before the tricuspid valve, the first
heart sound may be split.
For a short period, as the forces are developing, both the AV and the semilunar valves are closed as the ventricular
pressure is still less than that in the pulmonary artery and aorta, and no ejection occurs. This is isovolumetric
contraction.
The increasing pressure makes the AV valves bulge into the atria, causing a small atrial pressure wave (the c wave of
the JVP waveform).
When the ventricular pressure exceeds that in the pulmonary artery and the aorta, the semilunar valves open and
blood is ejected, initially rapidly (rapid ejection phase) and then more slowly (reduced ejection phase).
Atrial pressure initially decreases as the atrial base is pulled downward during ejection, expanding the atrial chamber
(the x descent of the JVP waveform). Atrial filling begins in the rapid ejection phase and continues during the
reduced ejection phase and atrial pressure begins to rise (the v wave of the JVP waveform).
During the second half of ejection, the ventricles stop actively contracting, the ventricular pressure starts to
decrease and the muscle starts to repolarise; this causes the T wave on the ECG, which marks the end of both
ventricular contraction and rapid ventricular ejection.
The ventricular pressure during the reduced ejection phase begins to decrease. Aortic pressure also decreases
because of the runoff of blood from large arteries into smaller arteries. The ventricular pressure falls slightly
below that in the aorta, but initially blood continues to flow out of the ventricle because of momentum;
eventually the ventricular pressure falls sufficiently and the semilunar valves close.
Closure of the semilunar valves causes a small increase in aortic pressure (the dicrotic notch on the arterial waveform),
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and the second heart sound. Inspiration delays closure of the pulmonary valve and thus causes splitting of the second
heart sound.
The amount of blood ejected is the stroke volume (SV), and is usually about 70 mL (therefore about 50 mL is left;
this is the end-systolic volume). The proportion of EDV that is ejected (i.e. the SV/EDV) is the ejection fraction and
this is normally about 0.6.
Immediately after the closure of the semilunar valves, the ventricles rapidly relax and ventricular pressure
decreases rapidly but the AV valves remain closed as initially the ventricular pressure is still greater than atrial
pressure. This is isovolumetric relaxation.
Atrial pressure continues to rise because of venous return, with the v wave of the JVP waveform peaking during
this phase. As the ventricles continue to relax, the ventricular pressure falls below that of the atrial pressure and
the AV valves open.
When the AV valves open, the atrial pressure falls (the y descent of the JVP waveform) and the ventricles refill,
initially rapidly (the rapid filling phase) and then more slowly as the ventricles expand, become less complicant, and
ventricular pressures rise (the reduced filling phase). Rapid flow of blood from the atria into the ventricles causes
the third heart sound, which is normal in children but, in adults, is associated with disease such as ventricular
dilation.
Diastole is usually twice the length of systole at rest, but decreases with increased heart rate. During systole,
contraction of the ventricles compresses the coronary arteries and suppresses blood flow. This is particularly evident
in the left ventricle, where during systole the ventricular pressure is the same as or greater than that in the arteries
and as a result more than 85% of left ventricular perfusion occurs during diastole. This becomes a problem if the
heart rate is increased as the diastolic interval is shorter and can result in ischaemia.
Atrial systole Open (atrial pressure > ventricular Closed (arterial pressure > ventricular
pressure) pressure)
Isovolumetric Closed (ventricular pressure > atrial Closed (arterial pressure > ventricular
contraction pressure) pressure)
Ventricular ejection Closed (ventricular pressure > atrial Open (ventricular pressure > arterial
pressure) pressure)
Isovolumetric Closed (ventricular pressure > atrial Closed (arterial pressure > ventricular
relaxation pressure) pressure)
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Ventricular filling Open (atrial pressure > ventricular Closed (arterial pressure > ventricular
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pressure) pressure)
c wave Isovolumetric Occurs due to the bulging of the tricuspid valve into the right atrium
contraction during right isovolumetric ventricular contraction
(early systole)
x descent Rapid ventricular Occurs due to a combination of right atrial relaxation, the downward
ejection (mid systole) displacement of the tricuspid valve during right ventricular contraction,
and the ejection of blood from both the ventricles
v wave Ventricular ejection Occurs due to right atrial filling from venous return
and isovolumetric
relaxation (late
systole)
y descent Ventricular filling Occurs due to opening of the tricuspid valve and the subsequent rapid
(early diastole) inflow of blood from the right atrium to the right ventricle
First Start of systole Caused by closure of the atrioventricular (mitral & tricuspid) valves
heart
sound
Second heart End of systole Caused by closure of the semilunar (aortic and pulmonary) valves
sound
Third heart Early diastole Caused by rapid flow of blood from the atria into the ventricles during the
sound ventricular filling phase
Fourth heart Late diastole Caused by filling of an abnormally stiff ventricle in atrial systole
sound
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ECG Event
Answer
First Start of systole Caused by closure of the atrioventricular (mitral & tricuspid) valves
heart
sound
Second heart End of systole Caused by closure of the semilunar (aortic and pulmonary) valves
sound
Third heart Early diastole Caused by rapid flow of blood from the atria into the ventricles during the
sound ventricular filling phase
Fourth heart Late diastole Caused by filling of an abnormally stiff ventricle in atrial systole
sound
Notes
The cardiac cycle describes the events that occur during one beat of the heart.
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At the start of the cardiac cycle, towards the end of diastole, the whole of the heart is relaxed. The atrioventricular
(AV) valves are open because the atrial pressure is still slightly greater than the ventricular pressure. The semilunar
valves are closed, as the pressure in the pulmonary artery and aorta is greater than the ventricular pressures. The
cycle starts when the sinoatrial node (SAN) initiates atrial systole.
Atrial depolarisation causes the P wave on the ECG and initiates atrial contraction (atrial repolarisation is too
diffuse to be seen on the ECG).
As the atria contract, the atrial pressure increases which forces more blood flow across the open AV valves, leading
to rapid flow of blood into the ventricles. There are no valves between the veins and atria and atrial systole causes
a small pressure rise in the great veins (the a wave on the JVP waveform).
At rest, atrial contraction only contributes the last 15 – 20% of the final ventricular volume, as most of the
ventricular filling has occurred passively in diastole due to venous pressure. The proportion of atrial contribution
increases with heart rate as diastole shortens and there is less time for passive ventricular filling.
The end-diastolic volume (EDV) is usually about 120 – 140 mL, and the end-diastolic pressure is less than 10
mmHg (and higher in the left ventricle than the right due to the thicker and therefore stiffer left ventricle).
In ventricular hypertrophy, filling of the ‘stiff’ ventricle by atrial systole causes a fourth heart sound, which is not
audible in normal adults.
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Systole: Isovolumetric contraction (all valves closed)
Ventricular depolarisation causes the QRS complex on the ECG, and triggers excitation-contraction coupling and
myocyte contraction.
The ventricular pressure rises sharply during contraction and the AV valves close as soon as this is greater than
the atrial pressure (causing the first heart sound). Because the mitral valve closes before the tricuspid valve, the first
heart sound may be split.
For a short period, as the forces are developing, both the AV and the semilunar valves are closed as the ventricular
pressure is still less than that in the pulmonary artery and aorta, and no ejection occurs. This is isovolumetric
contraction.
The increasing pressure makes the AV valves bulge into the atria, causing a small atrial pressure wave (the c wave of
the JVP waveform).
When the ventricular pressure exceeds that in the pulmonary artery and the aorta, the semilunar valves open and
blood is ejected, initially rapidly (rapid ejection phase) and then more slowly (reduced ejection phase).
Atrial pressure initially decreases as the atrial base is pulled downward during ejection, expanding the atrial chamber
(the x descent of the JVP waveform). Atrial filling begins in the rapid ejection phase and continues during the
reduced ejection phase and atrial pressure begins to rise (the v wave of the JVP waveform).
During the second half of ejection, the ventricles stop actively contracting, the ventricular pressure starts to
decrease and the muscle starts to repolarise; this causes the T wave on the ECG, which marks the end of both
ventricular contraction and rapid ventricular ejection.
The ventricular pressure during the reduced ejection phase begins to decrease. Aortic pressure also decreases
because of the runoff of blood from large arteries into smaller arteries. The ventricular pressure falls slightly
below that in the aorta, but initially blood continues to flow out of the ventricle because of momentum;
eventually the ventricular pressure falls sufficiently and the semilunar valves close.
Closure of the semilunar valves causes a small increase in aortic pressure (the dicrotic notch on the arterial
waveform), and the second heart sound. Inspiration delays closure of the pulmonary valve and thus causes splitting of
the second heart sound.
The amount of blood ejected is the stroke volume (SV), and is usually about 70 mL (therefore about 50 mL is left;
this is the end-systolic volume). The proportion of EDV that is ejected (i.e. the SV/EDV) is the ejection fraction and
this is normally about 0.6.
Immediately after the closure of the semilunar valves, the ventricles rapidly relax and ventricular pressure
decreases rapidly but the AV valves remain closed as initially the ventricular pressure is still greater than atrial
pressure. This is isovolumetric relaxation.
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Atrial pressure continues to rise because of venous return, with the v wave of the JVP waveform peaking during
this phase. As the ventricles continue to relax, the ventricular pressure falls below that of the atrial pressure and
the AV valves open.
When the AV valves open, the atrial pressure falls (the y descent of the JVP waveform) and the ventricles refill,
initially rapidly (the rapid filling phase) and then more slowly as the ventricles expand, become less complicant, and
ventricular pressures rise (the reduced filling phase). Rapid flow of blood from the atria into the ventricles causes
the third heart sound, which is normal in children but, in adults, is associated with disease such as ventricular
dilation.
Diastole is usually twice the length of systole at rest, but decreases with increased heart rate. During systole,
contraction of the ventricles compresses the coronary arteries and suppresses blood flow. This is particularly evident
in the left ventricle, where during systole the ventricular pressure is the same as or greater than that in the arteries
and as a result more than 85% of left ventricular perfusion occurs during diastole. This becomes a problem if the
heart rate is increased as the diastolic interval is shorter and can result in ischaemia.
Atrial systole Open (atrial pressure > ventricular Closed (arterial pressure > ventricular
pressure) pressure)
Isovolumetric Closed (ventricular pressure > atrial Closed (arterial pressure > ventricular
contraction pressure) pressure)
Ventricular ejection Closed (ventricular pressure > atrial Open (ventricular pressure > arterial
pressure) pressure)
Isovolumetric Closed (ventricular pressure > atrial Closed (arterial pressure > ventricular
relaxation pressure) pressure)
Ventricular filling Open (atrial pressure > ventricular Closed (arterial pressure > ventricular
pressure) pressure)
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c wave Isovolumetric Occurs due to the bulging of the tricuspid valve into the right atrium
contraction during right isovolumetric ventricular contraction
(early systole)
x descent Rapid ventricular Occurs due to a combination of right atrial relaxation, the downward
ejection (mid systole) displacement of the tricuspid valve during right ventricular contraction,
and the ejection of blood from both the ventricles
v wave Ventricular ejection Occurs due to right atrial filling from venous return
and isovolumetric
relaxation (late
systole)
y descent Ventricular filling Occurs due to opening of the tricuspid valve and the subsequent rapid
(early diastole) inflow of blood from the right atrium to the right ventricle
First Start of systole Caused by closure of the atrioventricular (mitral & tricuspid) valves
heart
sound
Second heart End of systole Caused by closure of the semilunar (aortic and pulmonary) valves
sound
Third heart Early diastole Caused by rapid flow of blood from the atria into the ventricles during the
sound ventricular filling phase
Fourth heart Late diastole Caused by filling of an abnormally stiff ventricle in atrial systole
sound
ECG Event
Sympathetic stimulation causes all of the following cardiovascular effects, EXCEPT for:
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Answer
Sympathetic stimulation increases heart rate and cardiac contractility. Activation of sympathetic nerves also causes
arterial and venous vasoconstriction. Arterial vasoconstriction increases total peripheral resistance (TPR) and thus
reduces flow, so downstream pressure and venous return will fall. Venoconstriction does not significantly impede
flow because venous resistance is low compared to arteries, but it reduces their compliance and hence capacity.
Thus vasoconstriction has the same effect as increasing blood volume, and increases CVP. Sympathetic stimulation
thus increases cardiac output by increasing heart rate, contractility and CVP, and increases blood pressure by
increasing TPR and cardiac output.
Notes
Both the heart rate and contractility can be modulated by the autonomic nervous system.
Sympathetic stimulation increases heart rate and cardiac contractility. Activation of sympathetic nerves also causes
arterial and venous vasoconstriction. Arterial vasoconstriction increases total peripheral resistance (TPR) and thus
reduces flow, so downstream pressure and venous return will fall. Venoconstriction does not significantly impede
flow because venous resistance is low compared to arteries, but it reduces their compliance and hence capacity.
Thus vasoconstriction has the same effect as increasing blood volume, and increases CVP. Sympathetic stimulation
thus increases cardiac output by increasing heart rate, contractility and CVP, and increases blood pressure by
increasing TPR and cardiac output.
Parasympathetic stimulation causes a marked decrease in heart rate (negative chronotropic effect) but only a slight
decrease in heart muscle contractility (negative inotropic effect) as parasympathetic ventricular innervation is
sparse.
In the isovolumetric contraction phase of the cardiac cycle, all of the following statements
are true EXCEPT for:
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Answer
The ventricular pressure rises sharply during contraction and the AV valves close as soon as this is greater than
the atrial pressure (causing the first heart sound). Because the mitral valve closes before the tricuspid valve, the first
heart sound may be split. For a short period, as the forces are developing, both the AV and the semilunar valves
are closed as the ventricular pressure is still less than that in the pulmonary artery and aorta, and no ejection
occurs. This is isovolumetric contraction. The increasing pressure makes the AV valves bulge into the atria, causing
a small atrial pressure wave (the c wave of the JVP waveform).
Notes
The cardiac cycle describes the events that occur during one beat of the heart.
At the start of the cardiac cycle, towards the end of diastole, the whole of the heart is relaxed. The atrioventricular
(AV) valves are open because the atrial pressure is still slightly greater than the ventricular pressure. The semilunar
valves are closed, as the pressure in the pulmonary artery and aorta is greater than the ventricular pressures. The
cycle starts when the sinoatrial node (SAN) initiates atrial systole.
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Atrial depolarisation causes the P wave on the ECG and initiates atrial contraction (atrial repolarisation is too
diffuse to be seen on the ECG).
As the atria contract, the atrial pressure increases which forces more blood flow across the open AV valves, leading
to rapid flow of blood into the ventricles. There are no valves between the veins and atria and atrial systole causes
a small pressure rise in the great veins (the a wave on the JVP waveform).
At rest, atrial contraction only contributes the last 15 – 20% of the final ventricular volume, as most of the
ventricular filling has occurred passively in diastole due to venous pressure. The proportion of atrial contribution
increases with heart rate as diastole shortens and there is less time for passive ventricular filling.
The end-diastolic volume (EDV) is usually about 120 – 140 mL, and the end-diastolic pressure is less than 10
mmHg (and higher in the left ventricle than the right due to the thicker and therefore stiffer left ventricle).
In ventricular hypertrophy, filling of the ‘stiff’ ventricle by atrial systole causes a fourth heart sound, which is not
audible in normal adults.
Ventricular depolarisation causes the QRS complex on the ECG, and triggers excitation-contraction coupling and
myocyte contraction.
The ventricular pressure rises sharply during contraction and the AV valves close as soon as this is greater than
the atrial pressure (causing the first heart sound). Because the mitral valve closes before the tricuspid valve, the first
heart sound may be split.
For a short period, as the forces are developing, both the AV and the semilunar valves are closed as the ventricular
pressure is still less than that in the pulmonary artery and aorta, and no ejection occurs. This is isovolumetric
contraction.
The increasing pressure makes the AV valves bulge into the atria, causing a small atrial pressure wave (the c wave of
the JVP waveform).
When the ventricular pressure exceeds that in the pulmonary artery and the aorta, the semilunar valves open and
blood is ejected, initially rapidly (rapid ejection phase) and then more slowly (reduced ejection phase).
Atrial pressure initially decreases as the atrial base is pulled downward during ejection, expanding the atrial chamber
(the x descent of the JVP waveform). Atrial filling begins in the rapid ejection phase and continues during the
reduced ejection phase and atrial pressure begins to rise (the v wave of the JVP waveform).
During the second half of ejection, the ventricles stop actively contracting, the ventricular pressure starts to
decrease and the muscle starts to repolarise; this causes the T wave on the ECG, which marks the end of both
ventricular contraction and rapid ventricular ejection.
The ventricular pressure during the reduced ejection phase begins to decrease. Aortic pressure also decreases
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because of the runoff of blood from large arteries into smaller arteries. The ventricular pressure falls slightly
below that in the aorta, but initially blood continues to flow out of the ventricle because of momentum;
eventually the ventricular pressure falls sufficiently and the semilunar valves close.
Closure of the semilunar valves causes a small increase in aortic pressure (the dicrotic notch on the arterial
waveform), and the second heart sound. Inspiration delays closure of the pulmonary valve and thus causes splitting of
the second heart sound.
The amount of blood ejected is the stroke volume (SV), and is usually about 70 mL (therefore about 50 mL is left;
this is the end-systolic volume). The proportion of EDV that is ejected (i.e. the SV/EDV) is the ejection fraction and
this is normally about 0.6.
Immediately after the closure of the semilunar valves, the ventricles rapidly relax and ventricular pressure
decreases rapidly but the AV valves remain closed as initially the ventricular pressure is still greater than atrial
pressure. This is isovolumetric relaxation.
Atrial pressure continues to rise because of venous return, with the v wave of the JVP waveform peaking during
this phase. As the ventricles continue to relax, the ventricular pressure falls below that of the atrial pressure and
the AV valves open.
When the AV valves open, the atrial pressure falls (the y descent of the JVP waveform) and the ventricles refill,
initially rapidly (the rapid filling phase) and then more slowly as the ventricles expand, become less complicant, and
ventricular pressures rise (the reduced filling phase). Rapid flow of blood from the atria into the ventricles causes
the third heart sound, which is normal in children but, in adults, is associated with disease such as ventricular
dilation.
Diastole is usually twice the length of systole at rest, but decreases with increased heart rate. During systole,
contraction of the ventricles compresses the coronary arteries and suppresses blood flow. This is particularly evident
in the left ventricle, where during systole the ventricular pressure is the same as or greater than that in the arteries
and as a result more than 85% of left ventricular perfusion occurs during diastole. This becomes a problem if the
heart rate is increased as the diastolic interval is shorter and can result in ischaemia.
Atrial systole Open (atrial pressure > ventricular Closed (arterial pressure > ventricular
pressure) pressure)
Isovolumetric Closed (ventricular pressure > atrial Closed (arterial pressure > ventricular
contraction pressure) pressure)
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Ventricular ejection Closed (ventricular pressure > atrial Open (ventricular pressure > arterial
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pressure) pressure)
Isovolumetric Closed (ventricular pressure > atrial Closed (arterial pressure > ventricular
relaxation pressure) pressure)
Ventricular filling Open (atrial pressure > ventricular Closed (arterial pressure > ventricular
pressure) pressure)
c wave Isovolumetric Occurs due to the bulging of the tricuspid valve into the right atrium
contraction during right isovolumetric ventricular contraction
(early systole)
x descent Rapid ventricular Occurs due to a combination of right atrial relaxation, the downward
ejection (mid systole) displacement of the tricuspid valve during right ventricular contraction,
and the ejection of blood from both the ventricles
v wave Ventricular ejection Occurs due to right atrial filling from venous return
and isovolumetric
relaxation (late
systole)
y descent Ventricular filling Occurs due to opening of the tricuspid valve and the subsequent rapid
(early diastole) inflow of blood from the right atrium to the right ventricle
First Start of systole Caused by closure of the atrioventricular (mitral & tricuspid) valves
heart
sound
Second heart End of systole Caused by closure of the semilunar (aortic and pulmonary) valves
sound
Third heart Early diastole Caused by rapid flow of blood from the atria into the ventricles during the
sound ventricular filling phase
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Fourth heart Late diastole Caused by filling of an abnormally stiff ventricle in atrial systole
sound
ECG Event
Most vasoconstrictors act to bring about this effect by which of the following mechanisms
of action:
Answer
The endothelium plays a vital role in regulation of vascular tone (as well as regulation of haemostasis, angiogenesis
and inflammatory response). Most vasoconstrictors bind to G-protein coupled receptors which mediate elevation in
2+
intracellular [Ca ], leading to vascular smooth muscle contraction. Important vasoconstrictors include endothelin-
1,
2+ 2+
angiotensin II and noradrenaline. The increase in intracellular [Ca ] is brought about by release of Ca from the
2+ 2+
sarcoplasmic reticulum and by depolarisation and entry of Ca via L-type voltage-gated Ca channels. Most types of
vascular smooth muscle do not generate action potentials, but instead depolarisation is graded, allowing graded entry
2+
of Ca .
Notes
The endothelium
The endothelium plays a vital role in regulation of vascular tone (as well as regulation of haemostasis, angiogenesis and
inflammatory response).
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In response to substances in the blood, endothelial damage or changes in blood flow, it can synthesise several
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important substances; nitric oxide and prostacyclin are important vasodilators and endothelin-1 and thromboxane
A2 are potent vasoconstrictors.
2+
Nitric oxide (NO) production by the endothelium is increased by factors that elevate intracellular Ca , including
local mediators such as bradykinin, histamine and serotonin, and some neurotransmitters (e.g. substance P). Increased
flow (shear stress) also stimulates NO production and additionally activates prostacyclin synthesis. The basal
production of NO continuously modulates vascular resistance. Nitric oxide also inhibits platelet activation and
thrombosis.
Endothelin-1 (ET-1) is an extremely potent vasoconstrictor peptide which is released from the endothelium in the
presence of many other vasoconstrictors, including angiotensin II, antidiuretic hormone (ADH) and noradrenaline,
and may be increased in disease and hypoxia.
The eicosanoids prostacyclin (PGI2) and thromboxane A2 (TXA2) are synthesised by the cyclooxygenase pathway from
arachidonic acid, which is made from membrane phospholipids by phospholipase A2.
Vasoconstriction
2+
Most vasoconstrictors bind to G-protein coupled receptors which mediate elevation in intracellular [Ca ], leading
to vascular smooth muscle contraction. Important vasoconstrictors include endothelin-1, angiotensin II and
noradrenaline.
2+ 2+
The increase in intracellular [Ca ] is brought about by release of Ca from the sarcoplasmic reticulum and by
2+ 2+
depolarisation and entry of Ca via L-type voltage-gated Ca channels. Most types of vascular smooth muscle do not
2+
generate action potentials, but instead depolarisation is graded, allowing graded entry of Ca .
Vasodilation
2+ 2+
Vasodilation occurs by decreasing intracellular [Ca ] by sequestration by the sarcoplasmic reticulum Ca
2+ + 2+
ATPase and by removal from the cell by a plasma membrane Ca ATPase and Na /Ca exchange.
Most endogenous vasodilators cause relaxation by increasing cyclic guanosine monophosphate (cGMP) (e.g. nitric
oxide) or cyclic adenosine monophosphate (cAMP) (e.g. prostacyclin, beta-adrenergic receptor agonists), which
2+
activate protein kinases causing substrate level phosphorylation. L-type Ca channel blocker drugs are clinically
effective vasodilators.
Thromboxane A2 Prostacyclin
Angiotensin II Beta-agonists
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a) Na+ influx
b) K+ influx
c) Ca2+ influx
d) K+ efflux
e) Ca2+ efflux
Something wrong?
Answer
+ +
Repolarisation occurs due to activation of voltage-gated K rectifier channels and a K efflux. As the AP lasts
almost as long as contraction, its refractory period prevents another AP being initiated until the muscle relaxes,
thus cardiac muscle cannot exhibit tetanus.
Notes
Cardiac myocyte action potential
The resting potential of ventricular myocytes is about -90 mV. An action potential (AP) is initiated when the
myocyte is depolarised to a threshold potential of about -65 mV, as a result of transmission from an adjacent
myocyte via gap junctions.
Depolarisation:
+ +
Fast voltage-gated Na channels are activated and a Na influx depolarises the membrane rapidly to about +30
mV. This initial depolarisation is similar to that in nerve and skeletal muscle, and assists the transmission to the
next myocyte.
+
Na channels and currents rapidly inactivate, but in cardiac myocytes, the initial depolarisation activates voltage-
2+ 2+
gated Ca channels (slow L-type channels, threshold approximately – 45 mV) through which Ca floods into the
cell. The
2+
resulting influx of Ca prevents the cell from repolarising and causes a plateau phase, that is maintained for about
250 ms until the L-type channels inactivate. The cardiac AP is thus much longer than that in nerve or skeletal
muscle.
Repolarisation:
+ +
Repolarisation occurs due to activation of voltage-gated K rectifier channels and a K efflux. As the AP lasts
almost as long as contraction, its refractory period prevents another AP being initiated until the muscle relaxes,
thus cardiac muscle cannot exhibit tetanus.
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Image modified by FRCEM Success. [CC-BY-SA-3.0 (or GFDL (], via Wikimedia Commons
Atrial myocytes have a similar but more triangular AP compared to the ventricles (less plateau). Purkinje fibres in
the conduction system are also similar to ventricular myocytes, but have a spike at the peak of the upstroke
+
reflecting a larger Na current that contributes to their fast conduction velocity.
Answer
The brain receives around 15% of the total cardiac output and has a high capillary density. The endothelial cells of
the capillaries of the blood-brain barrier have very tight junctions, and contain membrane transporters that control
the movement of substances, such as ions, glucose and amino acids, and tightly regulate the composition of
cerebrospinal fluid. This is continuous except where substances need to be absorbed or released e.g. pituitary gland,
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choroid plexus.
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The autoregulation of cerebral blood flow can maintain a constant flow for blood pressures between 50 and 170
+
mmHg. CO2 and K are particularly important metabolic regulators in the brain, with increasing concentration
causing vasodilation and a functional hyperaemia. Hyperventilation reduces blood PCO2 and can cause fainting due
to cerebral
vasoconstriction.
Notes
Skeletal muscle circulation
The skeletal muscle circulation normally receives about 15 – 20% of the cardiac output, but this may rise to > 80%
during exercise. Skeletal muscle provides a major contribution to the total peripheral resistance and sympathetic
regulation of muscle blood flow is important in the baroreceptor reflex. At rest most capillaries are not perfused as
their arterioles are constricted. Capillaries are recruited during exercise by metabolic hyperaemia, caused by release
of
+
K and CO2 from the muscle and adenosine. This overrides sympathetic vasoconstriction in working muscle; the latter
reduces flow in non-working muscle conserving cardiac output.
Pulmonary circulation
The pulmonary circulation is not controlled by either autonomic nerves or metabolic products, and the most
important mechanism regulating flow is hypoxic pulmonary vasoconstriction, in which small arteries constrict in
response to hypoxia (in contrast to elsewhere in the body).
If an area of lung is poorly ventilated and the alveolar partial pressure of oxygen is low, pulmonary blood vessels
are constricted and blood is diverted to areas of the lung that are better ventilated, thus maintaining optimal
ventilation- perfusion matching. This effect is accentuated by high alveolar PCO 2.
The response is unhelpful in the presence of global lung hypoxia, at altitude or in respiratory failure, where it may
contribute to the development of pulmonary hypertension and right-sided heart failure (cor pulmonale).
Cutaneous circulation
The main function of the cutaneous circulation is thermoregulation. Arteriovenous anastomoses (AVAs) directly
linked arterioles and venules, allowing a high blood flow into the venous plexus and thus radiation of heat. AVAs
are mostly found in the hands, feet and areas of the face.
Temperature is sensed by peripheral thermoreceptors and the hypothalamus coordinates the response.
Increased temperatures reduce sympathetic adrenergic stimulation, causing vasodilation and allowing more blood
to flow to the skin and radiate its heat to the environment, whereas activation of sympathetic cholinergic fibres
promotes sweating and the release of bradykinin, which also causes vasodilation.
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Cerebral circulation
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The brain receives around 15% of the total cardiac output and has a high capillary density.
The endothelial cells of the capillaries of the blood-brain barrier have very tight junctions, and contain membrane
transporters that control the movement of substances, such as ions, glucose and amino acids, and tightly regulate
the composition of cerebrospinal fluid. This is continuous except where substances need to be absorbed or released
e.g. pituitary gland, choroid plexus.
The autoregulation of cerebral blood flow can maintain a constant flow for blood pressures between 50 and 170
+
mmHg. CO2 and K are particularly important metabolic regulators in the brain, with increasing concentration
causing vasodilation and a functional hyperaemia.
Hyperventilation reduces blood PCO2 and can cause fainting due to cerebral vasoconstriction.
Coronary circulation
The heart has a high metabolic demand and its high capillary density allow it to extract an unusually large fraction
(about 70%) of oxygen from the blood.
In exercise, the reduced diastolic interval and increased oxygen consumption demand a greatly increased blood
+
flow which is achieved by metabolic hyperaemia mediated by adenosine, K and hypoxia. This overrides the
vasoconstriction mediated by sympathetic nerves acting at alpha-adrenergic receptors and is assisted by circulating
adrenaline which causes vasodilation by acting on beta-adrenergic receptors.
Answer
On standing from a prone position, gravity causes blood to pool in veins in the legs. Central venous pressure (CVP)
falls, causing a fall in stroke volume and cardiac output (due to Starling’s law) and thus a fall in blood pressure.
Normally this fall in BP is rapidly corrected by the baroreceptor reflex which causes venoconstriction (partially
restoring CVP), and an increase in heart rate and contractility, so restoring cardiac output and blood pressure.
Impaired autonomic nervous activity in the elderly accounts for the greater likelihood of postural hypotension. Any
symptoms of dizziness, blurred vision or syncope is due to a transient fall in cerebral perfusion that occurs before
cardiac output and MAP can be corrected.
Notes
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Mean arterial pressure (MAP) = Cardiac output (CO) x Total peripheral resistance (TPR).
Cardiac output is itself dependent on the central venous pressure (CVP), which in turn is highly dependent on the
blood volume. Alterations of any of these variables may change MAP.
Postural hypotension
On standing from a prone position, gravity causes blood to pool in veins in the legs. Central venous pressure (CVP)
falls, causing a fall in stroke volume and cardiac output (due to Starling’s law) and thus a fall in blood pressure.
Normally this fall in BP is rapidly corrected by the baroreceptor reflex which causes venoconstriction (partially
restoring CVP), and an increase in heart rate and contractility, so restoring cardiac output and blood pressure.
Impaired autonomic nervous activity in the elderly accounts for the greater likelihood of postural hypotension. Any
symptoms of dizziness, blurred vision or syncope is due to a transient fall in cerebral perfusion that occurs before
cardiac output and MAP can be corrected.
Baroreceptor reflex
Arterial baroreceptors are located in the carotid sinus and aortic arch, and detect the mean arterial pressure (MAP).
A decrease in MAP (such as in postural hypotension, or haemorrhage) reduces arterial stretch and decreases
baroreceptor activity, resulting in decreased firing in afferent nerves travelling via the glossopharyngeal nerve
(carotid sinus) and vagus nerve (aortic arch) to the medulla where the activity of the autonomic nervous system is
coordinated.
Sympathetic nerve activity consequently increases, causing an increase in heart rate and cardiac contractility,
peripheral vasoconstriction with an increase in TPR, and venoconstriction with an increase in CVP and thus an
increase in cardiac output and blood pressure. Parasympathetic activity (vagal tone) decreases, contributing to the
rise in heart rate. MAP therefore returns to normal. An increase in MAP has the opposite effect.
The baroreceptors are most sensitive between 80 and 150 mmHg and their sensitivity is increased by a large pulse
pressure. They also show adaptation; if a new pressure is maintained for a few hours, activity slowly moves
towards normal. The baroreceptor reflex is important for buffering short-term changes in MAP e.g. with postural
changes, or when muscle blood flow increases rapidly in exercise.
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Answer
First Start of systole Caused by closure of the atrioventricular (mitral & tricuspid) valves
heart
sound
Second heart End of systole Caused by closure of the semilunar (aortic and pulmonary) valves
sound
Third heart Early diastole Caused by rapid flow of blood from the atria into the ventricles during the
sound ventricular filling phase
Fourth heart Late diastole Caused by filling of an abnormally stiff ventricle in atrial systole
sound
Notes
The cardiac cycle describes the events that occur during one beat of the heart.
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At the start of the cardiac cycle, towards the end of diastole, the whole of the heart is relaxed. The atrioventricular
(AV) valves are open because the atrial pressure is still slightly greater than the ventricular pressure. The semilunar
valves are closed, as the pressure in the pulmonary artery and aorta is greater than the ventricular pressures. The
cycle starts when the sinoatrial node (SAN) initiates atrial systole.
Atrial depolarisation causes the P wave on the ECG and initiates atrial contraction (atrial repolarisation is too
diffuse to be seen on the ECG).
As the atria contract, the atrial pressure increases which forces more blood flow across the open AV valves, leading
to rapid flow of blood into the ventricles. There are no valves between the veins and atria and atrial systole causes
a small pressure rise in the great veins (the a wave on the JVP waveform).
At rest, atrial contraction only contributes the last 15 – 20% of the final ventricular volume, as most of the
ventricular filling has occurred passively in diastole due to venous pressure. The proportion of atrial contribution
increases with heart rate as diastole shortens and there is less time for passive ventricular filling.
The end-diastolic volume (EDV) is usually about 120 – 140 mL, and the end-diastolic pressure is less than 10
mmHg (and higher in the left ventricle than the right due to the thicker and therefore stiffer left ventricle).
In ventricular hypertrophy, filling of the ‘stiff’ ventricle by atrial systole causes a fourth heart sound, which is not
audible in normal adults.
Ventricular depolarisation causes the QRS complex on the ECG, and triggers excitation-contraction coupling and
myocyte contraction.
The ventricular pressure rises sharply during contraction and the AV valves close as soon as this is greater than the
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atrial pressure (causing the first heart sound). Because the mitral valve closes before the tricuspid valve, the first heart
sound may be split.
For a short period, as the forces are developing, both the AV and the semilunar valves are closed as the ventricular
pressure is still less than that in the pulmonary artery and aorta, and no ejection occurs. This is isovolumetric
contraction.
The increasing pressure makes the AV valves bulge into the atria, causing a small atrial pressure wave (the c wave of
the JVP waveform).
When the ventricular pressure exceeds that in the pulmonary artery and the aorta, the semilunar valves open and
blood is ejected, initially rapidly (rapid ejection phase) and then more slowly (reduced ejection phase).
Atrial pressure initially decreases as the atrial base is pulled downward during ejection, expanding the atrial chamber
(the x descent of the JVP waveform). Atrial filling begins in the rapid ejection phase and continues during the
reduced ejection phase and atrial pressure begins to rise (the v wave of the JVP waveform).
During the second half of ejection, the ventricles stop actively contracting, the ventricular pressure starts to
decrease and the muscle starts to repolarise; this causes the T wave on the ECG, which marks the end of both
ventricular contraction and rapid ventricular ejection.
The ventricular pressure during the reduced ejection phase begins to decrease. Aortic pressure also decreases
because of the runoff of blood from large arteries into smaller arteries. The ventricular pressure falls slightly
below that in the aorta, but initially blood continues to flow out of the ventricle because of momentum;
eventually the ventricular pressure falls sufficiently and the semilunar valves close.
Closure of the semilunar valves causes a small increase in aortic pressure (the dicrotic notch on the arterial
waveform), and the second heart sound. Inspiration delays closure of the pulmonary valve and thus causes splitting of
the second heart sound.
The amount of blood ejected is the stroke volume (SV), and is usually about 70 mL (therefore about 50 mL is left;
this is the end-systolic volume). The proportion of EDV that is ejected (i.e. the SV/EDV) is the ejection fraction and
this is normally about 0.6.
Immediately after the closure of the semilunar valves, the ventricles rapidly relax and ventricular pressure
decreases rapidly but the AV valves remain closed as initially the ventricular pressure is still greater than atrial
pressure. This is isovolumetric relaxation.
Atrial pressure continues to rise because of venous return, with the v wave of the JVP waveform peaking during
this phase. As the ventricles continue to relax, the ventricular pressure falls below that of the atrial pressure and
the AV valves open.
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When the AV valves open, the atrial pressure falls (the y descent of the JVP waveform) and the ventricles refill,
initially rapidly (the rapid filling phase) and then more slowly as the ventricles expand, become less complicant, and
ventricular pressures rise (the reduced filling phase). Rapid flow of blood from the atria into the ventricles causes
the third heart sound, which is normal in children but, in adults, is associated with disease such as ventricular
dilation.
Diastole is usually twice the length of systole at rest, but decreases with increased heart rate. During systole,
contraction of the ventricles compresses the coronary arteries and suppresses blood flow. This is particularly evident
in the left ventricle, where during systole the ventricular pressure is the same as or greater than that in the arteries
and as a result more than 85% of left ventricular perfusion occurs during diastole. This becomes a problem if the
heart rate is increased as the diastolic interval is shorter and can result in ischaemia.
Atrial systole Open (atrial pressure > ventricular Closed (arterial pressure > ventricular
pressure) pressure)
Isovolumetric Closed (ventricular pressure > atrial Closed (arterial pressure > ventricular
contraction pressure) pressure)
Ventricular ejection Closed (ventricular pressure > atrial Open (ventricular pressure > arterial
pressure) pressure)
Isovolumetric Closed (ventricular pressure > atrial Closed (arterial pressure > ventricular
relaxation pressure) pressure)
Ventricular filling Open (atrial pressure > ventricular Closed (arterial pressure > ventricular
pressure) pressure)
c wave Isovolumetric Occurs due to the bulging of the tricuspid valve into the right atrium
contraction during right isovolumetric ventricular contraction
(early systole)
x descent Rapid ventricular Occurs due to a combination of right atrial relaxation, the downward
ejection (mid systole) displacement of the tricuspid valve during right ventricular contraction,
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and the ejection of blood from both the ventricles
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v wave Ventricular ejection Occurs due to right atrial filling from venous return
and isovolumetric
relaxation (late
systole)
y descent Ventricular filling Occurs due to opening of the tricuspid valve and the subsequent rapid
(early diastole) inflow of blood from the right atrium to the right ventricle
First Start of systole Caused by closure of the atrioventricular (mitral & tricuspid) valves
heart
sound
Second heart End of systole Caused by closure of the semilunar (aortic and pulmonary) valves
sound
Third heart Early diastole Caused by rapid flow of blood from the atria into the ventricles during the
sound ventricular filling phase
Fourth heart Late diastole Caused by filling of an abnormally stiff ventricle in atrial systole
sound
ECG Event
Something wrong?
Answer
During systole, the pressure in the left ventricle increases and blood is ejected into the aorta. The rise in pressure
stretches the elastic walls of the aorta and large arteries and drives blood flow. Systolic pressure is the maximum
arterial pressure during systole. During diastole, arterial blood flow is partly maintained by elastic recoil of the walls
of large arteries. The minimum pressure reached before the next systole is the diastolic pressure. The difference
between the systolic and diastolic pressure is the pulse pressure.
Notes
Total blood volume, cardiac output and stroke volume
The total blood volume in the circulatory system of a healthy adult is about 5 L.
The stroke volume is the volume of blood ejected per beat. It is usually about 70 mL/beat at
rest. The heart rate is the number of beats per minute. It is usually about 70 beats/minute
at rest.
The cardiac output is the volume of blood pumped out of heart via the aorta per minute.
Cardiac output (CO) = Stroke volume x Heart rate = 70 mL/beat x 70 beats/min = 4900
During systole, the pressure in the left ventricle increases and blood is ejected into the aorta. The rise in pressure
stretches the elastic walls of the aorta and large arteries and drives blood flow. Systolic pressure is the maximum
arterial pressure during systole. During diastole, arterial blood flow is partly maintained by elastic recoil of the walls
of large arteries. The minimum pressure reached before the next systole is the diastolic pressure. The difference
between the systolic and diastolic pressure is the pulse pressure.
The mean arterial pressure (MAP) cannot be calculated by averaging these pressures, because for about 60% of
the time, the heart is in diastole. It is instead estimated as the diastolic + one-third of the pulse pressure, e.g. = 80
+ 1/3(110 – 80) = 90 mmHg where BP 110/80 mmHg.
The mean arterial pressure (MAP) at the start of the arterioles is about 65 mmHg. The pressure on the arterial side
of capillaries is about 25 mmHg, and on the venous side is about 15 mmHg. Venules converge into veins and finally
the vena cava. The pressure in the vena cava at the level of the heart (the central venous pressure) is usually close
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to 0 mmHg.
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a) The a wave
b) The c wave
c) The v wave
d) The x descent
e) The y descent
Something wrong?
Answer
c wave Isovolumetric Occurs due to the bulging of the tricuspid valve into the right atrium
contraction during right isovolumetric ventricular contraction
(early systole)
x descent Rapid ventricular Occurs due to a combination of right atrial relaxation, the downward
ejection (mid systole) displacement of the tricuspid valve during right ventricular contraction,
and the ejection of blood from both the ventricles
v wave Ventricular ejection Occurs due to right atrial filling from venous return
and isovolumetric
relaxation (late
systole)
y descent Ventricular filling Occurs due to opening of the tricuspid valve and the subsequent rapid
(early diastole) inflow of blood from the right atrium to the right ventricle
Notes
The cardiac cycle describes the events that occur during one beat of the heart.
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At the start of the cardiac cycle, towards the end of diastole, the whole of the heart is relaxed. The atrioventricular
(AV) valves are open because the atrial pressure is still slightly greater than the ventricular pressure. The semilunar
valves are closed, as the pressure in the pulmonary artery and aorta is greater than the ventricular pressures. The
cycle starts when the sinoatrial node (SAN) initiates atrial systole.
Atrial depolarisation causes the P wave on the ECG and initiates atrial contraction (atrial repolarisation is too
diffuse to be seen on the ECG).
As the atria contract, the atrial pressure increases which forces more blood flow across the open AV valves, leading
to rapid flow of blood into the ventricles. There are no valves between the veins and atria and atrial systole causes
a small pressure rise in the great veins (the a wave on the JVP waveform).
At rest, atrial contraction only contributes the last 15 – 20% of the final ventricular volume, as most of the
ventricular filling has occurred passively in diastole due to venous pressure. The proportion of atrial contribution
increases with heart rate as diastole shortens and there is less time for passive ventricular filling.
The end-diastolic volume (EDV) is usually about 120 – 140 mL, and the end-diastolic pressure is less than 10
mmHg (and higher in the left ventricle than the right due to the thicker and therefore stiffer left ventricle).
In ventricular hypertrophy, filling of the ‘stiff’ ventricle by atrial systole causes a fourth heart sound, which is not
audible in normal adults.
Ventricular depolarisation causes the QRS complex on the ECG, and triggers excitation-contraction coupling and
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myocyte contraction.
The ventricular pressure rises sharply during contraction and the AV valves close as soon as this is greater than
the atrial pressure (causing the first heart sound). Because the mitral valve closes before the tricuspid valve, the first
heart sound may be split.
For a short period, as the forces are developing, both the AV and the semilunar valves are closed as the ventricular
pressure is still less than that in the pulmonary artery and aorta, and no ejection occurs. This is isovolumetric
contraction.
The increasing pressure makes the AV valves bulge into the atria, causing a small atrial pressure wave (the c wave of
the JVP waveform).
When the ventricular pressure exceeds that in the pulmonary artery and the aorta, the semilunar valves open and
blood is ejected, initially rapidly (rapid ejection phase) and then more slowly (reduced ejection phase).
Atrial pressure initially decreases as the atrial base is pulled downward during ejection, expanding the atrial chamber
(the x descent of the JVP waveform). Atrial filling begins in the rapid ejection phase and continues during the
reduced ejection phase and atrial pressure begins to rise (the v wave of the JVP waveform).
During the second half of ejection, the ventricles stop actively contracting, the ventricular pressure starts to
decrease and the muscle starts to repolarise; this causes the T wave on the ECG, which marks the end of both
ventricular contraction and rapid ventricular ejection.
The ventricular pressure during the reduced ejection phase begins to decrease. Aortic pressure also decreases
because of the runoff of blood from large arteries into smaller arteries. The ventricular pressure falls slightly
below that in the aorta, but initially blood continues to flow out of the ventricle because of momentum;
eventually the ventricular pressure falls sufficiently and the semilunar valves close.
Closure of the semilunar valves causes a small increase in aortic pressure (the dicrotic notch on the arterial
waveform), and the second heart sound. Inspiration delays closure of the pulmonary valve and thus causes splitting of
the second heart sound.
The amount of blood ejected is the stroke volume (SV), and is usually about 70 mL (therefore about 50 mL is left;
this is the end-systolic volume). The proportion of EDV that is ejected (i.e. the SV/EDV) is the ejection fraction and
this is normally about 0.6.
Immediately after the closure of the semilunar valves, the ventricles rapidly relax and ventricular pressure
decreases rapidly but the AV valves remain closed as initially the ventricular pressure is still greater than atrial
pressure. This is isovolumetric relaxation.
Atrial pressure continues to rise because of venous return, with the v wave of the JVP waveform peaking during
this phase. As the ventricles continue to relax, the ventricular pressure falls below that of the atrial pressure and
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the AV
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valves open.
When the AV valves open, the atrial pressure falls (the y descent of the JVP waveform) and the ventricles refill,
initially rapidly (the rapid filling phase) and then more slowly as the ventricles expand, become less complicant, and
ventricular pressures rise (the reduced filling phase). Rapid flow of blood from the atria into the ventricles causes
the third heart sound, which is normal in children but, in adults, is associated with disease such as ventricular
dilation.
Diastole is usually twice the length of systole at rest, but decreases with increased heart rate. During systole,
contraction of the ventricles compresses the coronary arteries and suppresses blood flow. This is particularly evident
in the left ventricle, where during systole the ventricular pressure is the same as or greater than that in the arteries
and as a result more than 85% of left ventricular perfusion occurs during diastole. This becomes a problem if the
heart rate is increased as the diastolic interval is shorter and can result in ischaemia.
Atrial systole Open (atrial pressure > ventricular Closed (arterial pressure > ventricular
pressure) pressure)
Isovolumetric Closed (ventricular pressure > atrial Closed (arterial pressure > ventricular
contraction pressure) pressure)
Ventricular ejection Closed (ventricular pressure > atrial Open (ventricular pressure > arterial
pressure) pressure)
Isovolumetric Closed (ventricular pressure > atrial Closed (arterial pressure > ventricular
relaxation pressure) pressure)
Ventricular filling Open (atrial pressure > ventricular Closed (arterial pressure > ventricular
pressure) pressure)
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c wave Isovolumetric Occurs due to the bulging of the tricuspid valve into the right atrium
contraction during right isovolumetric ventricular contraction
(early systole)
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x descent Rapid ventricular Occurs due to a combination of right atrial relaxation, the downward
ejection (mid systole) displacement of the tricuspid valve during right ventricular contraction,
and the ejection of blood from both the ventricles
v wave Ventricular ejection Occurs due to right atrial filling from venous return
and isovolumetric
relaxation (late
systole)
y descent Ventricular filling Occurs due to opening of the tricuspid valve and the subsequent rapid
(early diastole) inflow of blood from the right atrium to the right ventricle
First Start of systole Caused by closure of the atrioventricular (mitral & tricuspid) valves
heart
sound
Second heart End of systole Caused by closure of the semilunar (aortic and pulmonary) valves
sound
Third heart Early diastole Caused by rapid flow of blood from the atria into the ventricles during the
sound ventricular filling phase
Fourth heart Late diastole Caused by filling of an abnormally stiff ventricle in atrial systole
sound
ECG Event
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b) Endothelin-1 release is stimulated by angiotensin II and antidiuretic hormone.
c) Endothelin-1 production may be increased in hypoxia.
d) Endothelin-1 (ET-1) is released from the endothelium.
e) Endothelin-1 (ET-1) is an extremely potent vasoconstrictor peptide.
Something wrong?
Answer
Endothelin-1 (ET-1) is an extremely potent vasoconstrictor peptide which is released from the endothelium in the
presence of many other vasoconstrictors, including angiotensin II, antidiuretic hormone (ADH) and noradrenaline,
and may be increased in disease and hypoxia.
Notes
The endothelium
The endothelium plays a vital role in regulation of vascular tone (as well as regulation of haemostasis, angiogenesis and
inflammatory response).
In response to substances in the blood, endothelial damage or changes in blood flow, it can synthesise several
important substances; nitric oxide and prostacyclin are important vasodilators and endothelin-1 and thromboxane
A2 are potent vasoconstrictors.
2+
Nitric oxide (NO) production by the endothelium is increased by factors that elevate intracellular Ca , including
local mediators such as bradykinin, histamine and serotonin, and some neurotransmitters (e.g. substance P). Increased
flow (shear stress) also stimulates NO production and additionally activates prostacyclin synthesis. The basal
production of NO continuously modulates vascular resistance. Nitric oxide also inhibits platelet activation and
thrombosis.
Endothelin-1 (ET-1) is an extremely potent vasoconstrictor peptide which is released from the endothelium in the
presence of many other vasoconstrictors, including angiotensin II, antidiuretic hormone (ADH) and noradrenaline,
and may be increased in disease and hypoxia.
The eicosanoids prostacyclin (PGI2) and thromboxane A2 (TXA2) are synthesised by the cyclooxygenase pathway from
arachidonic acid, which is made from membrane phospholipids by phospholipase A2.
Vasoconstriction
2+
Most vasoconstrictors bind to G-protein coupled receptors which mediate elevation in intracellular [Ca ], leading
to vascular smooth muscle contraction. Important vasoconstrictors include endothelin-1, angiotensin II and
noradrenaline.
2+ 2+
The increase in intracellular [Ca ] is brought about by release of Ca from the sarcoplasmic reticulum and by
2+ 2+
depolarisation and entry of Ca via L-type voltage-gated Ca channels. Most types of vascular smooth muscle do not
2+
generate action potentials, but instead depolarisation is graded, allowing graded entry of Ca .
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Vasodilation
2+ 2+
Vasodilation occurs by decreasing intracellular [Ca ] by sequestration by the sarcoplasmic reticulum Ca
2+ + 2+
ATPase and by removal from the cell by a plasma membrane Ca ATPase and Na /Ca exchange.
Most endogenous vasodilators cause relaxation by increasing cyclic guanosine monophosphate (cGMP) (e.g. nitric
oxide) or cyclic adenosine monophosphate (cAMP) (e.g. prostacyclin, beta-adrenergic receptor agonists), which
2+
activate protein kinases causing substrate level phosphorylation. L-type Ca channel blocker drugs are clinically
effective vasodilators.
Thromboxane A2 Prostacyclin
Angiotensin II Beta-agonists
a) Non-polar lipophilic substances like O2 can cross the endothelial lipid bilayer easily.
b) The membrane is more impermeable to hydrophilic molecules such as glucose.
c) Capillary permeability is regulated by tight junctions and the glycocalyx.
d) Fenestrated capillaries have large gaps between cells allowing passage of red blood cells.
e) Continuous capillaries are found at the blood-brain barrier.
Something wrong?
Answer
Non-polar lipophilic substances e.g. CO2 and O2 can cross the endothelial lipid bilayer membrane easily. The
membrane is however more impermeable to hydrophilic molecules such as glucose and polar molecules and ions.
Such substances mainly cross the wall of continuous capillaries through the gaps between endothelial cells, slowed
down by tight junctions between cells and by the glycocalyx so that diffusion is much slower than for lipophilic
substances. Continuous capillaries with tight junctions are found at the blood-brain barrier. Discontinuous, not
fenestrated capillaries, have large gaps between cells allow the transport of proteins and red blood cells.
Notes
Capillaries and the smallest venules are formed from a single layer of endothelial cells supported on the outside by
a basal lamina containing collagen. The luminal surface is covered by the glycoprotein network called the
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glycocalyx.
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Capillary permeability
Capillaries throughout the body vary in their permeability based on the size of their pores. There are three basic types:
Continuous capillaries, found in the skin, lungs, muscles and CNS, are the most selective with low permeability,
as junctions between the endothelial cells are very tight, restricting the flow of molecules with MW >
10,000. Fenestrated capillaries, found in renal glomeruli, endocrine glands and intestinal villi, are more
permeable with less tight junctions, and the endothelial cells are also punctured by pores which allow large
amounts of fluids or metabolites to pass.
Discontinuous capillaries, found in the reticuloendothelial system (bone marrow, liver and spleen), have large
gaps between endothelial cells and are permeable to red blood cells.
Water, gases and other substances cross the capillary wall mainly by diffusion down their concentration gradients.
Non-polar lipophilic substances e.g. CO2 and O2 can cross the endothelial lipid bilayer membrane easily. The
membrane is however more impermeable to hydrophilic molecules such as glucose and polar molecules and ions.
Such substances mainly cross the wall of continuous capillaries through the gaps between endothelial cells, slowed
down by tight junctions between cells and by the glycocalyx so that diffusion is much slower than for lipophilic
substances.
This small pore system also prevents the diffusion of substances greater than 10,000 Da such as plasma proteins.
Plasma proteins can cross the capillary wall, but extremely slowly; this may involve large pores through endothelial
cells, such as in fenestrated capillaries or large spaces between endothelial cells, such as in discontinuous
capillaries.
All of the following cause a leftward shift along the Starling curve EXCEPT for:
a) Hypovolaemia
b) Tachycardia
c) Decreased central venous pressure
d) Atrial fibrillation
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Answer
The volume of blood in the ventricle at the start of systole, the end-diastolic volume (EDV), depends on the end-
diastolic pressure (EDP) and the compliance of the ventricular wall. Right ventricular EDP is dependent on right
atrial and hence central venous pressure (CVP). If EDP (and thus EDV) is increased, the force of the following
contraction, and thus stroke volume increases; this is known as the Frank-Starling relationship. This represents a
rightward shift along the Starling function curve. A decrease in EDP will cause a leftward shift along the Starling
curve.
Notes
Cardiac output is determined by the heart rate and stroke volume. Stroke volume is dependent on the filling
pressure (the preload), the cardiac muscle force (the contractility) and the pressure against which the heart has to
pump (the afterload).
Frank-Starling relationship
The volume of blood in the ventricle at the start of systole, the end-diastolic volume (EDV), depends on the end-
diastolic pressure (EDP) and the compliance of the ventricular wall. Right ventricular EDP is dependent on right
atrial and hence central venous pressure (CVP). If EDP (and thus EDV) is increased, the force of the following
contraction, and thus stroke volume increases; this is known as the Frank-Starling relationship.
Starling’s law of the heart states that ‘the energy released during contraction depends on the initial fibre length’. An
increase in EDV causes an increase in ventricular fibre length, which produces an increase in developed tension and
results in an increased force of systolic contraction. As muscle is stretched, more myosin cross-bridges can form,
increasing force. However, cardiac muscle has a much steeper relationship between stretch and force than skeletal
2+
muscle, because in the heart stretch also increases the Ca sensitivity of troponin, so more force is generated for the
2+
same intracellular Ca .
The most important consequence of Starling’s law is that output is matched between the right and left ventricles.
It thus explains how CVP, although only perceived by the right ventricle, also influences left ventricular function
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and cardiac output, and why postural hypotension and haemorrhage reduce cardiac output. It also allows the
heart to
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sustain output when afterload is increased, or contractility is reduced, as both lead to accumulation of venous
blood and a raised EDP, which increases ventricular force and restores stroke volume.
Preload
Increases in preload cause a rightward shift along the
curve Decreases in preload cause a leftward shift along the
curve
Contractility
Increases in contractility shift the curve upward
Decreases in contractility shift the curve downwards
Afterload
Increases in afterload shift the curve downwards and to the
right Decreases in afterload shift the curve upwards and to the
left
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Preload can be defined as the initial stretching of the cardiac myocytes prior to contraction. Preload, therefore, is
related to muscle sarcomere length. Because sarcomere length cannot be determined in the intact heart, other
indices of preload are used such as ventricular end-diastolic volume or pressure. When venous return to the heart is
increased, the end-diastolic pressure and volume of the ventricles are increased, which stretches the sarcomeres,
thereby increasing their preload.
Contractility
Contractility (inotropy) is the intrinsic ability of cardiac muscle to develop force at a given muscle length. It is
2+
determined by the intracellular [Ca ] and can be estimated by the ejection fraction. Increases in contractility
cause an
increase in stroke volume/cardiac output for any level of right atrial pressure or end-diastolic volume, and hence
shift the Starling curve upwards. Decreases in contractility cause a decrease in stroke volume/cardiac output for
any level of right atrial pressure or end-diastolic volume and hence shift the Starling curve downwards.
Afterload
Afterload is determined by the resistance to outflow from the ventricle, which for the left ventricle is mainly
determined by the aortic pressure, and for the right, the pulmonary artery pressure.
An increase in afterload (e.g. hypertension, valve stenosis) means that the ventricles must eject blood against a
higher pressure, resulting in a decrease in stroke volume and a downward shift of the Starling curve.
This decrease in stroke volume however results in an increase in end-systolic volume. As a result, blood
accumulates on the venous side and filling pressure rises. This will result in a secondary increase in preload and
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a rightward shift along the Starling curve; cardiac output is restored at the expense of an increased EDP.
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a) 500 mL/min
b) 1 L/min
c) 2 L/min
d) 3.5 L/min
e) 5 L/min
Something wrong?
Answer
The cardiac output is the volume of blood pumped out of heart via the aorta per minute, Cardiac output (CO) = Stroke
volume x Heart rate. The cardiac output is usually about 5 L/minute at rest in humans.
Notes
Total blood volume, cardiac output and stroke volume
The total blood volume in the circulatory system of a healthy adult is about 5 L.
The stroke volume is the volume of blood ejected per beat. It is usually about 70 mL/beat at
rest. The heart rate is the number of beats per minute. It is usually about 70 beats/minute
at rest.
The cardiac output is the volume of blood pumped out of heart via the aorta per minute.
Cardiac output (CO) = Stroke volume x Heart rate = 70 mL/beat x 70 beats/min = 4900
During systole, the pressure in the left ventricle increases and blood is ejected into the aorta. The rise in pressure
stretches the elastic walls of the aorta and large arteries and drives blood flow. Systolic pressure is the maximum
arterial pressure during systole. During diastole, arterial blood flow is partly maintained by elastic recoil of the walls
of large arteries. The minimum pressure reached before the next systole is the diastolic pressure. The difference
between the systolic and diastolic pressure is the pulse pressure.
The mean arterial pressure (MAP) cannot be calculated by averaging these pressures, because for about 60% of
the time, the heart is in diastole. It is instead estimated as the diastolic + one-third of the pulse pressure, e.g. = 80
+ 1/3(110 – 80) = 90 mmHg where BP 110/80 mmHg.
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The mean arterial pressure (MAP) at the start of the arterioles is about 65 mmHg. The pressure on the arterial side
of capillaries is about 25 mmHg, and on the venous side is about 15 mmHg. Venules converge into veins and finally
the vena cava. The pressure in the vena cava at the level of the heart (the central venous pressure) is usually close
to 0 mmHg.
Answer
The main function of the cutaneous circulation is thermoregulation. Arteriovenous anastomoses (AVAs) directly
linked arterioles and venules, allowing a high blood flow into the venous plexus and thus radiation of heat. AVAs
are mostly found in the hands, feet and areas of the face. Temperature is sensed by peripheral thermoreceptors
and the hypothalamus coordinates the response. When temperature is low, sympathetic stimulation of alpha-
adrenergic receptors causes vasoconstriction of cutaneous vessels minimising loss of body heat (a similar response
occurs in the baroreceptor reflex). Piloerection traps insulating air. Increased temperatures reduce sympathetic
adrenergic stimulation, causing vasodilation and allowing more blood to flow to the skin and radiate its heat to the
environment, whereas activation of sympathetic cholinergic fibres promotes sweating and the release of bradykinin,
which also causes vasodilation.
Notes
The skeletal muscle circulation normally receives about 15 – 20% of the cardiac output, but this may rise to > 80%
during exercise. Skeletal muscle provides a major contribution to the total peripheral resistance and sympathetic
regulation of muscle blood flow is important in the baroreceptor reflex. At rest most capillaries are not perfused as
their arterioles are constricted. Capillaries are recruited during exercise by metabolic hyperaemia, caused by release
of
+
K and CO2 from the muscle and adenosine. This overrides sympathetic vasoconstriction in working muscle; the latter
reduces flow in non-working muscle conserving cardiac output.
Pulmonary circulation
The pulmonary circulation is not controlled by either autonomic nerves or metabolic products, and the most
important mechanism regulating flow is hypoxic pulmonary vasoconstriction, in which small arteries constrict in
response to hypoxia (in contrast to elsewhere in the body).
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If an area of lung is poorly ventilated and the alveolar partial pressure of oxygen is low, pulmonary blood vessels
are constricted and blood is diverted to areas of the lung that are better ventilated, thus maintaining optimal
ventilation- perfusion matching. This effect is accentuated by high alveolar PCO 2.
The response is unhelpful in the presence of global lung hypoxia, at altitude or in respiratory failure, where it may
contribute to the development of pulmonary hypertension and right-sided heart failure (cor pulmonale).
Cutaneous circulation
The main function of the cutaneous circulation is thermoregulation. Arteriovenous anastomoses (AVAs) directly
linked arterioles and venules, allowing a high blood flow into the venous plexus and thus radiation of heat. AVAs
are mostly found in the hands, feet and areas of the face.
Temperature is sensed by peripheral thermoreceptors and the hypothalamus coordinates the response.
Increased temperatures reduce sympathetic adrenergic stimulation, causing vasodilation and allowing more blood
to flow to the skin and radiate its heat to the environment, whereas activation of sympathetic cholinergic fibres
promotes sweating and the release of bradykinin, which also causes vasodilation.
Cerebral circulation
The brain receives around 15% of the total cardiac output and has a high capillary density.
The endothelial cells of the capillaries of the blood-brain barrier have very tight junctions, and contain membrane
transporters that control the movement of substances, such as ions, glucose and amino acids, and tightly regulate
the composition of cerebrospinal fluid. This is continuous except where substances need to be absorbed or released
e.g. pituitary gland, choroid plexus.
The autoregulation of cerebral blood flow can maintain a constant flow for blood pressures between 50 and 170
+
mmHg. CO2 and K are particularly important metabolic regulators in the brain, with increasing concentration
causing vasodilation and a functional hyperaemia.
Hyperventilation reduces blood PCO2 and can cause fainting due to cerebral vasoconstriction.
Coronary circulation
The heart has a high metabolic demand and its high capillary density allow it to extract an unusually large fraction
(about 70%) of oxygen from the blood.
In exercise, the reduced diastolic interval and increased oxygen consumption demand a greatly increased blood
+
flow which is achieved by metabolic hyperaemia mediated by adenosine, K and hypoxia. This overrides the
vasoconstriction mediated by sympathetic nerves acting at alpha-adrenergic receptors and is assisted by circulating
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adrenaline which causes vasodilation by acting on beta-adrenergic receptors.
Answer
On standing from a prone position, gravity causes blood to pool in veins in the legs. Central venous pressure (CVP)
falls, causing a fall in stroke volume and cardiac output (due to Starling’s law) and thus a fall in blood pressure.
Normally this fall in BP is rapidly corrected by the baroreceptor reflex which causes venoconstriction (partially
restoring CVP), and an increase in heart rate and contractility, so restoring cardiac output and blood pressure.
Impaired autonomic nervous activity in the elderly accounts for the greater likelihood of postural hypotension. Any
symptoms of dizziness, blurred vision or syncope is due to a transient fall in cerebral perfusion that occurs before
cardiac output and MAP can be corrected.
Notes
Mean arterial pressure (MAP) = Cardiac output (CO) x Total peripheral resistance (TPR).
Cardiac output is itself dependent on the central venous pressure (CVP), which in turn is highly dependent on the
blood volume. Alterations of any of these variables may change MAP.
Postural hypotension
On standing from a prone position, gravity causes blood to pool in veins in the legs. Central venous pressure (CVP)
falls, causing a fall in stroke volume and cardiac output (due to Starling’s law) and thus a fall in blood pressure.
Normally this fall in BP is rapidly corrected by the baroreceptor reflex which causes venoconstriction (partially
restoring CVP), and an increase in heart rate and contractility, so restoring cardiac output and blood pressure.
Impaired autonomic nervous activity in the elderly accounts for the greater likelihood of postural hypotension. Any
symptoms of dizziness, blurred vision or syncope is due to a transient fall in cerebral perfusion that occurs before
cardiac output and MAP can be corrected.
Baroreceptor reflex
Arterial baroreceptors are located in the carotid sinus and aortic arch, and detect the mean arterial pressure (MAP).
A decrease in MAP (such as in postural hypotension, or haemorrhage) reduces arterial stretch and decreases
baroreceptor activity, resulting in decreased firing in afferent nerves travelling via the glossopharyngeal nerve
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(carotid
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sinus) and vagus nerve (aortic arch) to the medulla where the activity of the autonomic nervous system is coordinated.
Sympathetic nerve activity consequently increases, causing an increase in heart rate and cardiac contractility,
peripheral vasoconstriction with an increase in TPR, and venoconstriction with an increase in CVP and thus an
increase in cardiac output and blood pressure. Parasympathetic activity (vagal tone) decreases, contributing to the
rise in heart rate. MAP therefore returns to normal. An increase in MAP has the opposite effect.
The baroreceptors are most sensitive between 80 and 150 mmHg and their sensitivity is increased by a large pulse
pressure. They also show adaptation; if a new pressure is maintained for a few hours, activity slowly moves
towards normal. The baroreceptor reflex is important for buffering short-term changes in MAP e.g. with postural
changes, or when muscle blood flow increases rapidly in exercise.
Blood flows from the right atrium into the right ventricle via:
Answer
Blood flows from the right atrium into the right ventricle via the tricuspid atrioventricular valve and from the left
atrium into the left ventricle via the mitral atrioventricular valve. Blood is ejected from the right ventricle through
the pulmonary semilunar valve into the pulmonary artery and from the left ventricle via the aortic semilunar valve
into the aorta.
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Notes
The heart consists of four chambers – two thin-walled atria and two muscular ventricles. The atria are separated
from the ventricles by a band of fibrous connective tissue called the annulus fibrosus, which provides a skeleton for
the attachment of muscle and cardiac valves, and prevents electrical conduction between the atria and ventricles
(except at the atrioventricular node).
Basic anatomy
The walls of the heart are formed from myocardium, and the left side has more muscle than the right (as the
systemic circulation has greater resistance to flow, the left ventricle requires more force).
The inner surface of the heart is covered by the endocardium which provides an anti-thrombogenic surface. The
outer surface is covered by epicardium, a layer of mesothelial cells. The whole heart is enclosed in a thin fibrous
sheath, the pericardium.
Valves
Blood flows from the right atrium into the right ventricle via the tricuspid atrioventricular valve and from the left
atrium into the left ventricle via the mitral atrioventricular valve. Blood is ejected from the right ventricle through
the pulmonary semilunar valve into the pulmonary artery and from the left ventricle via the aortic semilunar valve
into the aorta.
By National Heart Lung and Blood Institute (NIH) (National Heart Lung and Blood Institute (NIH)) [Public domain], via Wikimedia Common
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a) The cycle starts when the atrioventricular node initiates atrial systole.
b) Atrial systole contributes about 60% of the final ventricular volume at rest.
c) The end-diastolic pressure is normally around 50 mmHg.
d) There are no valves between the vena cava and the right atrium.
e) The end-diastolic volume is usually around 300 mL.
Something wrong?
Answer
The cycle starts when the sinoatrial node (SAN) initiates atrial systole. At rest, atrial contraction only contributes
the last 15 – 20% of the final ventricular volume, as most of the ventricular filling has occurred passively in diastole
due to venous pressure. The proportion of atrial contribution increases with heart rate as diastole shortens and
there is less time for passive ventricular filling. The end-diastolic volume (EDV) is usually about 120 – 140 mL, and
the end-diastolic pressure is less than 10 mmHg (and higher in the left ventricle than the right due to the thicker
and therefore stiffer left ventricle). There are no valves between the veins and atria and atrial systole causes a
small pressure rise in the great veins (the a wave on the JVP waveform).
Notes
The cardiac cycle describes the events that occur during one beat of the heart.
At the start of the cardiac cycle, towards the end of diastole, the whole of the heart is relaxed. The atrioventricular
(AV) valves are open because the atrial pressure is still slightly greater than the ventricular pressure. The semilunar
valves are closed, as the pressure in the pulmonary artery and aorta is greater than the ventricular pressures. The
cycle starts when the sinoatrial node (SAN) initiates atrial systole.
Atrial depolarisation causes the P wave on the ECG and initiates atrial contraction (atrial repolarisation is too
diffuse to be seen on the ECG).
As the atria contract, the atrial pressure increases which forces more blood flow across the open AV valves, leading
to rapid flow of blood into the ventricles. There are no valves between the veins and atria and atrial systole causes
a small pressure rise in the great veins (the a wave on the JVP waveform).
At rest, atrial contraction only contributes the last 15 – 20% of the final ventricular volume, as most of the
ventricular filling has occurred passively in diastole due to venous pressure. The proportion of atrial contribution
increases with heart rate as diastole shortens and there is less time for passive ventricular filling.
The end-diastolic volume (EDV) is usually about 120 – 140 mL, and the end-diastolic pressure is less than 10
mmHg (and higher in the left ventricle than the right due to the thicker and therefore stiffer left ventricle).
In ventricular hypertrophy, filling of the ‘stiff’ ventricle by atrial systole causes a fourth heart sound, which is not
audible in normal adults.
Ventricular depolarisation causes the QRS complex on the ECG, and triggers excitation-contraction coupling and
myocyte contraction.
The ventricular pressure rises sharply during contraction and the AV valves close as soon as this is greater than
the atrial pressure (causing the first heart sound). Because the mitral valve closes before the tricuspid valve, the first
heart sound may be split.
For a short period, as the forces are developing, both the AV and the semilunar valves are closed as the ventricular
pressure is still less than that in the pulmonary artery and aorta, and no ejection occurs. This is isovolumetric
contraction.
The increasing pressure makes the AV valves bulge into the atria, causing a small atrial pressure wave (the c wave of
the JVP waveform).
When the ventricular pressure exceeds that in the pulmonary artery and the aorta, the semilunar valves open and
blood is ejected, initially rapidly (rapid ejection phase) and then more slowly (reduced ejection phase).
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Atrial pressure initially decreases as the atrial base is pulled downward during ejection, expanding the atrial chamber
(the x descent of the JVP waveform). Atrial filling begins in the rapid ejection phase and continues during the
reduced ejection phase and atrial pressure begins to rise (the v wave of the JVP waveform).
During the second half of ejection, the ventricles stop actively contracting, the ventricular pressure starts to
decrease and the muscle starts to repolarise; this causes the T wave on the ECG, which marks the end of both
ventricular contraction and rapid ventricular ejection.
The ventricular pressure during the reduced ejection phase begins to decrease. Aortic pressure also decreases
because of the runoff of blood from large arteries into smaller arteries. The ventricular pressure falls slightly
below that in the aorta, but initially blood continues to flow out of the ventricle because of momentum;
eventually the ventricular pressure falls sufficiently and the semilunar valves close.
Closure of the semilunar valves causes a small increase in aortic pressure (the dicrotic notch on the arterial
waveform), and the second heart sound. Inspiration delays closure of the pulmonary valve and thus causes splitting of
the second heart sound.
The amount of blood ejected is the stroke volume (SV), and is usually about 70 mL (therefore about 50 mL is left;
this is the end-systolic volume). The proportion of EDV that is ejected (i.e. the SV/EDV) is the ejection fraction and
this is normally about 0.6.
Immediately after the closure of the semilunar valves, the ventricles rapidly relax and ventricular pressure
decreases rapidly but the AV valves remain closed as initially the ventricular pressure is still greater than atrial
pressure. This is isovolumetric relaxation.
Atrial pressure continues to rise because of venous return, with the v wave of the JVP waveform peaking during
this phase. As the ventricles continue to relax, the ventricular pressure falls below that of the atrial pressure and
the AV valves open.
When the AV valves open, the atrial pressure falls (the y descent of the JVP waveform) and the ventricles refill,
initially rapidly (the rapid filling phase) and then more slowly as the ventricles expand, become less complicant, and
ventricular pressures rise (the reduced filling phase). Rapid flow of blood from the atria into the ventricles causes
the third heart sound, which is normal in children but, in adults, is associated with disease such as ventricular
dilation.
Diastole is usually twice the length of systole at rest, but decreases with increased heart rate. During systole,
contraction of the ventricles compresses the coronary arteries and suppresses blood flow. This is particularly evident
in the left ventricle, where during systole the ventricular pressure is the same as or greater than that in the arteries
and as a result more than 85% of left ventricular perfusion occurs during diastole. This becomes a problem if the
heart rate is increased as the diastolic interval is shorter and can result in ischaemia.
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Cardiac cycle phase Atrioventricular valves Semilunar valves
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Atrial systole Open (atrial pressure > ventricular Closed (arterial pressure > ventricular
pressure) pressure)
Isovolumetric Closed (ventricular pressure > atrial Closed (arterial pressure > ventricular
contraction pressure) pressure)
Ventricular ejection Closed (ventricular pressure > atrial Open (ventricular pressure > arterial
pressure) pressure)
Isovolumetric Closed (ventricular pressure > atrial Closed (arterial pressure > ventricular
relaxation pressure) pressure)
Ventricular filling Open (atrial pressure > ventricular Closed (arterial pressure > ventricular
pressure) pressure)
c wave Isovolumetric Occurs due to the bulging of the tricuspid valve into the right atrium
contraction during right isovolumetric ventricular contraction
(early systole)
x descent Rapid ventricular Occurs due to a combination of right atrial relaxation, the downward
ejection (mid systole) displacement of the tricuspid valve during right ventricular contraction,
and the ejection of blood from both the ventricles
v wave Ventricular ejection Occurs due to right atrial filling from venous return
and isovolumetric
relaxation (late
systole)
y descent Ventricular filling Occurs due to opening of the tricuspid valve and the subsequent rapid
(early diastole) inflow of blood from the right atrium to the right ventricle
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First Start of systole Caused by closure of the atrioventricular (mitral & tricuspid) valves
heart
sound
Second heart End of systole Caused by closure of the semilunar (aortic and pulmonary) valves
sound
Third heart Early diastole Caused by rapid flow of blood from the atria into the ventricles during the
sound ventricular filling phase
Fourth heart Late diastole Caused by filling of an abnormally stiff ventricle in atrial systole
sound
ECG Event
All of the following cause a rightward shift along the Starling curve, EXCEPT for:
a) Increased inotropy
b) Increased ventricular compliance
c) Increased central venous pressure
d) Increased thoracic blood volume
e) Reduced heart rate
Something wrong?
Answer
The volume of blood in the ventricle at the start of systole, the end-diastolic volume (EDV), depends on the end-
diastolic pressure (EDP) and the compliance of the ventricular wall. Right ventricular EDP is dependent on right
atrial and hence central venous pressure (CVP). If EDP (and thus EDV) is increased, the force of the following
contraction, and thus stroke volume increases; this is known as the Frank-Starling relationship. This represents a
rightward shift along the Starling function curve.
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Increased central venous pressure which can result from:
Decreased venous compliance caused by venoconstriction
Increased thoracic blood volume caused by either an increase in total blood volume or an increase in
venous return (augmented by increased respiratory activity, increased skeletal muscle pump activity or
by gravity in head-down tilt).
Increased ventricular compliance
Increased atrial activity caused by sympathetic stimulation or from increased filling of the atria
Reduced heart rate (which increases ventricular filling time)
Notes
Cardiac output is determined by the heart rate and stroke volume. Stroke volume is dependent on the filling
pressure (the preload), the cardiac muscle force (the contractility) and the pressure against which the heart has to
pump (the afterload).
Frank-Starling relationship
The volume of blood in the ventricle at the start of systole, the end-diastolic volume (EDV), depends on the end-
diastolic pressure (EDP) and the compliance of the ventricular wall. Right ventricular EDP is dependent on right
atrial and hence central venous pressure (CVP). If EDP (and thus EDV) is increased, the force of the following
contraction, and thus stroke volume increases; this is known as the Frank-Starling relationship.
Starling’s law of the heart states that ‘the energy released during contraction depends on the initial fibre length’. An
increase in EDV causes an increase in ventricular fibre length, which produces an increase in developed tension and
results in an increased force of systolic contraction. As muscle is stretched, more myosin cross-bridges can form,
increasing force. However, cardiac muscle has a much steeper relationship between stretch and force than skeletal
2+
muscle, because in the heart stretch also increases the Ca sensitivity of troponin, so more force is generated for the
2+
same intracellular Ca .
The most important consequence of Starling’s law is that output is matched between the right and left ventricles.
It thus explains how CVP, although only perceived by the right ventricle, also influences left ventricular function
and cardiac output, and why postural hypotension and haemorrhage reduce cardiac output. It also allows the
heart to sustain output when afterload is increased, or contractility is reduced, as both lead to accumulation of
venous blood and a raised EDP, which increases ventricular force and restores stroke volume.
Preload
Increases in preload cause a rightward shift along the
curve Decreases in preload cause a leftward shift along the
curve
Contractility
Increases in contractility shift the curve upward
Decreases in contractility shift the curve downwards
Afterload
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Increases in afterload shift the curve downwards and to the right
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Decreases in afterload shift the curve upwards and to the left
Preload can be defined as the initial stretching of the cardiac myocytes prior to contraction. Preload, therefore, is
related to muscle sarcomere length. Because sarcomere length cannot be determined in the intact heart, other
indices of preload are used such as ventricular end-diastolic volume or pressure. When venous return to the heart is
increased, the end-diastolic pressure and volume of the ventricles are increased, which stretches the sarcomeres,
thereby increasing their preload.
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Increased atrial activity caused by sympathetic stimulation or from increased filling of the atria
Reduced heart rate (which increases ventricular filling time)
Contractility
Contractility (inotropy) is the intrinsic ability of cardiac muscle to develop force at a given muscle length. It is
2+
determined by the intracellular [Ca ] and can be estimated by the ejection fraction. Increases in contractility
cause an
increase in stroke volume/cardiac output for any level of right atrial pressure or end-diastolic volume, and hence
shift the Starling curve upwards. Decreases in contractility cause a decrease in stroke volume/cardiac output for
any level of right atrial pressure or end-diastolic volume and hence shift the Starling curve downwards.
Afterload
Afterload is determined by the resistance to outflow from the ventricle, which for the left ventricle is mainly
determined by the aortic pressure, and for the right, the pulmonary artery pressure.
An increase in afterload (e.g. hypertension, valve stenosis) means that the ventricles must eject blood against a
higher pressure, resulting in a decrease in stroke volume and a downward shift of the Starling curve.
This decrease in stroke volume however results in an increase in end-systolic volume. As a result, blood
accumulates on the venous side and filling pressure rises. This will result in a secondary increase in preload and
a rightward shift along the Starling curve; cardiac output is restored at the expense of an increased EDP.
a) T wave
b) QRS complex
c) P wave
d) PR interval
e) ST segment
Something wrong?
Answer
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ECG Event
Notes
The cardiac cycle describes the events that occur during one beat of the heart.
At the start of the cardiac cycle, towards the end of diastole, the whole of the heart is relaxed. The atrioventricular
(AV) valves are open because the atrial pressure is still slightly greater than the ventricular pressure. The semilunar
valves are closed, as the pressure in the pulmonary artery and aorta is greater than the ventricular pressures. The
cycle starts when the sinoatrial node (SAN) initiates atrial systole.
Atrial depolarisation causes the P wave on the ECG and initiates atrial contraction (atrial repolarisation is too diffuse
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to be seen on the ECG).
As the atria contract, the atrial pressure increases which forces more blood flow across the open AV valves, leading
to rapid flow of blood into the ventricles. There are no valves between the veins and atria and atrial systole causes
a small pressure rise in the great veins (the a wave on the JVP waveform).
At rest, atrial contraction only contributes the last 15 – 20% of the final ventricular volume, as most of the
ventricular filling has occurred passively in diastole due to venous pressure. The proportion of atrial contribution
increases with heart rate as diastole shortens and there is less time for passive ventricular filling.
The end-diastolic volume (EDV) is usually about 120 – 140 mL, and the end-diastolic pressure is less than 10
mmHg (and higher in the left ventricle than the right due to the thicker and therefore stiffer left ventricle).
In ventricular hypertrophy, filling of the ‘stiff’ ventricle by atrial systole causes a fourth heart sound, which is not
audible in normal adults.
Ventricular depolarisation causes the QRS complex on the ECG, and triggers excitation-contraction coupling and
myocyte contraction.
The ventricular pressure rises sharply during contraction and the AV valves close as soon as this is greater than
the atrial pressure (causing the first heart sound). Because the mitral valve closes before the tricuspid valve, the first
heart sound may be split.
For a short period, as the forces are developing, both the AV and the semilunar valves are closed as the ventricular
pressure is still less than that in the pulmonary artery and aorta, and no ejection occurs. This is isovolumetric
contraction.
The increasing pressure makes the AV valves bulge into the atria, causing a small atrial pressure wave (the c wave of
the JVP waveform).
When the ventricular pressure exceeds that in the pulmonary artery and the aorta, the semilunar valves open and
blood is ejected, initially rapidly (rapid ejection phase) and then more slowly (reduced ejection phase).
Atrial pressure initially decreases as the atrial base is pulled downward during ejection, expanding the atrial chamber
(the x descent of the JVP waveform). Atrial filling begins in the rapid ejection phase and continues during the
reduced ejection phase and atrial pressure begins to rise (the v wave of the JVP waveform).
During the second half of ejection, the ventricles stop actively contracting, the ventricular pressure starts to
decrease and the muscle starts to repolarise; this causes the T wave on the ECG, which marks the end of both
ventricular contraction and rapid ventricular ejection.
The ventricular pressure during the reduced ejection phase begins to decrease. Aortic pressure also decreases
because of the runoff of blood from large arteries into smaller arteries. The ventricular pressure falls slightly below
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that in the aorta, but initially blood continues to flow out of the ventricle because of momentum; eventually the
ventricular pressure falls sufficiently and the semilunar valves close.
Closure of the semilunar valves causes a small increase in aortic pressure (the dicrotic notch on the arterial
waveform), and the second heart sound. Inspiration delays closure of the pulmonary valve and thus causes splitting of
the second heart sound.
The amount of blood ejected is the stroke volume (SV), and is usually about 70 mL (therefore about 50 mL is left;
this is the end-systolic volume). The proportion of EDV that is ejected (i.e. the SV/EDV) is the ejection fraction and
this is normally about 0.6.
Immediately after the closure of the semilunar valves, the ventricles rapidly relax and ventricular pressure
decreases rapidly but the AV valves remain closed as initially the ventricular pressure is still greater than atrial
pressure. This is isovolumetric relaxation.
Atrial pressure continues to rise because of venous return, with the v wave of the JVP waveform peaking during
this phase. As the ventricles continue to relax, the ventricular pressure falls below that of the atrial pressure and
the AV valves open.
When the AV valves open, the atrial pressure falls (the y descent of the JVP waveform) and the ventricles refill,
initially rapidly (the rapid filling phase) and then more slowly as the ventricles expand, become less complicant, and
ventricular pressures rise (the reduced filling phase). Rapid flow of blood from the atria into the ventricles causes
the third heart sound, which is normal in children but, in adults, is associated with disease such as ventricular
dilation.
Diastole is usually twice the length of systole at rest, but decreases with increased heart rate. During systole,
contraction of the ventricles compresses the coronary arteries and suppresses blood flow. This is particularly evident
in the left ventricle, where during systole the ventricular pressure is the same as or greater than that in the arteries
and as a result more than 85% of left ventricular perfusion occurs during diastole. This becomes a problem if the
heart rate is increased as the diastolic interval is shorter and can result in ischaemia.
Atrial systole Open (atrial pressure > ventricular Closed (arterial pressure > ventricular
pressure) pressure)
Isovolumetric Closed (ventricular pressure > atrial Closed (arterial pressure > ventricular
contraction pressure) pressure)
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Ventricular ejection Closed (ventricular pressure > atrial Open (ventricular pressure > arterial
pressure) pressure)
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Isovolumetric Closed (ventricular pressure > atrial Closed (arterial pressure > ventricular
relaxation pressure) pressure)
Ventricular filling Open (atrial pressure > ventricular Closed (arterial pressure > ventricular
pressure) pressure)
c wave Isovolumetric Occurs due to the bulging of the tricuspid valve into the right atrium
contraction during right isovolumetric ventricular contraction
(early systole)
x descent Rapid ventricular Occurs due to a combination of right atrial relaxation, the downward
ejection (mid systole) displacement of the tricuspid valve during right ventricular contraction,
and the ejection of blood from both the ventricles
v wave Ventricular ejection Occurs due to right atrial filling from venous return
and isovolumetric
relaxation (late
systole)
y descent Ventricular filling Occurs due to opening of the tricuspid valve and the subsequent rapid
(early diastole) inflow of blood from the right atrium to the right ventricle
First Start of systole Caused by closure of the atrioventricular (mitral & tricuspid) valves
heart
sound
Second heart End of systole Caused by closure of the semilunar (aortic and pulmonary) valves
sound
Third heart Early diastole Caused by rapid flow of blood from the atria into the ventricles during the
sound ventricular filling phase
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Fourth heart Late diastole Caused by filling of an abnormally stiff ventricle in atrial systole
sound
ECG Event
a) End-systolic volume
b) Stroke volume
c) Heart rate
d) Cardiac output
e) Mean arterial pressure
Something wrong?
Answer
An increase in ejection fraction means that a higher fraction of the end-diastolic volume is ejected in the stroke
volume (e.g. because of the administration of a positive inotropic agent). When this situation occurs, the volume
remaining in the ventricle after systole, the end-systolic volume, will be reduced. Cardiac output, stroke volume,
and mean arterial pressure will be increased.
Notes
Cardiac output is determined by the heart rate and stroke volume. Stroke volume is dependent on the filling
pressure (the preload), the cardiac muscle force (the contractility) and the pressure against which the heart has to
pump (the afterload).
Frank-Starling relationship
The volume of blood in the ventricle at the start of systole, the end-diastolic volume (EDV), depends on the end-
diastolic pressure (EDP) and the compliance of the ventricular wall. Right ventricular EDP is dependent on right
atrial and hence central venous pressure (CVP). If EDP (and thus EDV) is increased, the force of the following
contraction, and thus stroke volume increases; this is known as the Frank-Starling relationship.
Starling’s law of the heart states that ‘the energy released during contraction depends on the initial fibre length’. An
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increase in EDV causes an increase in ventricular fibre length, which produces an increase in developed tension and
results in an increased force of systolic contraction. As muscle is stretched, more myosin cross-bridges can form,
increasing force. However, cardiac muscle has a much steeper relationship between stretch and force than skeletal
2+
muscle, because in the heart stretch also increases the Ca sensitivity of troponin, so more force is generated for the
2+
same intracellular Ca .
The most important consequence of Starling’s law is that output is matched between the right and left ventricles.
It thus explains how CVP, although only perceived by the right ventricle, also influences left ventricular function
and cardiac output, and why postural hypotension and haemorrhage reduce cardiac output. It also allows the
heart to sustain output when afterload is increased, or contractility is reduced, as both lead to accumulation of
venous blood and a raised EDP, which increases ventricular force and restores stroke volume.
Preload
Increases in preload cause a rightward shift along the
curve Decreases in preload cause a leftward shift along the
curve
Contractility
Increases in contractility shift the curve upward
Decreases in contractility shift the curve downwards
Afterload
Increases in afterload shift the curve downwards and to the
right Decreases in afterload shift the curve upwards and to the
left
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Preload
Preload can be defined as the initial stretching of the cardiac myocytes prior to contraction. Preload, therefore, is
related to muscle sarcomere length. Because sarcomere length cannot be determined in the intact heart, other
indices of preload are used such as ventricular end-diastolic volume or pressure. When venous return to the heart is
increased, the end-diastolic pressure and volume of the ventricles are increased, which stretches the sarcomeres,
thereby increasing their preload.
Contractility
Contractility (inotropy) is the intrinsic ability of cardiac muscle to develop force at a given muscle length. It is
2+
determined by the intracellular [Ca ] and can be estimated by the ejection fraction. Increases in contractility
cause an
increase in stroke volume/cardiac output for any level of right atrial pressure or end-diastolic volume, and hence
shift the Starling curve upwards. Decreases in contractility cause a decrease in stroke volume/cardiac output for
any level of right atrial pressure or end-diastolic volume and hence shift the Starling curve downwards.
Afterload
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Afterload is determined by the resistance to outflow from the ventricle, which for the left ventricle is mainly
determined by the aortic pressure, and for the right, the pulmonary artery pressure.
An increase in afterload (e.g. hypertension, valve stenosis) means that the ventricles must eject blood against a
higher pressure, resulting in a decrease in stroke volume and a downward shift of the Starling curve.
This decrease in stroke volume however results in an increase in end-systolic volume. As a result, blood
accumulates on the venous side and filling pressure rises. This will result in a secondary increase in preload and
a rightward shift along the Starling curve; cardiac output is restored at the expense of an increased EDP.
Answer
The cardiac output is the volume of blood pumped out of heart via the aorta per minute, Cardiac output (CO) = Stroke
volume x Heart rate.
Notes
Total blood volume, cardiac output and stroke volume
The total blood volume in the circulatory system of a healthy adult is about 5 L.
The stroke volume is the volume of blood ejected per beat. It is usually about 70 mL/beat at
rest. The heart rate is the number of beats per minute. It is usually about 70 beats/minute
at rest.
The cardiac output is the volume of blood pumped out of heart via the aorta per minute.
Cardiac output (CO) = Stroke volume x Heart rate = 70 mL/beat x 70 beats/min = 4900
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During systole, the pressure in the left ventricle increases and blood is ejected into the aorta. The rise in pressure
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stretches the elastic walls of the aorta and large arteries and drives blood flow. Systolic pressure is the maximum
arterial pressure during systole. During diastole, arterial blood flow is partly maintained by elastic recoil of the walls
of large arteries. The minimum pressure reached before the next systole is the diastolic pressure. The difference
between the systolic and diastolic pressure is the pulse pressure.
The mean arterial pressure (MAP) cannot be calculated by averaging these pressures, because for about 60% of
the time, the heart is in diastole. It is instead estimated as the diastolic + one-third of the pulse pressure, e.g. = 80
+ 1/3(110 – 80) = 90 mmHg where BP 110/80 mmHg.
The mean arterial pressure (MAP) at the start of the arterioles is about 65 mmHg. The pressure on the arterial side
of capillaries is about 25 mmHg, and on the venous side is about 15 mmHg. Venules converge into veins and finally
the vena cava. The pressure in the vena cava at the level of the heart (the central venous pressure) is usually close
to 0 mmHg.
In the ventricular myocyte action potential, depolarisation occurs through the opening of:
Answer
An action potential (AP) is initiated when the myocyte is depolarised to a threshold potential of about -65 mV, as a
+
result of transmission from an adjacent myocyte via gap junctions. Fast voltage-gated Na channels are activated and a
+
Na influx depolarises the membrane rapidly to about +30 mV. This initial depolarisation is similar to that in nerve
and skeletal muscle, and assists the transmission to the next myocyte.
Notes
Cardiac myocyte action potential
The resting potential of ventricular myocytes is about -90 mV. An action potential (AP) is initiated when the
myocyte is depolarised to a threshold potential of about -65 mV, as a result of transmission from an adjacent
myocyte via gap junctions.
Depolarisation:
+ +
Fast voltage-gated Na channels are activated and a Na influx depolarises the membrane rapidly to about +30
mV. This initial depolarisation is similar to that in nerve and skeletal muscle, and assists the transmission to the
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next
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myocyte.
+
Na channels and currents rapidly inactivate, but in cardiac myocytes, the initial depolarisation activates voltage-
2+ 2+
gated Ca channels (slow L-type channels, threshold approximately – 45 mV) through which Ca floods into the
cell. The
2+
resulting influx of Ca prevents the cell from repolarising and causes a plateau phase, that is maintained for about
250 ms until the L-type channels inactivate. The cardiac AP is thus much longer than that in nerve or skeletal
muscle.
Repolarisation:
+ +
Repolarisation occurs due to activation of voltage-gated K rectifier channels and a K efflux. As the AP lasts
almost as long as contraction, its refractory period prevents another AP being initiated until the muscle relaxes,
thus cardiac muscle cannot exhibit tetanus.
Image modified by FRCEM Success. [CC-BY-SA-3.0 (or GFDL (], via Wikimedia Commons
Atrial myocytes have a similar but more triangular AP compared to the ventricles (less plateau). Purkinje fibres in
the conduction system are also similar to ventricular myocytes, but have a spike at the peak of the upstroke
+
reflecting a larger Na current that contributes to their fast conduction velocity.
Regarding the sinoatrial node (SAN), which of the following statements is CORRECT:
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Answer
The resting potential of the SAN is about – 60 mV, and it decays steadily with time until it reaches a threshold
potential of about – 40 mV, when an action potential is initiated. The upstroke of the AP is slow, as it is not due to
+ 2+
activation of fast Na channels like cardiac myocytes, but instead slow L-type Ca channels; the SA node contains
no functional
+
fast Na channels. The rate of decay of the SAN resting potential determines the rate of AP and therefore of heart
rate, it is therefore called the pacemaker potential. Factors that affect these currents alter the rate of decay and
the time to reach threshold and thus heart rate and are called chronotropic agents. Noradrenaline (the sympathetic
neurotransmitter) is a positive chronotrope and causes a faster rate of decay and thus heart rate whereas
acetylcholine (the parasympathetic neurotransmitter) is a negative chronotrope and lengthens the time to reach
threshold and decreases heart rate.
Notes
Sinoatrial node action potential
The action potential (AP) of the sinoatrial node (SAN) differs from that in ventricular muscle.
The resting potential of the SAN is about – 60 mV, and it decays steadily with time until it reaches a threshold
potential of about – 40 mV, when an action potential is initiated.
+
The upstroke of the AP is slow, as it is not due to activation of fast Na channels like cardiac myocytes, but instead
2+ +
slow L-type Ca channels; the SA node contains no functional fast Na channels. The slow upstroke means that
conduction
between nodal myocytes is slow, which is particularly important at the atrioventricular node (which has a similar AP
to the SAN).
The rate of decay of the SAN resting potential determines the rate of AP and therefore of heart rate, it is therefore
+
called the pacemaker potential. The pacemaker potential decays because of a slowly reducing outward K current
set
against inward currents. Factors that affect these currents alter the rate of decay and the time to reach threshold
and thus heart rate and are called chronotropic agents.
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Chronotropic agents
Noradrenaline (the sympathetic neurotransmitter) is a positive chronotrope and causes a faster rate of decay and thus
heart rate whereas acetylcholine (the parasympathetic neurotransmitter) is a negative chronotrope and lengthens the
time to reach threshold and decreases heart rate.
Other atrial cells, the AV node, the bundle of His and Purkinje system may also exhibit decaying resting potentials
that can act as pacemakers. However the SAN is normally fastest and predominates – this is called overdrive
suppression.
What is the mean arterial pressure (MAP) in a patient with a blood pressure of 110/80 mmHg:
a) 80 mmHg
b) 100 mmHg
c) 120 mmHg
d) 95 mmHg
e) 90 mmHg
Something wrong?
Answer
The difference between the systolic and diastolic pressure is the pulse pressure. The mean arterial pressure (MAP)
cannot be calculated by averaging these pressures, because for about 60% of the time, the heart is in diastole. It
is instead estimated as the diastolic + one-third of the pulse pressure, e.g. = 80 + 1/3(110 – 80) = 90 mmHg where BP
110/80 mmHg.
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Notes
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The total blood volume in the circulatory system of a healthy adult is about 5 L.
The stroke volume is the volume of blood ejected per beat. It is usually about 70 mL/beat at
rest. The heart rate is the number of beats per minute. It is usually about 70 beats/minute
at rest.
The cardiac output is the volume of blood pumped out of heart via the aorta per minute.
Cardiac output (CO) = Stroke volume x Heart rate = 70 mL/beat x 70 beats/min = 4900
During systole, the pressure in the left ventricle increases and blood is ejected into the aorta. The rise in pressure
stretches the elastic walls of the aorta and large arteries and drives blood flow. Systolic pressure is the maximum
arterial pressure during systole. During diastole, arterial blood flow is partly maintained by elastic recoil of the walls
of large arteries. The minimum pressure reached before the next systole is the diastolic pressure. The difference
between the systolic and diastolic pressure is the pulse pressure.
The mean arterial pressure (MAP) cannot be calculated by averaging these pressures, because for about 60% of
the time, the heart is in diastole. It is instead estimated as the diastolic + one-third of the pulse pressure, e.g. = 80
+ 1/3(110 – 80) = 90 mmHg where BP 110/80 mmHg.
The mean arterial pressure (MAP) at the start of the arterioles is about 65 mmHg. The pressure on the arterial side
of capillaries is about 25 mmHg, and on the venous side is about 15 mmHg. Venules converge into veins and finally
the vena cava. The pressure in the vena cava at the level of the heart (the central venous pressure) is usually close
to 0 mmHg.
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Answer
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The myocardium is composed of cardiac muscle cells called myocytes. The cells are striated due to the
arrangement of the thick and thin filaments which make up the bulk of the muscle, although they are less
organised than in skeletal muscle. The myocytes are small and branched, with a single nucleus and are rich in
mitochondria. Adjacent cardiac myocytes are connected to each other by intercalated discs.
Notes
Myocytes
The myocardium is composed of cardiac muscle cells called myocytes. The cells are striated due to the
arrangement of the thick and thin filaments which make up the bulk of the muscle, although they are less
organised than in skeletal muscle. The myocytes are small and branched, with a single nucleus and are rich in
mitochondria. The normal pumping action of the heart is dependent on the synchronised contraction of all cardiac
cells.
Intercalated discs
The synchronicity between myocytes occurs because all the adjacent cells are connected by intercalated discs. The
intercalated discs provide both a structural attachment by ‘glueing’ cells together at desmosomes and an electrical
contact made up of proteins called connexons, called a gap junction, which essentially creates a low-resistance
pathway between cells. Gap junctions allow action potentials to spread rapidly from one cell to another and allows
the myocardium to act as a functional syncytium.
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Cardiac pacemaker
Cardiac myocyte contraction is not dependent on an external nerve supply but instead the heart generates its own
rhythm, demonstrating inherent rhythmicity.
The heartbeat is initiated by spontaneous depolarisation of the sinoatrial node (SAN), a region of specialised
myocytes in the right atrium, close to the coronary sinus. The rate is modulated by the autonomic nervous system.
Action potentials in the SAN activate adjacent atrial myocytes and a wave of depolarisation and contraction
therefore spreads through atrial muscle. This is prevented from reaching the ventricles directly by the annulus
fibrosis.
This impulse is channelled through the atrioventricular node (AVN), located between the right atrium and ventricle
near the atrial septum. The AVN contains small cells and thus conducts slowly and delays the impulse for about 120
ms, allowing time for atrial contraction to complete ventricular filling.
Once complete, the impulse is then transmitted by specialised, wide, fast conducting myocytes in the bundle of His
and Purkinje fibres, by which it is distributed over the inner surface of both ventricles. From here a wave of
depolarisation and contraction moves from myocyte to myocyte across the endocardium until the whole ventricular
mass is activated.
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Electrocardiogram (ECG)
The wave of depolarisation through the heart causes local currents in surrounding fluid which are detected at the
body surface as small changes in voltage. This forms the basis of the ECG. The classical ECG records voltage
between the left and right arm (lead I), the right arm and left leg (lead II) and the left arm and left leg (lead III).
This is represented by Einthoven’s triangle. The size of the voltage at any time depends on the quantity of muscle
depolarisation and the direction in which the wave of depolarisation is travelling. Thus lead II normally shows the
largest deflection during ventricular depolarisation, as the muscle mass is greatest and depolarisation travels from
apex to base, more or less parallel to a line from the left hip to the right shoulder.
By Npatchett (Own work) [CC BY-SA 4.0 (], via Wikimedia Commons
Regarding the sinoatrial node (SAN), which of the following statements is CORRECT:
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Answer
The resting potential of the SAN is about – 60 mV, and it decays steadily with time until it reaches a threshold
potential of about – 40 mV, when an action potential is initiated. The upstroke of the AP is slow, as it is not due to
+ 2+
activation of fast Na channels like cardiac myocytes, but instead slow L-type Ca channels; the SA node contains
no functional
+
fast Na channels. The rate of decay of the SAN resting potential determines the rate of AP and therefore of heart
rate, it is therefore called the pacemaker potential. Factors that affect this rate of decay, and thus the heart rate
are called chronotropes.
Notes
Sinoatrial node action potential
The action potential (AP) of the sinoatrial node (SAN) differs from that in ventricular muscle.
The resting potential of the SAN is about – 60 mV, and it decays steadily with time until it reaches a threshold
potential of about – 40 mV, when an action potential is initiated.
+
The upstroke of the AP is slow, as it is not due to activation of fast Na channels like cardiac myocytes, but instead
2+ +
slow L-type Ca channels; the SA node contains no functional fast Na channels. The slow upstroke means that
conduction
between nodal myocytes is slow, which is particularly important at the atrioventricular node (which has a similar AP
to the SAN).
The rate of decay of the SAN resting potential determines the rate of AP and therefore of heart rate, it is therefore
+
called the pacemaker potential. The pacemaker potential decays because of a slowly reducing outward K current
set
against inward currents. Factors that affect these currents alter the rate of decay and the time to reach threshold
and thus heart rate and are called chronotropic agents.
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Chronotropic agents
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Noradrenaline (the sympathetic neurotransmitter) is a positive chronotrope and causes a faster rate of decay and thus
heart rate whereas acetylcholine (the parasympathetic neurotransmitter) is a negative chronotrope and lengthens the
time to reach threshold and decreases heart rate.
Other atrial cells, the AV node, the bundle of His and Purkinje system may also exhibit decaying resting potentials
that can act as pacemakers. However the SAN is normally fastest and predominates – this is called overdrive
suppression.
Notes
Contractility (inotropy) is the intrinsic ability of cardiac muscle to develop force at a given muscle length. It is
2+
determined by the intracellular [Ca ] and can be estimated by the ejection fraction. Increases in contractility
cause an
increase in stroke volume/cardiac output for any level of right atrial pressure or end-diastolic volume, and hence
shift the Starling curve upwards. Decreases in contractility cause a decrease in stroke volume/cardiac output for
any level of right atrial pressure or end-diastolic volume and hence shift the Starling curve downwards.
Frank-Starling relationship
The volume of blood in the ventricle at the start of systole, the end-diastolic volume (EDV), depends on the end-
diastolic pressure (EDP) and the compliance of the ventricular wall. Right ventricular EDP is dependent on right
atrial and hence central venous pressure (CVP). If EDP (and thus EDV) is increased, the force of the following
contraction, and thus stroke volume increases; this is known as the Frank-Starling relationship.
Starling’s law of the heart states that ‘the energy released during contraction depends on the initial fibre length’. An
increase in EDV causes an increase in ventricular fibre length, which produces an increase in developed tension and
results in an increased force of systolic contraction. As muscle is stretched, more myosin cross-bridges can form,
increasing force. However, cardiac muscle has a much steeper relationship between stretch and force than skeletal
2+
muscle, because in the heart stretch also increases the Ca sensitivity of troponin, so more force is generated for the
2+
same intracellular Ca .
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The most important consequence of Starling’s law is that output is matched between the right and left ventricles.
It thus explains how CVP, although only perceived by the right ventricle, also influences left ventricular function
and
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cardiac output, and why postural hypotension and haemorrhage reduce cardiac output. It also allows the heart
to sustain output when afterload is increased, or contractility is reduced, as both lead to accumulation of venous
blood and a raised EDP, which increases ventricular force and restores stroke volume.
Preload
Increases in preload cause a rightward shift along the
curve Decreases in preload cause a leftward shift along the
curve
Contractility
Increases in contractility shift the curve upward
Decreases in contractility shift the curve downwards
Afterload
Increases in afterload shift the curve downwards and to the
right Decreases in afterload shift the curve upwards and to the
left
Preload
Preload can be defined as the initial stretching of the cardiac myocytes prior to contraction. Preload, therefore, is
related to muscle sarcomere length. Because sarcomere length cannot be determined in the intact heart, other
indices of preload are used such as ventricular end-diastolic volume or pressure. When venous return to the heart is
increased, the end-diastolic pressure and volume of the ventricles are increased, which stretches the sarcomeres,
thereby increasing their preload.
Contractility
Contractility (inotropy) is the intrinsic ability of cardiac muscle to develop force at a given muscle length. It is
2+
determined by the intracellular [Ca ] and can be estimated by the ejection fraction. Increases in contractility
cause an
increase in stroke volume/cardiac output for any level of right atrial pressure or end-diastolic volume, and hence
shift the Starling curve upwards. Decreases in contractility cause a decrease in stroke volume/cardiac output for
any level of right atrial pressure or end-diastolic volume and hence shift the Starling curve downwards.
Afterload
Afterload is determined by the resistance to outflow from the ventricle, which for the left ventricle is mainly
determined by the aortic pressure, and for the right, the pulmonary artery pressure.
An increase in afterload (e.g. hypertension, valve stenosis) means that the ventricles must eject blood against a
higher pressure, resulting in a decrease in stroke volume and a downward shift of the Starling curve.
This decrease in stroke volume however results in an increase in end-systolic volume. As a result, blood
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accumulates on the venous side and filling pressure rises. This will result in a secondary increase in preload and
a rightward shift
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along the Starling curve; cardiac output is restored at the expense of an increased EDP.
Answer
Autoregulation is the ability to maintain a constant blood flow despite variations in blood pressure (between 50 –
170 mmHg). It is particularly important in the brain, kidney and heart. There are two main methods contributing to
autoregulation.
The myogenic mechanism involves arterial constriction in response to stretching of the vessel wall,
2+ 2+
probably due to activation of smooth muscle stretch-activated Ca channels and Ca entry. A reduction
in pressure and stretch closes these channels, causing vasodilatation.
The second mechanism of autoregulation is due to locally produced vasodilating factors; an increase in blood
flow dilutes these factors causing vasoconstriction, whereas decreased blood flow has the opposite
effect.
Notes
In addition to central control of blood pressure, tissues can regulate their own blood flow to match their
requirements via autoregulation, metabolic factors and local hormones (autocoids).
Autoregulation
Autoregulation is the ability to maintain a constant blood flow despite variations in blood pressure (between 50 –
170 mmHg). It is particularly important in the brain, kidney and heart. There are two main methods contributing to
autoregulation.
The myogenic mechanism involves arterial constriction in response to stretching of the vessel wall,
2+ 2+
probably due to activation of smooth muscle stretch-activated Ca channels and Ca entry. A reduction
in pressure and stretch closes these channels, causing vasodilatation.
The second mechanism of autoregulation is due to locally produced vasodilating factors; an increase in blood
flow dilutes these factors causing vasoconstriction, whereas decreased blood flow has the opposite
effect.
Metabolic factors
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+
Many factors may contribute to metabolic hyperaemia (increased blood flow), with the most important being K , CO2
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and adenosine, and in some cases hypoxia itself.
+ +
K , released from active tissues and in ischaemia, causes vasodilation partly by stimulating the Na pump, thus
2+
increasing Ca removal from smooth muscle cells and hyperpolarising the cell.
CO2 and acidosis cause vasodilation largely through increased nitric oxide production and inhibition of smooth
2+
muscle Ca entry.
Adenosine, released from the heart, skeletal muscle and brain during increased metabolism and
hypoxia, causes vasodilation by stimulating the production of cAMP in smooth muscle.
+
Hypoxia may reduce ATP sufficiently for K channels to activate causing hyperpolarisation.
Autocoids
In inflammation, local inflammatory mediators such as histamine and bradykinin cause vasodilation
and increased permeability of exchange vessels, leading to swelling but allowing access by immune
cells to damaged tissues.
In clotting, serotonin and thromboxane A2 released from activated platelets cause vasoconstriction to help
reduce bleeding.
a) Blood flow involves arteriovenous anastomoses which directly link arterioles and venules.
b) The brain receives around 40% of the total cardiac output.
c) The endothelial cells of the cerebral circulation are connected by gap junctions.
d) The blood-brain barrier is continuous throughout the brain.
e) Cerebral autoregulation can regulate blood flow for blood pressures between 50 and 170 mmHg.
Something wrong?
Answer
The brain receives around 15% of the total cardiac output and has a high capillary density. The endothelial cells of
the capillaries of the blood-brain barrier have very tight junctions, and contain membrane transporters that control
the movement of substances, such as ions, glucose and amino acids, and tightly regulate the composition of
cerebrospinal fluid. This is continuous except where substances need to be absorbed or released e.g. pituitary gland,
choroid plexus. The autoregulation of cerebral blood flow can maintain a constant flow for blood pressures between
50 and 170
+
mmHg. CO2 and K are particularly important metabolic regulators in the brain, with increasing concentration causing
vasodilation and a functional hyperaemia. Hyperventilation reduces blood PCO2 and can cause fainting due to cerebral
vasoconstriction.
Notes
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Skeletal muscle circulation
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The skeletal muscle circulation normally receives about 15 – 20% of the cardiac output, but this may rise to > 80%
during exercise. Skeletal muscle provides a major contribution to the total peripheral resistance and sympathetic
regulation of muscle blood flow is important in the baroreceptor reflex. At rest most capillaries are not perfused as
their arterioles are constricted. Capillaries are recruited during exercise by metabolic hyperaemia, caused by release
of
+
K and CO2 from the muscle and adenosine. This overrides sympathetic vasoconstriction in working muscle; the latter
reduces flow in non-working muscle conserving cardiac output.
Pulmonary circulation
The pulmonary circulation is not controlled by either autonomic nerves or metabolic products, and the most
important mechanism regulating flow is hypoxic pulmonary vasoconstriction, in which small arteries constrict in
response to hypoxia (in contrast to elsewhere in the body).
If an area of lung is poorly ventilated and the alveolar partial pressure of oxygen is low, pulmonary blood vessels
are constricted and blood is diverted to areas of the lung that are better ventilated, thus maintaining optimal
ventilation- perfusion matching. This effect is accentuated by high alveolar PCO 2.
The response is unhelpful in the presence of global lung hypoxia, at altitude or in respiratory failure, where it may
contribute to the development of pulmonary hypertension and right-sided heart failure (cor pulmonale).
Cutaneous circulation
The main function of the cutaneous circulation is thermoregulation. Arteriovenous anastomoses (AVAs) directly
linked arterioles and venules, allowing a high blood flow into the venous plexus and thus radiation of heat. AVAs
are mostly found in the hands, feet and areas of the face.
Temperature is sensed by peripheral thermoreceptors and the hypothalamus coordinates the response.
Increased temperatures reduce sympathetic adrenergic stimulation, causing vasodilation and allowing more blood
to flow to the skin and radiate its heat to the environment, whereas activation of sympathetic cholinergic fibres
promotes sweating and the release of bradykinin, which also causes vasodilation.
Cerebral circulation
The brain receives around 15% of the total cardiac output and has a high capillary density.
The endothelial cells of the capillaries of the blood-brain barrier have very tight junctions, and contain membrane
transporters that control the movement of substances, such as ions, glucose and amino acids, and tightly regulate
the composition of cerebrospinal fluid. This is continuous except where substances need to be absorbed or released
e.g. pituitary gland, choroid plexus.
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The autoregulation of cerebral blood flow can maintain a constant flow for blood pressures between 50 and 170
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+
mmHg. CO2 and K are particularly important metabolic regulators in the brain, with increasing concentration causing
vasodilation and a functional hyperaemia.
Hyperventilation reduces blood PCO2 and can cause fainting due to cerebral vasoconstriction.
Coronary circulation
The heart has a high metabolic demand and its high capillary density allow it to extract an unusually large fraction
(about 70%) of oxygen from the blood.
In exercise, the reduced diastolic interval and increased oxygen consumption demand a greatly increased blood
+
flow which is achieved by metabolic hyperaemia mediated by adenosine, K and hypoxia. This overrides the
vasoconstriction mediated by sympathetic nerves acting at alpha-adrenergic receptors and is assisted by circulating
adrenaline which causes vasodilation by acting on beta-adrenergic receptors.
a) Stroke volume
b) Ventricular compliance
c) End-diastolic volume
d) Heart rate
e) End-systolic volume
Something wrong?
Answer
Preload can be defined as the initial stretching of the cardiac myocytes prior to contraction. Preload, therefore, is
related to muscle sarcomere length. Because sarcomere length cannot be determined in the intact heart, other
indices of preload are used such as ventricular end-diastolic volume or pressure. When venous return to the heart is
increased, the end-diastolic pressure and volume of the ventricles are increased, which stretches the sarcomeres,
thereby increasing their preload.
Notes
Cardiac output is determined by the heart rate and stroke volume. Stroke volume is dependent on the filling
pressure (the preload), the cardiac muscle force (the contractility) and the pressure against which the heart has to
pump (the afterload).
Frank-Starling relationship
The volume of blood in the ventricle at the start of systole, the end-diastolic volume (EDV), depends on the end-
diastolic pressure (EDP) and the compliance of the ventricular wall. Right ventricular EDP is dependent on right
atrial and hence central venous pressure (CVP). If EDP (and thus EDV) is increased, the force of the following
contraction, and thus stroke volume increases; this is known as the Frank-Starling relationship.
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Starling’s law of the heart states that ‘the energy released during contraction depends on the initial fibre length’. An
increase in EDV causes an increase in ventricular fibre length, which produces an increase in developed tension and
results in an increased force of systolic contraction. As muscle is stretched, more myosin cross-bridges can form,
increasing force. However, cardiac muscle has a much steeper relationship between stretch and force than skeletal
2+
muscle, because in the heart stretch also increases the Ca sensitivity of troponin, so more force is generated for the
2+
same intracellular Ca .
The most important consequence of Starling’s law is that output is matched between the right and left ventricles.
It thus explains how CVP, although only perceived by the right ventricle, also influences left ventricular function
and cardiac output, and why postural hypotension and haemorrhage reduce cardiac output. It also allows the
heart to sustain output when afterload is increased, or contractility is reduced, as both lead to accumulation of
venous blood and a raised EDP, which increases ventricular force and restores stroke volume.
Preload
Increases in preload cause a rightward shift along the
curve Decreases in preload cause a leftward shift along the
curve
Contractility
Increases in contractility shift the curve upward
Decreases in contractility shift the curve downwards
Afterload
Increases in afterload shift the curve downwards and to the
right Decreases in afterload shift the curve upwards and to the
left
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Preload
Preload can be defined as the initial stretching of the cardiac myocytes prior to contraction. Preload, therefore, is
related to muscle sarcomere length. Because sarcomere length cannot be determined in the intact heart, other
indices of preload are used such as ventricular end-diastolic volume or pressure. When venous return to the heart is
increased, the end-diastolic pressure and volume of the ventricles are increased, which stretches the sarcomeres,
thereby increasing their preload.
Contractility
Contractility (inotropy) is the intrinsic ability of cardiac muscle to develop force at a given muscle length. It is
2+
determined by the intracellular [Ca ] and can be estimated by the ejection fraction. Increases in contractility
cause an
increase in stroke volume/cardiac output for any level of right atrial pressure or end-diastolic volume, and hence
shift the Starling curve upwards. Decreases in contractility cause a decrease in stroke volume/cardiac output for
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any level of right atrial pressure or end-diastolic volume and hence shift the Starling curve downwards.
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Afterload
Afterload is determined by the resistance to outflow from the ventricle, which for the left ventricle is mainly
determined by the aortic pressure, and for the right, the pulmonary artery pressure.
An increase in afterload (e.g. hypertension, valve stenosis) means that the ventricles must eject blood against a
higher pressure, resulting in a decrease in stroke volume and a downward shift of the Starling curve.
This decrease in stroke volume however results in an increase in end-systolic volume. As a result, blood
accumulates on the venous side and filling pressure rises. This will result in a secondary increase in preload and
a rightward shift along the Starling curve; cardiac output is restored at the expense of an increased EDP.
When a person changes from a supine to an upright position, which of the following
compensatory changes occurs:
Answer
On standing from a prone position, gravity causes blood to pool in veins in the legs. Central venous pressure (CVP)
falls, causing a fall in stroke volume and cardiac output (due to Starling’s law) and thus a fall in blood pressure.
Normally this fall in BP is rapidly corrected by the baroreceptor reflex which causes venoconstriction (partially
restoring CVP), and an increase in heart rate and contractility, so restoring cardiac output and blood pressure.
Notes
Mean arterial pressure (MAP) = Cardiac output (CO) x Total peripheral resistance (TPR).
Cardiac output is itself dependent on the central venous pressure (CVP), which in turn is highly dependent on the
blood volume. Alterations of any of these variables may change MAP.
Postural hypotension
On standing from a prone position, gravity causes blood to pool in veins in the legs. Central venous pressure (CVP)
falls, causing a fall in stroke volume and cardiac output (due to Starling’s law) and thus a fall in blood pressure.
Normally this fall in BP is rapidly corrected by the baroreceptor reflex which causes venoconstriction (partially
restoring CVP), and an increase in heart rate and contractility, so restoring cardiac output and blood pressure.
Impaired autonomic nervous activity in the elderly accounts for the greater likelihood of postural hypotension. Any
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symptoms of dizziness, blurred
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vision or syncope is due to a transient fall in cerebral perfusion that occurs before cardiac output and MAP can be
corrected.
Baroreceptor reflex
Arterial baroreceptors are located in the carotid sinus and aortic arch, and detect the mean arterial pressure (MAP).
A decrease in MAP (such as in postural hypotension, or haemorrhage) reduces arterial stretch and decreases
baroreceptor activity, resulting in decreased firing in afferent nerves travelling via the glossopharyngeal nerve
(carotid sinus) and vagus nerve (aortic arch) to the medulla where the activity of the autonomic nervous system is
coordinated.
Sympathetic nerve activity consequently increases, causing an increase in heart rate and cardiac contractility,
peripheral vasoconstriction with an increase in TPR, and venoconstriction with an increase in CVP and thus an
increase in cardiac output and blood pressure. Parasympathetic activity (vagal tone) decreases, contributing to the
rise in heart rate. MAP therefore returns to normal. An increase in MAP has the opposite effect.
The baroreceptors are most sensitive between 80 and 150 mmHg and their sensitivity is increased by a large pulse
pressure. They also show adaptation; if a new pressure is maintained for a few hours, activity slowly moves
towards normal. The baroreceptor reflex is important for buffering short-term changes in MAP e.g. with postural
changes, or when muscle blood flow increases rapidly in exercise.
At the start of the cardiac cycle, towards the end of diastole, all of the following
statements are true EXCEPT for:
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Something wrong?
Answer
At the start of the cardiac cycle, towards the end of diastole, the whole of the heart is relaxed. The atrioventricular
(AV) valves are open because the atrial pressure is still slightly greater than the ventricular pressure. The semilunar
valves are closed, as the pressure in the pulmonary artery and aorta is greater than the ventricular pressures. The
cycle starts when the sinoatrial node (SAN) initiates atrial systole.
Notes
The cardiac cycle describes the events that occur during one beat of the heart.
At the start of the cardiac cycle, towards the end of diastole, the whole of the heart is relaxed. The atrioventricular
(AV) valves are open because the atrial pressure is still slightly greater than the ventricular pressure. The semilunar
valves are closed, as the pressure in the pulmonary artery and aorta is greater than the ventricular pressures. The
cycle starts when the sinoatrial node (SAN) initiates atrial systole.
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Atrial depolarisation causes the P wave on the ECG and initiates atrial contraction (atrial repolarisation is too
diffuse to be seen on the ECG).
As the atria contract, the atrial pressure increases which forces more blood flow across the open AV valves, leading
to rapid flow of blood into the ventricles. There are no valves between the veins and atria and atrial systole causes
a small pressure rise in the great veins (the a wave on the JVP waveform).
At rest, atrial contraction only contributes the last 15 – 20% of the final ventricular volume, as most of the
ventricular filling has occurred passively in diastole due to venous pressure. The proportion of atrial contribution
increases with heart rate as diastole shortens and there is less time for passive ventricular filling.
The end-diastolic volume (EDV) is usually about 120 – 140 mL, and the end-diastolic pressure is less than 10
mmHg (and higher in the left ventricle than the right due to the thicker and therefore stiffer left ventricle).
In ventricular hypertrophy, filling of the ‘stiff’ ventricle by atrial systole causes a fourth heart sound, which is not
audible in normal adults.
Ventricular depolarisation causes the QRS complex on the ECG, and triggers excitation-contraction coupling and
myocyte contraction.
The ventricular pressure rises sharply during contraction and the AV valves close as soon as this is greater than
the atrial pressure (causing the first heart sound). Because the mitral valve closes before the tricuspid valve, the first
heart sound may be split.
For a short period, as the forces are developing, both the AV and the semilunar valves are closed as the ventricular
pressure is still less than that in the pulmonary artery and aorta, and no ejection occurs. This is isovolumetric
contraction.
The increasing pressure makes the AV valves bulge into the atria, causing a small atrial pressure wave (the c wave of
the JVP waveform).
When the ventricular pressure exceeds that in the pulmonary artery and the aorta, the semilunar valves open and
blood is ejected, initially rapidly (rapid ejection phase) and then more slowly (reduced ejection phase).
Atrial pressure initially decreases as the atrial base is pulled downward during ejection, expanding the atrial chamber
(the x descent of the JVP waveform). Atrial filling begins in the rapid ejection phase and continues during the
reduced ejection phase and atrial pressure begins to rise (the v wave of the JVP waveform).
During the second half of ejection, the ventricles stop actively contracting, the ventricular pressure starts to
decrease and the muscle starts to repolarise; this causes the T wave on the ECG, which marks the end of both
ventricular contraction and rapid ventricular ejection.
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The ventricular pressure during the reduced ejection phase begins to decrease. Aortic pressure also decreases
because of the runoff of blood from large arteries into smaller arteries. The ventricular pressure falls slightly
below that in the aorta, but initially blood continues to flow out of the ventricle because of momentum;
eventually the ventricular pressure falls sufficiently and the semilunar valves close.
Closure of the semilunar valves causes a small increase in aortic pressure (the dicrotic notch on the arterial
waveform), and the second heart sound. Inspiration delays closure of the pulmonary valve and thus causes splitting of
the second heart sound.
The amount of blood ejected is the stroke volume (SV), and is usually about 70 mL (therefore about 50 mL is left;
this is the end-systolic volume). The proportion of EDV that is ejected (i.e. the SV/EDV) is the ejection fraction and
this is normally about 0.6.
Immediately after the closure of the semilunar valves, the ventricles rapidly relax and ventricular pressure
decreases rapidly but the AV valves remain closed as initially the ventricular pressure is still greater than atrial
pressure. This is isovolumetric relaxation.
Atrial pressure continues to rise because of venous return, with the v wave of the JVP waveform peaking during
this phase. As the ventricles continue to relax, the ventricular pressure falls below that of the atrial pressure and
the AV valves open.
When the AV valves open, the atrial pressure falls (the y descent of the JVP waveform) and the ventricles refill,
initially rapidly (the rapid filling phase) and then more slowly as the ventricles expand, become less complicant, and
ventricular pressures rise (the reduced filling phase). Rapid flow of blood from the atria into the ventricles causes
the third heart sound, which is normal in children but, in adults, is associated with disease such as ventricular
dilation.
Diastole is usually twice the length of systole at rest, but decreases with increased heart rate. During systole,
contraction of the ventricles compresses the coronary arteries and suppresses blood flow. This is particularly evident
in the left ventricle, where during systole the ventricular pressure is the same as or greater than that in the arteries
and as a result more than 85% of left ventricular perfusion occurs during diastole. This becomes a problem if the
heart rate is increased as the diastolic interval is shorter and can result in ischaemia.
Atrial systole Open (atrial pressure > ventricular Closed (arterial pressure > ventricular
pressure) pressure)
Isovolumetric Closed (ventricular pressure > atrial Closed (arterial pressure > ventricular
contraction pressure) pressure)
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Ventricular ejection Closed (ventricular pressure > atrial Open (ventricular pressure > arterial
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pressure) pressure)
Isovolumetric Closed (ventricular pressure > atrial Closed (arterial pressure > ventricular
relaxation pressure) pressure)
Ventricular filling Open (atrial pressure > ventricular Closed (arterial pressure > ventricular
pressure) pressure)
c wave Isovolumetric Occurs due to the bulging of the tricuspid valve into the right atrium
contraction during right isovolumetric ventricular contraction
(early systole)
x descent Rapid ventricular Occurs due to a combination of right atrial relaxation, the downward
ejection (mid systole) displacement of the tricuspid valve during right ventricular contraction,
and the ejection of blood from both the ventricles
v wave Ventricular ejection Occurs due to right atrial filling from venous return
and isovolumetric
relaxation (late
systole)
y descent Ventricular filling Occurs due to opening of the tricuspid valve and the subsequent rapid
(early diastole) inflow of blood from the right atrium to the right ventricle
First Start of systole Caused by closure of the atrioventricular (mitral & tricuspid) valves
heart
sound
Second heart End of systole Caused by closure of the semilunar (aortic and pulmonary) valves
sound
Third heart Early diastole Caused by rapid flow of blood from the atria into the ventricles during the
sound ventricular filling phase
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Fourth heart Late diastole Caused by filling of an abnormally stiff ventricle in atrial systole
sound
ECG Event
In the ventricular filling phase of the cardiac cycle, all of the following statements are true
EXCEPT for:
Answer
The semilunar valves remain closed during the ventricular filling phase. When the AV valves open, the atrial
pressure falls (the y descent of the JVP waveform) and the ventricles refill, initially rapidly (the rapid filling phase) and
then more slowly as the ventricles expand, become less complicant, and ventricular pressures rise (the reduced
filling phase).
Rapid flow of blood from the atria into the ventricles causes the third heart sound, which is normal in children but, in
adults, is associated with disease such as ventricular dilation.
Notes
The cardiac cycle describes the events that occur during one beat of the heart.
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At the start of the cardiac cycle, towards the end of diastole, the whole of the heart is relaxed. The atrioventricular
(AV) valves are open because the atrial pressure is still slightly greater than the ventricular pressure. The semilunar
valves are closed, as the pressure in the pulmonary artery and aorta is greater than the ventricular pressures. The
cycle starts when the sinoatrial node (SAN) initiates atrial systole.
Atrial depolarisation causes the P wave on the ECG and initiates atrial contraction (atrial repolarisation is too
diffuse to be seen on the ECG).
As the atria contract, the atrial pressure increases which forces more blood flow across the open AV valves, leading
to rapid flow of blood into the ventricles. There are no valves between the veins and atria and atrial systole causes
a small pressure rise in the great veins (the a wave on the JVP waveform).
At rest, atrial contraction only contributes the last 15 – 20% of the final ventricular volume, as most of the
ventricular filling has occurred passively in diastole due to venous pressure. The proportion of atrial contribution
increases with heart rate as diastole shortens and there is less time for passive ventricular filling.
The end-diastolic volume (EDV) is usually about 120 – 140 mL, and the end-diastolic pressure is less than 10
mmHg (and higher in the left ventricle than the right due to the thicker and therefore stiffer left ventricle).
In ventricular hypertrophy, filling of the ‘stiff’ ventricle by atrial systole causes a fourth heart sound, which is not
audible in normal adults.
Ventricular depolarisation causes the QRS complex on the ECG, and triggers excitation-contraction coupling and
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myocyte contraction.
The ventricular pressure rises sharply during contraction and the AV valves close as soon as this is greater than
the atrial pressure (causing the first heart sound). Because the mitral valve closes before the tricuspid valve, the first
heart sound may be split.
For a short period, as the forces are developing, both the AV and the semilunar valves are closed as the ventricular
pressure is still less than that in the pulmonary artery and aorta, and no ejection occurs. This is isovolumetric
contraction.
The increasing pressure makes the AV valves bulge into the atria, causing a small atrial pressure wave (the c wave of
the JVP waveform).
When the ventricular pressure exceeds that in the pulmonary artery and the aorta, the semilunar valves open and
blood is ejected, initially rapidly (rapid ejection phase) and then more slowly (reduced ejection phase).
Atrial pressure initially decreases as the atrial base is pulled downward during ejection, expanding the atrial chamber
(the x descent of the JVP waveform). Atrial filling begins in the rapid ejection phase and continues during the
reduced ejection phase and atrial pressure begins to rise (the v wave of the JVP waveform).
During the second half of ejection, the ventricles stop actively contracting, the ventricular pressure starts to
decrease and the muscle starts to repolarise; this causes the T wave on the ECG, which marks the end of both
ventricular contraction and rapid ventricular ejection.
The ventricular pressure during the reduced ejection phase begins to decrease. Aortic pressure also decreases
because of the runoff of blood from large arteries into smaller arteries. The ventricular pressure falls slightly
below that in the aorta, but initially blood continues to flow out of the ventricle because of momentum;
eventually the ventricular pressure falls sufficiently and the semilunar valves close.
Closure of the semilunar valves causes a small increase in aortic pressure (the dicrotic notch on the arterial
waveform), and the second heart sound. Inspiration delays closure of the pulmonary valve and thus causes splitting of
the second heart sound.
The amount of blood ejected is the stroke volume (SV), and is usually about 70 mL (therefore about 50 mL is left;
this is the end-systolic volume). The proportion of EDV that is ejected (i.e. the SV/EDV) is the ejection fraction and
this is normally about 0.6.
Immediately after the closure of the semilunar valves, the ventricles rapidly relax and ventricular pressure
decreases rapidly but the AV valves remain closed as initially the ventricular pressure is still greater than atrial
pressure. This is isovolumetric relaxation.
Atrial pressure continues to rise because of venous return, with the v wave of the JVP waveform peaking during
this phase. As the ventricles continue to relax, the ventricular pressure falls below that of the atrial pressure and
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the AV
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valves open.
When the AV valves open, the atrial pressure falls (the y descent of the JVP waveform) and the ventricles refill,
initially rapidly (the rapid filling phase) and then more slowly as the ventricles expand, become less complicant, and
ventricular pressures rise (the reduced filling phase). Rapid flow of blood from the atria into the ventricles causes
the third heart sound, which is normal in children but, in adults, is associated with disease such as ventricular
dilation.
Diastole is usually twice the length of systole at rest, but decreases with increased heart rate. During systole,
contraction of the ventricles compresses the coronary arteries and suppresses blood flow. This is particularly evident
in the left ventricle, where during systole the ventricular pressure is the same as or greater than that in the arteries
and as a result more than 85% of left ventricular perfusion occurs during diastole. This becomes a problem if the
heart rate is increased as the diastolic interval is shorter and can result in ischaemia.
Atrial systole Open (atrial pressure > ventricular Closed (arterial pressure > ventricular
pressure) pressure)
Isovolumetric Closed (ventricular pressure > atrial Closed (arterial pressure > ventricular
contraction pressure) pressure)
Ventricular ejection Closed (ventricular pressure > atrial Open (ventricular pressure > arterial
pressure) pressure)
Isovolumetric Closed (ventricular pressure > atrial Closed (arterial pressure > ventricular
relaxation pressure) pressure)
Ventricular filling Open (atrial pressure > ventricular Closed (arterial pressure > ventricular
pressure) pressure)
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c wave Isovolumetric Occurs due to the bulging of the tricuspid valve into the right atrium
contraction during right isovolumetric ventricular contraction
(early systole)
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x descent Rapid ventricular Occurs due to a combination of right atrial relaxation, the downward
ejection (mid systole) displacement of the tricuspid valve during right ventricular contraction,
and the ejection of blood from both the ventricles
v wave Ventricular ejection Occurs due to right atrial filling from venous return
and isovolumetric
relaxation (late
systole)
y descent Ventricular filling Occurs due to opening of the tricuspid valve and the subsequent rapid
(early diastole) inflow of blood from the right atrium to the right ventricle
First Start of systole Caused by closure of the atrioventricular (mitral & tricuspid) valves
heart
sound
Second heart End of systole Caused by closure of the semilunar (aortic and pulmonary) valves
sound
Third heart Early diastole Caused by rapid flow of blood from the atria into the ventricles during the
sound ventricular filling phase
Fourth heart Late diastole Caused by filling of an abnormally stiff ventricle in atrial systole
sound
ECG Event
Digoxin exhibits its positive inotropic effect by which of the following mechanisms:
Answer
2+ + +/ +
Cardiac glycosides (e.g. digoxin) slow the removal of Ca from the cell by inhibiting the membrane Na pump (Na K
+ 2+ + 2+
ATPase) which generates the Na gradient required for driving the export of Ca by Na /Ca exchange;
2+ 2+
consequently the removal of Ca from the myocyte is slowed and more Ca is available for the next contraction.
Notes
2+
Cardiac muscle contracts when intracellular Ca rises (> 100
2+
Although Ca entry during the action potential (AP) is essential for contraction, it only accounts for about 25% of the
2+ 2+
rise in intracellular Ca . The rest is released from Ca stores in the sarcoplasmic reticulum (SR).
APs travel down invaginations of the sarcolemma called T-tubules, which are close to, but do not touch, the
2+ 2+ 2+
terminal cisternae of the SR. During the AP plateau, Ca enters the cell and activates Ca sensitive Ca release
2+ 2+
channels in the sarcoplasmic reticulum allowing stored Ca to flood into the cytosol; this is called Ca -induced
2+ 2+ 2+
Ca release. The amount of Ca released is dependent on how much is stored, and on the size of the initial Ca
influx during the AP.
2+ 2+
In relaxation, about 80% of Ca is rapidly pumped back into the SR (sequestered) by Ca ATPase pumps. The
2+ + 2+
Ca that entered the cell during the AP is transported out of the cell primarily by the Na /Ca exchanger in the
membrane
2+ + +
which pumps one Ca ion out in exchange for three Na ions in, using the Na electrochemical gradient as an
energy source. This is relatively slow and continues during diastole.
2+
Treppe effect: When more action potentials occur per unit time, more Ca enters the cell during the AP plateau,
2+ 2+ 2+
more Ca is stored in the SR, more Ca is released from the SR and thus more Ca is left inside the cell and
greater tension is produced during contraction. Increased heart rate increases the force of contraction in a
stepwise fashion as
2+
intracellular [Ca ] increases cumulatively over several beats.
Inotropic agents
2+
Factors that affect intracellular [Ca ] and hence cardiac contractility are called inotropes.
2+ +
Cardiac glycosides (e.g. digoxin) slow the removal of Ca from the cell by inhibiting the membrane Na pump which
+ 2+ 2+
generates the Na gradient required for driving the export of Ca ; consequently the removal of Ca from the
2+
myocyte is slowed and more Ca is available for the next contraction.
+ 2+
Acidosis is negatively inotropic, largely because H competes for Ca binding sites.
Answer
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+ +
Repolarisation occurs due to activation of voltage-gated K rectifier channels and a K efflux. As the AP lasts
almost as long as contraction, its refractory period prevents another AP being initiated until the muscle relaxes,
thus cardiac muscle cannot exhibit tetanus.
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Notes
Cardiac myocyte action potential
The resting potential of ventricular myocytes is about -90 mV. An action potential (AP) is initiated when the
myocyte is depolarised to a threshold potential of about -65 mV, as a result of transmission from an adjacent
myocyte via gap junctions.
Depolarisation:
+ +
Fast voltage-gated Na channels are activated and a Na influx depolarises the membrane rapidly to about +30
mV. This initial depolarisation is similar to that in nerve and skeletal muscle, and assists the transmission to the
next myocyte.
+
Na channels and currents rapidly inactivate, but in cardiac myocytes, the initial depolarisation activates voltage-
2+ 2+
gated Ca channels (slow L-type channels, threshold approximately – 45 mV) through which Ca floods into the
cell. The
2+
resulting influx of Ca prevents the cell from repolarising and causes a plateau phase, that is maintained for about
250 ms until the L-type channels inactivate. The cardiac AP is thus much longer than that in nerve or skeletal
muscle.
Repolarisation:
+ +
Repolarisation occurs due to activation of voltage-gated K rectifier channels and a K efflux. As the AP lasts
almost as long as contraction, its refractory period prevents another AP being initiated until the muscle relaxes,
thus cardiac muscle cannot exhibit tetanus.
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Image modified by FRCEM Success. [CC-BY-SA-3.0 (or GFDL (], via Wikimedia Commons
Atrial myocytes have a similar but more triangular AP compared to the ventricles (less plateau). Purkinje fibres in
the conduction system are also similar to ventricular myocytes, but have a spike at the peak of the upstroke
+
reflecting a larger Na current that contributes to their fast conduction velocity.
a) The a wave
b) The c wave
c) The v wave
d) The x descent
e) The y descent
Something wrong?
Answer
c wave Isovolumetric Occurs due to the bulging of the tricuspid valve into the right atrium
contraction during right isovolumetric ventricular contraction
(early systole)
x descent Rapid ventricular Occurs due to a combination of right atrial relaxation, the downward
ejection (mid systole) displacement of the tricuspid valve during right ventricular contraction,
and the ejection of blood from both the ventricles
v wave Ventricular ejection Occurs due to right atrial filling from venous return
and isovolumetric
relaxation (late
systole)
y descent Ventricular filling Occurs due to opening of the tricuspid valve and the subsequent rapid
(early diastole) inflow of blood from the right atrium to the right ventricle
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Notes
The cardiac cycle describes the events that occur during one beat of the heart.
At the start of the cardiac cycle, towards the end of diastole, the whole of the heart is relaxed. The atrioventricular
(AV) valves are open because the atrial pressure is still slightly greater than the ventricular pressure. The semilunar
valves are closed, as the pressure in the pulmonary artery and aorta is greater than the ventricular pressures. The
cycle starts when the sinoatrial node (SAN) initiates atrial systole.
Atrial depolarisation causes the P wave on the ECG and initiates atrial contraction (atrial repolarisation is too
diffuse to be seen on the ECG).
As the atria contract, the atrial pressure increases which forces more blood flow across the open AV valves, leading
to rapid flow of blood into the ventricles. There are no valves between the veins and atria and atrial systole causes
a small pressure rise in the great veins (the a wave on the JVP waveform).
At rest, atrial contraction only contributes the last 15 – 20% of the final ventricular volume, as most of the
ventricular filling has occurred passively in diastole due to venous pressure. The proportion of atrial contribution
increases with
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heart rate as diastole shortens and there is less time for passive ventricular filling.
The end-diastolic volume (EDV) is usually about 120 – 140 mL, and the end-diastolic pressure is less than 10
mmHg (and higher in the left ventricle than the right due to the thicker and therefore stiffer left ventricle).
In ventricular hypertrophy, filling of the ‘stiff’ ventricle by atrial systole causes a fourth heart sound, which is not
audible in normal adults.
Ventricular depolarisation causes the QRS complex on the ECG, and triggers excitation-contraction coupling and
myocyte contraction.
The ventricular pressure rises sharply during contraction and the AV valves close as soon as this is greater than
the atrial pressure (causing the first heart sound). Because the mitral valve closes before the tricuspid valve, the first
heart sound may be split.
For a short period, as the forces are developing, both the AV and the semilunar valves are closed as the ventricular
pressure is still less than that in the pulmonary artery and aorta, and no ejection occurs. This is isovolumetric
contraction.
The increasing pressure makes the AV valves bulge into the atria, causing a small atrial pressure wave (the c wave of
the JVP waveform).
When the ventricular pressure exceeds that in the pulmonary artery and the aorta, the semilunar valves open and
blood is ejected, initially rapidly (rapid ejection phase) and then more slowly (reduced ejection phase).
Atrial pressure initially decreases as the atrial base is pulled downward during ejection, expanding the atrial chamber
(the x descent of the JVP waveform). Atrial filling begins in the rapid ejection phase and continues during the
reduced ejection phase and atrial pressure begins to rise (the v wave of the JVP waveform).
During the second half of ejection, the ventricles stop actively contracting, the ventricular pressure starts to
decrease and the muscle starts to repolarise; this causes the T wave on the ECG, which marks the end of both
ventricular contraction and rapid ventricular ejection.
The ventricular pressure during the reduced ejection phase begins to decrease. Aortic pressure also decreases
because of the runoff of blood from large arteries into smaller arteries. The ventricular pressure falls slightly
below that in the aorta, but initially blood continues to flow out of the ventricle because of momentum;
eventually the ventricular pressure falls sufficiently and the semilunar valves close.
Closure of the semilunar valves causes a small increase in aortic pressure (the dicrotic notch on the arterial
waveform), and the second heart sound. Inspiration delays closure of the pulmonary valve and thus causes splitting of
the second heart sound.
The amount of blood ejected is the stroke volume (SV), and is usually about 70 mL (therefore about 50 mL is left; this is
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the end-systolic volume). The proportion of EDV that is ejected (i.e. the SV/EDV) is the ejection fraction and this is
normally about 0.6.
Immediately after the closure of the semilunar valves, the ventricles rapidly relax and ventricular pressure
decreases rapidly but the AV valves remain closed as initially the ventricular pressure is still greater than atrial
pressure. This is isovolumetric relaxation.
Atrial pressure continues to rise because of venous return, with the v wave of the JVP waveform peaking during
this phase. As the ventricles continue to relax, the ventricular pressure falls below that of the atrial pressure and
the AV valves open.
When the AV valves open, the atrial pressure falls (the y descent of the JVP waveform) and the ventricles refill,
initially rapidly (the rapid filling phase) and then more slowly as the ventricles expand, become less complicant, and
ventricular pressures rise (the reduced filling phase). Rapid flow of blood from the atria into the ventricles causes
the third heart sound, which is normal in children but, in adults, is associated with disease such as ventricular
dilation.
Diastole is usually twice the length of systole at rest, but decreases with increased heart rate. During systole,
contraction of the ventricles compresses the coronary arteries and suppresses blood flow. This is particularly evident
in the left ventricle, where during systole the ventricular pressure is the same as or greater than that in the arteries
and as a result more than 85% of left ventricular perfusion occurs during diastole. This becomes a problem if the
heart rate is increased as the diastolic interval is shorter and can result in ischaemia.
Atrial systole Open (atrial pressure > ventricular Closed (arterial pressure > ventricular
pressure) pressure)
Isovolumetric Closed (ventricular pressure > atrial Closed (arterial pressure > ventricular
contraction pressure) pressure)
Ventricular ejection Closed (ventricular pressure > atrial Open (ventricular pressure > arterial
pressure) pressure)
Isovolumetric Closed (ventricular pressure > atrial Closed (arterial pressure > ventricular
relaxation pressure) pressure)
Ventricular filling Open (atrial pressure > ventricular Closed (arterial pressure > ventricular
pressure) pressure)
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JVP waveform during cardiac cycle
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c wave Isovolumetric Occurs due to the bulging of the tricuspid valve into the right atrium
contraction during right isovolumetric ventricular contraction
(early systole)
x descent Rapid ventricular Occurs due to a combination of right atrial relaxation, the downward
ejection (mid systole) displacement of the tricuspid valve during right ventricular contraction,
and the ejection of blood from both the ventricles
v wave Ventricular ejection Occurs due to right atrial filling from venous return
and isovolumetric
relaxation (late
systole)
y descent Ventricular filling Occurs due to opening of the tricuspid valve and the subsequent rapid
(early diastole) inflow of blood from the right atrium to the right ventricle
First Start of systole Caused by closure of the atrioventricular (mitral & tricuspid) valves
heart
sound
Second heart End of systole Caused by closure of the semilunar (aortic and pulmonary) valves
sound
Third heart Early diastole Caused by rapid flow of blood from the atria into the ventricles during the
sound ventricular filling phase
Fourth heart Late diastole Caused by filling of an abnormally stiff ventricle in atrial systole
sound
ECG Event
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The physiological function of the slowed conduction through the atrioventricular node is
to allow sufficient time for which of the following:
Answer
The impulse from the sinoatrial node is channelled through the atrioventricular node (AVN), located between the
right atrium and ventricle near the atrial septum. The AVN contains small cells and thus conducts slowly and delays
the impulse for about 120 ms, allowing time for atrial contraction to complete ventricular filling.
Notes
Myocytes
The myocardium is composed of cardiac muscle cells called myocytes. The cells are striated due to the
arrangement of the thick and thin filaments which make up the bulk of the muscle, although they are less
organised than in skeletal muscle. The myocytes are small and branched, with a single nucleus and are rich in
mitochondria. The normal pumping action of the heart is dependent on the synchronised contraction of all cardiac
cells.
Intercalated discs
The synchronicity between myocytes occurs because all the adjacent cells are connected by intercalated discs. The
intercalated discs provide both a structural attachment by ‘glueing’ cells together at desmosomes and an electrical
contact made up of proteins called connexons, called a gap junction, which essentially creates a low-resistance
pathway between cells. Gap junctions allow action potentials to spread rapidly from one cell to another and allows
the myocardium to act as a functional syncytium.
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Cardiac pacemaker
Cardiac myocyte contraction is not dependent on an external nerve supply but instead the heart generates its own
rhythm, demonstrating inherent rhythmicity.
The heartbeat is initiated by spontaneous depolarisation of the sinoatrial node (SAN), a region of specialised
myocytes in the right atrium, close to the coronary sinus. The rate is modulated by the autonomic nervous system.
Action potentials in the SAN activate adjacent atrial myocytes and a wave of depolarisation and contraction
therefore spreads through atrial muscle. This is prevented from reaching the ventricles directly by the annulus
fibrosis.
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This impulse is channelled through the atrioventricular node (AVN), located between the right atrium and ventricle
near the atrial septum. The AVN contains small cells and thus conducts slowly and delays the impulse for about 120
ms, allowing time for atrial contraction to complete ventricular filling.
Once complete, the impulse is then transmitted by specialised, wide, fast conducting myocytes in the bundle of His
and Purkinje fibres, by which it is distributed over the inner surface of both ventricles. From here a wave of
depolarisation and contraction moves from myocyte to myocyte across the endocardium until the whole ventricular
mass is activated.
Electrocardiogram (ECG)
The wave of depolarisation through the heart causes local currents in surrounding fluid which are detected at the
body surface as small changes in voltage. This forms the basis of the ECG. The classical ECG records voltage
between the left and right arm (lead I), the right arm and left leg (lead II) and the left arm and left leg (lead III).
This is represented by Einthoven’s triangle. The size of the voltage at any time depends on the quantity of muscle
depolarisation and the direction in which the wave of depolarisation is travelling. Thus lead II normally shows the
largest deflection during ventricular depolarisation, as the muscle mass is greatest and depolarisation travels from
apex to base, more or less parallel to a line from the left hip to the right shoulder.
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By Npatchett (Own work) [CC BY-SA 4.0 (], via Wikimedia Commons
a) +20 mV
b) – 20 mV
c) – 40 mV
d) – 65 mV
e) – 90 mV
Something wrong?
Answer
The resting potential of the SAN is about – 60 mV, and it decays steadily with time until it reaches a threshold
potential of about – 40 mV, when an action potential is initiated.
Notes
The action potential (AP) of the sinoatrial node (SAN) differs from that in ventricular muscle.
The resting potential of the SAN is about – 60 mV, and it decays steadily with time until it reaches a threshold
potential of about – 40 mV, when an action potential is initiated.
+
The upstroke of the AP is slow, as it is not due to activation of fast Na channels like cardiac myocytes, but instead
2+ +
slow L-type Ca channels; the SA node contains no functional fast Na channels. The slow upstroke means that
conduction
between nodal myocytes is slow, which is particularly important at the atrioventricular node (which has a similar AP
to the SAN).
The rate of decay of the SAN resting potential determines the rate of AP and therefore of heart rate, it is therefore
+
called the pacemaker potential. The pacemaker potential decays because of a slowly reducing outward K current
set
against inward currents. Factors that affect these currents alter the rate of decay and the time to reach threshold
and thus heart rate and are called chronotropic agents.
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Chronotropic agents
Noradrenaline (the sympathetic neurotransmitter) is a positive chronotrope and causes a faster rate of decay and thus
heart rate whereas acetylcholine (the parasympathetic neurotransmitter) is a negative chronotrope and lengthens the
time to reach threshold and decreases heart rate.
Other atrial cells, the AV node, the bundle of His and Purkinje system may also exhibit decaying resting potentials
that can act as pacemakers. However the SAN is normally fastest and predominates – this is called overdrive
suppression.
The following are important mediators of metabolic hyperaemia in blood vessels, EXCEPT for:
a) High [K+]
b) Adenosine
c) High pCO2
d) Low pO2
e) High [Ca2+]
Something wrong?
Answer
+
Many factors may contribute to metabolic hyperaemia (increased blood flow), with the most important being K ,
CO2 and adenosine, and in some cases hypoxia itself.
+ +
K , released from active tissues and in ischaemia, causes vasodilation partly by stimulating the Na pump, thus
2+
increasing Ca removal from smooth muscle cells and hyperpolarising the cell.
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CO2 and acidosis cause vasodilation largely through increased nitric oxide production and inhibition of smooth
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2+
muscle Ca entry.
Adenosine, released from the heart, skeletal muscle and brain during increased metabolism and
hypoxia, causes vasodilation by stimulating the production of cAMP in smooth muscle.
+
Hypoxia may reduce ATP sufficiently for K channels to activate causing hyperpolarisation.
Notes
In addition to central control of blood pressure, tissues can regulate their own blood flow to match their
requirements via autoregulation, metabolic factors and local hormones (autocoids).
Autoregulation
Autoregulation is the ability to maintain a constant blood flow despite variations in blood pressure (between 50 –
170 mmHg). It is particularly important in the brain, kidney and heart. There are two main methods contributing to
autoregulation.
The myogenic mechanism involves arterial constriction in response to stretching of the vessel wall,
2+ 2+
probably due to activation of smooth muscle stretch-activated Ca channels and Ca entry. A reduction
in pressure and stretch closes these channels, causing vasodilatation.
The second mechanism of autoregulation is due to locally produced vasodilating factors; an increase in blood
flow dilutes these factors causing vasoconstriction, whereas decreased blood flow has the opposite
effect.
Metabolic factors
+
Many factors may contribute to metabolic hyperaemia (increased blood flow), with the most important being K ,
CO2 and adenosine, and in some cases hypoxia itself.
+ +
K , released from active tissues and in ischaemia, causes vasodilation partly by stimulating the Na pump, thus
2+
increasing Ca removal from smooth muscle cells and hyperpolarising the cell.
CO2 and acidosis cause vasodilation largely through increased nitric oxide production and inhibition of smooth
2+
muscle Ca entry.
Adenosine, released from the heart, skeletal muscle and brain during increased metabolism and
hypoxia, causes vasodilation by stimulating the production of cAMP in smooth muscle.
+
Hypoxia may reduce ATP sufficiently for K channels to activate causing hyperpolarisation.
Autocoids
In inflammation, local inflammatory mediators such as histamine and bradykinin cause vasodilation
and increased permeability of exchange vessels, leading to swelling but allowing access by immune
cells to damaged tissues.
In clotting, serotonin and thromboxane A2 released from activated platelets cause vasoconstriction to help
reduce bleeding.
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In the isovolumetric relaxation phase of the cardiac cycle, all of the following statements are
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true EXCEPT for:
Answer
Immediately after the closure of the semilunar valves, the ventricles rapidly relax and ventricular pressure
decreases rapidly but the AV valves remain closed as initially the ventricular pressure is still greater than atrial
pressure. This is isovolumetric relaxation. Atrial pressure continues to rise because of venous return, with the v
wave of the JVP waveform peaking during this phase. Rapid flow of blood from the atria into the ventricles during
the ventricular filling phase causes the third heart sound, which is normal in children but, in adults, is associated
with disease such as ventricular dilation.
Notes
The cardiac cycle describes the events that occur during one beat of the heart.
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Modified by FRCEM Success. Original image via Wikimedia Commons
At the start of the cardiac cycle, towards the end of diastole, the whole of the heart is relaxed. The atrioventricular
(AV) valves are open because the atrial pressure is still slightly greater than the ventricular pressure. The semilunar
valves are closed, as the pressure in the pulmonary artery and aorta is greater than the ventricular pressures. The
cycle starts when the sinoatrial node (SAN) initiates atrial systole.
Atrial depolarisation causes the P wave on the ECG and initiates atrial contraction (atrial repolarisation is too
diffuse to be seen on the ECG).
As the atria contract, the atrial pressure increases which forces more blood flow across the open AV valves, leading
to rapid flow of blood into the ventricles. There are no valves between the veins and atria and atrial systole causes
a small pressure rise in the great veins (the a wave on the JVP waveform).
At rest, atrial contraction only contributes the last 15 – 20% of the final ventricular volume, as most of the
ventricular filling has occurred passively in diastole due to venous pressure. The proportion of atrial contribution
increases with heart rate as diastole shortens and there is less time for passive ventricular filling.
The end-diastolic volume (EDV) is usually about 120 – 140 mL, and the end-diastolic pressure is less than 10
mmHg (and higher in the left ventricle than the right due to the thicker and therefore stiffer left ventricle).
In ventricular hypertrophy, filling of the ‘stiff’ ventricle by atrial systole causes a fourth heart sound, which is not
audible in normal adults.
Ventricular depolarisation causes the QRS complex on the ECG, and triggers excitation-contraction coupling and
myocyte contraction.
The ventricular pressure rises sharply during contraction and the AV valves close as soon as this is greater than
the atrial pressure (causing the first heart sound). Because the mitral valve closes before the tricuspid valve, the first
heart sound may be split.
For a short period, as the forces are developing, both the AV and the semilunar valves are closed as the ventricular
pressure is still less than that in the pulmonary artery and aorta, and no ejection occurs. This is isovolumetric
contraction.
The increasing pressure makes the AV valves bulge into the atria, causing a small atrial pressure wave (the c wave of
the JVP waveform).
When the ventricular pressure exceeds that in the pulmonary artery and the aorta, the semilunar valves open and
blood is ejected, initially rapidly (rapid ejection phase) and then more slowly (reduced ejection phase).
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Atrial pressure initially decreases as the atrial base is pulled downward during ejection, expanding the atrial chamber
(the x descent of the JVP waveform). Atrial filling begins in the rapid ejection phase and continues during the
reduced ejection phase and atrial pressure begins to rise (the v wave of the JVP waveform).
During the second half of ejection, the ventricles stop actively contracting, the ventricular pressure starts to
decrease and the muscle starts to repolarise; this causes the T wave on the ECG, which marks the end of both
ventricular contraction and rapid ventricular ejection.
The ventricular pressure during the reduced ejection phase begins to decrease. Aortic pressure also decreases
because of the runoff of blood from large arteries into smaller arteries. The ventricular pressure falls slightly
below that in the aorta, but initially blood continues to flow out of the ventricle because of momentum;
eventually the ventricular pressure falls sufficiently and the semilunar valves close.
Closure of the semilunar valves causes a small increase in aortic pressure (the dicrotic notch on the arterial
waveform), and the second heart sound. Inspiration delays closure of the pulmonary valve and thus causes splitting of
the second heart sound.
The amount of blood ejected is the stroke volume (SV), and is usually about 70 mL (therefore about 50 mL is left;
this is the end-systolic volume). The proportion of EDV that is ejected (i.e. the SV/EDV) is the ejection fraction and
this is normally about 0.6.
Immediately after the closure of the semilunar valves, the ventricles rapidly relax and ventricular pressure
decreases rapidly but the AV valves remain closed as initially the ventricular pressure is still greater than atrial
pressure. This is isovolumetric relaxation.
Atrial pressure continues to rise because of venous return, with the v wave of the JVP waveform peaking during
this phase. As the ventricles continue to relax, the ventricular pressure falls below that of the atrial pressure and
the AV valves open.
When the AV valves open, the atrial pressure falls (the y descent of the JVP waveform) and the ventricles refill,
initially rapidly (the rapid filling phase) and then more slowly as the ventricles expand, become less complicant, and
ventricular pressures rise (the reduced filling phase). Rapid flow of blood from the atria into the ventricles causes
the third heart sound, which is normal in children but, in adults, is associated with disease such as ventricular
dilation.
Diastole is usually twice the length of systole at rest, but decreases with increased heart rate. During systole,
contraction of the ventricles compresses the coronary arteries and suppresses blood flow. This is particularly evident
in the left ventricle, where during systole the ventricular pressure is the same as or greater than that in the arteries
and as a result more than 85% of left ventricular perfusion occurs during diastole. This becomes a problem if the
heart rate is increased as the diastolic interval is shorter and can result in ischaemia.
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Atrial systole Open (atrial pressure > ventricular Closed (arterial pressure > ventricular
pressure) pressure)
Isovolumetric Closed (ventricular pressure > atrial Closed (arterial pressure > ventricular
contraction pressure) pressure)
Ventricular ejection Closed (ventricular pressure > atrial Open (ventricular pressure > arterial
pressure) pressure)
Isovolumetric Closed (ventricular pressure > atrial Closed (arterial pressure > ventricular
relaxation pressure) pressure)
Ventricular filling Open (atrial pressure > ventricular Closed (arterial pressure > ventricular
pressure) pressure)
c wave Isovolumetric Occurs due to the bulging of the tricuspid valve into the right atrium
contraction during right isovolumetric ventricular contraction
(early systole)
x descent Rapid ventricular Occurs due to a combination of right atrial relaxation, the downward
ejection (mid systole) displacement of the tricuspid valve during right ventricular contraction,
and the ejection of blood from both the ventricles
v wave Ventricular ejection Occurs due to right atrial filling from venous return
and isovolumetric
relaxation (late
systole)
y descent Ventricular filling Occurs due to opening of the tricuspid valve and the subsequent rapid
(early diastole) inflow of blood from the right atrium to the right ventricle
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cardiac cycle
First Start of systole Caused by closure of the atrioventricular (mitral & tricuspid) valves
heart
sound
Second heart End of systole Caused by closure of the semilunar (aortic and pulmonary) valves
sound
Third heart Early diastole Caused by rapid flow of blood from the atria into the ventricles during the
sound ventricular filling phase
Fourth heart Late diastole Caused by filling of an abnormally stiff ventricle in atrial systole
sound
ECG Event
a) The annulus fibrosus conducts electrical impulses from the atria to the ventricles.
b) The internal surface of the heart is covered with the epicardium, a layer of mesothelial cells.
c) The left side of the heart has a thicker myocardium than the right side.
d) Blood flows from the left atrium to the left ventricle through the tricuspid valve.
e) Blood flows from the left ventricle into the aorta through the mitral valve.
Something wrong?
Answer
The annulus fibrosis prevents electrical conduction between the atria and the ventricles, except at the
atrioventricular node. The inner surface of the heart is covered by the endocardium which provides an anti-
thrombogenic surface, the outer surface is covered by epicardium, a layer of mesothelial cells. The walls of the
heart are formed from myocardium, and the left side has more muscle than the right (as the systemic circulation
has greater resistance to flow, the left ventricle requires more force). Blood flows from the left atrium into the left
ventricle via the mitral atrioventricular valve, and from the left ventricle into the aorta via the aortic semilunar
valve.
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Notes
The heart consists of four chambers – two thin-walled atria and two muscular ventricles. The atria are separated
from the ventricles by a band of fibrous connective tissue called the annulus fibrosus, which provides a skeleton for
the attachment of muscle and cardiac valves, and prevents electrical conduction between the atria and ventricles
(except at the atrioventricular node).
Basic anatomy
The walls of the heart are formed from myocardium, and the left side has more muscle than the right (as the
systemic circulation has greater resistance to flow, the left ventricle requires more force).
The inner surface of the heart is covered by the endocardium which provides an anti-thrombogenic surface. The
outer surface is covered by epicardium, a layer of mesothelial cells. The whole heart is enclosed in a thin fibrous
sheath, the pericardium.
Valves
Blood flows from the right atrium into the right ventricle via the tricuspid atrioventricular valve and from the left
atrium into the left ventricle via the mitral atrioventricular valve. Blood is ejected from the right ventricle through
the pulmonary semilunar valve into the pulmonary artery and from the left ventricle via the aortic semilunar valve
into the aorta.
By National Heart Lung and Blood Institute (NIH) (National Heart Lung and Blood Institute (NIH)) [Public domain], via Wikimedia Common
a) -45mV
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b) -65mV
c) -70mV
d) -90mV
e) -110mV
Something wrong?
Answer
The resting potential of ventricular myocytes is about -90 mV.
Notes
Cardiac myocyte action potential
The resting potential of ventricular myocytes is about -90 mV. An action potential (AP) is initiated when the
myocyte is depolarised to a threshold potential of about -65 mV, as a result of transmission from an adjacent
myocyte via gap junctions.
Depolarisation:
+ +
Fast voltage-gated Na channels are activated and a Na influx depolarises the membrane rapidly to about +30
mV. This initial depolarisation is similar to that in nerve and skeletal muscle, and assists the transmission to the
next myocyte.
+
Na channels and currents rapidly inactivate, but in cardiac myocytes, the initial depolarisation activates voltage-
2+ 2+
gated Ca channels (slow L-type channels, threshold approximately – 45 mV) through which Ca floods into the
cell. The
2+
resulting influx of Ca prevents the cell from repolarising and causes a plateau phase, that is maintained for about
250 ms until the L-type channels inactivate. The cardiac AP is thus much longer than that in nerve or skeletal
muscle.
Repolarisation:
+ +
Repolarisation occurs due to activation of voltage-gated K rectifier channels and a K efflux. As the AP lasts
almost as long as contraction, its refractory period prevents another AP being initiated until the muscle relaxes,
thus cardiac muscle cannot exhibit tetanus.
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Image modified by FRCEM Success. [CC-BY-SA-3.0 (or GFDL (], via Wikimedia Commons
Atrial myocytes have a similar but more triangular AP compared to the ventricles (less plateau). Purkinje fibres in
the conduction system are also similar to ventricular myocytes, but have a spike at the peak of the upstroke
+
reflecting a larger Na current that contributes to their fast conduction velocity.
a) It consists of a collection of specialised nerves that conduct electrical activity to the ventricle.
b) It conducts impulses rapidly to allow almost immediate activation of ventricular muscle.
c) The heartbeat is initiated by spontaneous depolarisation of the atrioventricular node.
d) It delays impulses for about 120 ms, allowing time to complete ventricular filling.
e) It is located in the right atrium, close to the coronary sinus.
Something wrong?
Answer
The heartbeat is initiated by spontaneous depolarisation of the sinoatrial node (SAN) which is conducted through
to the atrioventricular node (AVN). The AVN is a region of specialised myocytes, located between the right atrium
and ventricle near the atrial septum. The AVN contains small cells and thus conducts slowly and delays the
impulse for about 120 ms, allowing time for atrial contraction to complete ventricular filling.
Notes
Myocytes
The myocardium is composed of cardiac muscle cells called myocytes. The cells are striated due to the arrangement of
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the thick and thin filaments which make up the bulk of the muscle, although they are less organised than in
skeletal muscle. The myocytes are small and branched, with a single nucleus and are rich in mitochondria. The
normal pumping action of the heart is dependent on the synchronised contraction of all cardiac cells.
Intercalated discs
The synchronicity between myocytes occurs because all the adjacent cells are connected by intercalated discs. The
intercalated discs provide both a structural attachment by ‘glueing’ cells together at desmosomes and an electrical
contact made up of proteins called connexons, called a gap junction, which essentially creates a low-resistance
pathway between cells. Gap junctions allow action potentials to spread rapidly from one cell to another and allows
the myocardium to act as a functional syncytium.
Cardiac pacemaker
Cardiac myocyte contraction is not dependent on an external nerve supply but instead the heart generates its own
rhythm, demonstrating inherent rhythmicity.
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The heartbeat is initiated by spontaneous depolarisation of the sinoatrial node (SAN), a region of specialised
myocytes in the right atrium, close to the coronary sinus. The rate is modulated by the autonomic nervous system.
Action potentials in the SAN activate adjacent atrial myocytes and a wave of depolarisation and contraction
therefore spreads through atrial muscle. This is prevented from reaching the ventricles directly by the annulus
fibrosis.
This impulse is channelled through the atrioventricular node (AVN), located between the right atrium and ventricle
near the atrial septum. The AVN contains small cells and thus conducts slowly and delays the impulse for about 120
ms, allowing time for atrial contraction to complete ventricular filling.
Once complete, the impulse is then transmitted by specialised, wide, fast conducting myocytes in the bundle of His
and Purkinje fibres, by which it is distributed over the inner surface of both ventricles. From here a wave of
depolarisation and contraction moves from myocyte to myocyte across the endocardium until the whole ventricular
mass is activated.
Electrocardiogram (ECG)
The wave of depolarisation through the heart causes local currents in surrounding fluid which are detected at the
body surface as small changes in voltage. This forms the basis of the ECG. The classical ECG records voltage
between the left and right arm (lead I), the right arm and left leg (lead II) and the left arm and left leg (lead III).
This is represented by Einthoven’s triangle. The size of the voltage at any time depends on the quantity of muscle
depolarisation and the direction in which the wave of depolarisation is travelling. Thus lead II normally shows the
largest deflection during ventricular depolarisation, as the muscle mass is greatest and depolarisation travels from
apex to base, more or less parallel to a line from the left hip to the right shoulder.
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By Npatchett (Own work) [CC BY-SA 4.0 (], via Wikimedia Commons
Action potentials are transmitted from myocyte to myocyte via which of the following:
a) Tight junctions
b) Desmosomes
c) Cardioporins
d) Gap junctions
e) Purkinje fibres
Something wrong?
Answer
Action potentials are transmitted to adjacent myocytes via gap junctions.
Notes
Cardiac myocyte action potential
The resting potential of ventricular myocytes is about -90 mV. An action potential (AP) is initiated when the
myocyte is depolarised to a threshold potential of about -65 mV, as a result of transmission from an adjacent
myocyte via gap junctions.
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Depolarisation:
+ +
Fast voltage-gated Na channels are activated and a Na influx depolarises the membrane rapidly to about +30
mV. This initial depolarisation is similar to that in nerve and skeletal muscle, and assists the transmission to the
next myocyte.
+
Na channels and currents rapidly inactivate, but in cardiac myocytes, the initial depolarisation activates voltage-
2+ 2+
gated Ca channels (slow L-type channels, threshold approximately – 45 mV) through which Ca floods into the
cell. The
2+
resulting influx of Ca prevents the cell from repolarising and causes a plateau phase, that is maintained for about
250 ms until the L-type channels inactivate. The cardiac AP is thus much longer than that in nerve or skeletal
muscle.
Repolarisation:
+ +
Repolarisation occurs due to activation of voltage-gated K rectifier channels and a K efflux. As the AP lasts
almost as long as contraction, its refractory period prevents another AP being initiated until the muscle relaxes,
thus cardiac muscle cannot exhibit tetanus.
Image modified by FRCEM Success. [CC-BY-SA-3.0 (or GFDL (], via Wikimedia Commons
Atrial myocytes have a similar but more triangular AP compared to the ventricles (less plateau). Purkinje fibres in the
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conduction system are also similar to ventricular myocytes, but have a spike at the peak of the upstroke reflecting
+
a larger Na current that contributes to their fast conduction velocity.
a) Blood flow in the pulmonary circulation is increased during hypoxia due to vasodilation in small arteries.
b) Blood flow in the pulmonary circulation is primarily controlled by the autonomic nervous system.
c) Hypoxic vasoconstriction worsens V/Q mismatch.
d) Hypoxic vasoconstriction is accentuated by low alveolar PCO2.
e) Persistent hypoxic vasoconstriction may lead to cor pulmonale.
Something wrong?
Answer
The pulmonary circulation is not controlled by either autonomic nerves or metabolic products, and the most
important mechanism regulating flow is hypoxic pulmonary vasoconstriction, in which small arteries constrict in
response to hypoxia (in contrast to elsewhere in the body). If an area of lung is poorly ventilated and the alveolar
partial pressure of oxygen is low, pulmonary blood vessels are constricted and blood is diverted to areas of the
lung that are better ventilated, thus maintaining optimal ventilation-perfusion matching. This effect is accentuated
by high alveolar PCO2. The response is unhelpful in the presence of global lung hypoxia, at altitude or in
respiratory failure, where it may contribute to the development of pulmonary hypertension and right-sided heart
failure (cor pulmonale).
Notes
Skeletal muscle circulation
The skeletal muscle circulation normally receives about 15 – 20% of the cardiac output, but this may rise to > 80%
during exercise. Skeletal muscle provides a major contribution to the total peripheral resistance and sympathetic
regulation of muscle blood flow is important in the baroreceptor reflex. At rest most capillaries are not perfused as
their arterioles are constricted. Capillaries are recruited during exercise by metabolic hyperaemia, caused by release
of
+
K and CO2 from the muscle and adenosine. This overrides sympathetic vasoconstriction in working muscle; the latter
reduces flow in non-working muscle conserving cardiac output.
Pulmonary circulation
The pulmonary circulation is not controlled by either autonomic nerves or metabolic products, and the most
important mechanism regulating flow is hypoxic pulmonary vasoconstriction, in which small arteries constrict in
response to hypoxia (in contrast to elsewhere in the body).
If an area of lung is poorly ventilated and the alveolar partial pressure of oxygen is low, pulmonary blood vessels
are constricted and blood is diverted to areas of the lung that are better ventilated, thus maintaining optimal
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ventilation- perfusion matching. This effect is accentuated by high alveolar PCO 2.
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The response is unhelpful in the presence of global lung hypoxia, at altitude or in respiratory failure, where it may
contribute to the development of pulmonary hypertension and right-sided heart failure (cor pulmonale).
Cutaneous circulation
The main function of the cutaneous circulation is thermoregulation. Arteriovenous anastomoses (AVAs) directly
linked arterioles and venules, allowing a high blood flow into the venous plexus and thus radiation of heat. AVAs
are mostly found in the hands, feet and areas of the face.
Temperature is sensed by peripheral thermoreceptors and the hypothalamus coordinates the response.
Increased temperatures reduce sympathetic adrenergic stimulation, causing vasodilation and allowing more blood
to flow to the skin and radiate its heat to the environment, whereas activation of sympathetic cholinergic fibres
promotes sweating and the release of bradykinin, which also causes vasodilation.
Cerebral circulation
The brain receives around 15% of the total cardiac output and has a high capillary density.
The endothelial cells of the capillaries of the blood-brain barrier have very tight junctions, and contain membrane
transporters that control the movement of substances, such as ions, glucose and amino acids, and tightly regulate
the composition of cerebrospinal fluid. This is continuous except where substances need to be absorbed or released
e.g. pituitary gland, choroid plexus.
The autoregulation of cerebral blood flow can maintain a constant flow for blood pressures between 50 and 170
+
mmHg. CO2 and K are particularly important metabolic regulators in the brain, with increasing concentration
causing vasodilation and a functional hyperaemia.
Hyperventilation reduces blood PCO2 and can cause fainting due to cerebral vasoconstriction.
Coronary circulation
The heart has a high metabolic demand and its high capillary density allow it to extract an unusually large fraction
(about 70%) of oxygen from the blood.
In exercise, the reduced diastolic interval and increased oxygen consumption demand a greatly increased blood
+
flow which is achieved by metabolic hyperaemia mediated by adenosine, K and hypoxia. This overrides the
vasoconstriction mediated by sympathetic nerves acting at alpha-adrenergic receptors and is assisted by circulating
adrenaline which causes vasodilation by acting on beta-adrenergic receptors.
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a) The ejection fraction is normally about 0.8.
b) Splitting of the second heart sound is always pathological.
c) Repolarisation of the atria is represented by the T wave on ECG.
d) The dicrotic notch on arterial waveform corresponds with closing of the aortic valve.
e)
A third heart sound may be heard in late diastole caused by filling of an abnormally stiff ventricle in atrial systole.
Something wrong?
Answer
The amount of blood ejected is the stroke volume (SV), and is usually about 70 mL (therefore about 50 mL is left;
this is the end-systolic volume). The proportion of EDV that is ejected (i.e. the SV/EDV) is the ejection fraction and
this is normally about 0.6. During the second half of ejection, the ventricles stop actively contracting, the
ventricular pressure starts to decrease and the muscle starts to repolarise; this causes the T wave on the ECG,
which marks the end of both ventricular contraction and rapid ventricular ejection (atrial repolarisation is too diffuse
to be seen on the ECG).
Closure of the semilunar valves causes a small increase in aortic pressure (the dicrotic notch on the arterial
waveform), and the second heart sound. Inspiration delays closure of the pulmonary valve and thus causes splitting of
the second heart sound.
Notes
The cardiac cycle describes the events that occur during one beat of the heart.
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At the start of the cardiac cycle, towards the end of diastole, the whole of the heart is relaxed. The atrioventricular
(AV) valves are open because the atrial pressure is still slightly greater than the ventricular pressure. The semilunar
valves are closed, as the pressure in the pulmonary artery and aorta is greater than the ventricular pressures. The
cycle starts when the sinoatrial node (SAN) initiates atrial systole.
Atrial depolarisation causes the P wave on the ECG and initiates atrial contraction (atrial repolarisation is too
diffuse to be seen on the ECG).
As the atria contract, the atrial pressure increases which forces more blood flow across the open AV valves, leading
to rapid flow of blood into the ventricles. There are no valves between the veins and atria and atrial systole causes
a small pressure rise in the great veins (the a wave on the JVP waveform).
At rest, atrial contraction only contributes the last 15 – 20% of the final ventricular volume, as most of the
ventricular filling has occurred passively in diastole due to venous pressure. The proportion of atrial contribution
increases with heart rate as diastole shortens and there is less time for passive ventricular filling.
The end-diastolic volume (EDV) is usually about 120 – 140 mL, and the end-diastolic pressure is less than 10
mmHg (and higher in the left ventricle than the right due to the thicker and therefore stiffer left ventricle).
In ventricular hypertrophy, filling of the ‘stiff’ ventricle by atrial systole causes a fourth heart sound, which is not
audible in normal adults.
Ventricular depolarisation causes the QRS complex on the ECG, and triggers excitation-contraction coupling and
myocyte contraction.
The ventricular pressure rises sharply during contraction and the AV valves close as soon as this is greater than
the atrial pressure (causing the first heart sound). Because the mitral valve closes before the tricuspid valve, the first
heart sound may be split.
For a short period, as the forces are developing, both the AV and the semilunar valves are closed as the ventricular
pressure is still less than that in the pulmonary artery and aorta, and no ejection occurs. This is isovolumetric
contraction.
The increasing pressure makes the AV valves bulge into the atria, causing a small atrial pressure wave (the c wave of
the JVP waveform).
When the ventricular pressure exceeds that in the pulmonary artery and the aorta, the semilunar valves open and
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blood is ejected, initially rapidly (rapid ejection phase) and then more slowly (reduced ejection phase).
Atrial pressure initially decreases as the atrial base is pulled downward during ejection, expanding the atrial chamber
(the x descent of the JVP waveform). Atrial filling begins in the rapid ejection phase and continues during the
reduced ejection phase and atrial pressure begins to rise (the v wave of the JVP waveform).
During the second half of ejection, the ventricles stop actively contracting, the ventricular pressure starts to
decrease and the muscle starts to repolarise; this causes the T wave on the ECG, which marks the end of both
ventricular contraction and rapid ventricular ejection.
The ventricular pressure during the reduced ejection phase begins to decrease. Aortic pressure also decreases
because of the runoff of blood from large arteries into smaller arteries. The ventricular pressure falls slightly
below that in the aorta, but initially blood continues to flow out of the ventricle because of momentum;
eventually the ventricular pressure falls sufficiently and the semilunar valves close.
Closure of the semilunar valves causes a small increase in aortic pressure (the dicrotic notch on the arterial
waveform), and the second heart sound. Inspiration delays closure of the pulmonary valve and thus causes splitting of
the second heart sound.
The amount of blood ejected is the stroke volume (SV), and is usually about 70 mL (therefore about 50 mL is left;
this is the end-systolic volume). The proportion of EDV that is ejected (i.e. the SV/EDV) is the ejection fraction and
this is normally about 0.6.
Immediately after the closure of the semilunar valves, the ventricles rapidly relax and ventricular pressure
decreases rapidly but the AV valves remain closed as initially the ventricular pressure is still greater than atrial
pressure. This is isovolumetric relaxation.
Atrial pressure continues to rise because of venous return, with the v wave of the JVP waveform peaking during
this phase. As the ventricles continue to relax, the ventricular pressure falls below that of the atrial pressure and
the AV valves open.
When the AV valves open, the atrial pressure falls (the y descent of the JVP waveform) and the ventricles refill,
initially rapidly (the rapid filling phase) and then more slowly as the ventricles expand, become less complicant, and
ventricular pressures rise (the reduced filling phase). Rapid flow of blood from the atria into the ventricles causes
the third heart sound, which is normal in children but, in adults, is associated with disease such as ventricular
dilation.
Diastole is usually twice the length of systole at rest, but decreases with increased heart rate. During systole,
contraction of the ventricles compresses the coronary arteries and suppresses blood flow. This is particularly evident
in the left ventricle, where during systole the ventricular pressure is the same as or greater than that in the arteries
and as a result more than 85% of left ventricular perfusion occurs during diastole. This becomes a problem if the
heart rate is increased as the diastolic interval is shorter and can result in ischaemia.
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Valves during cardiac cycle
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Atrial systole Open (atrial pressure > ventricular Closed (arterial pressure > ventricular
pressure) pressure)
Isovolumetric Closed (ventricular pressure > atrial Closed (arterial pressure > ventricular
contraction pressure) pressure)
Ventricular ejection Closed (ventricular pressure > atrial Open (ventricular pressure > arterial
pressure) pressure)
Isovolumetric Closed (ventricular pressure > atrial Closed (arterial pressure > ventricular
relaxation pressure) pressure)
Ventricular filling Open (atrial pressure > ventricular Closed (arterial pressure > ventricular
pressure) pressure)
c wave Isovolumetric Occurs due to the bulging of the tricuspid valve into the right atrium
contraction during right isovolumetric ventricular contraction
(early systole)
x descent Rapid ventricular Occurs due to a combination of right atrial relaxation, the downward
ejection (mid systole) displacement of the tricuspid valve during right ventricular contraction,
and the ejection of blood from both the ventricles
v wave Ventricular ejection Occurs due to right atrial filling from venous return
and isovolumetric
relaxation (late
systole)
y descent Ventricular filling Occurs due to opening of the tricuspid valve and the subsequent rapid
(early diastole) inflow of blood from the right atrium to the right ventricle
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Heart sound Phase of Mechanical event
cardiac cycle
First Start of systole Caused by closure of the atrioventricular (mitral & tricuspid) valves
heart
sound
Second heart End of systole Caused by closure of the semilunar (aortic and pulmonary) valves
sound
Third heart Early diastole Caused by rapid flow of blood from the atria into the ventricles during the
sound ventricular filling phase
Fourth heart Late diastole Caused by filling of an abnormally stiff ventricle in atrial systole
sound
ECG Event
Answer
The heart has a high metabolic demand and its high capillary density allow it to extract an unusually large fraction
(about 70%) of oxygen from the blood. In exercise, the reduced diastolic interval and increased oxygen consumption
+
demand a greatly increased blood flow which is achieved by metabolic hyperaemia mediated by adenosine, K and
hypoxia. This overrides the vasoconstriction mediated by sympathetic nerves acting at alpha-adrenergic receptors
and is assisted by circulating adrenaline which causes vasodilation by acting on beta-adrenergic receptors.
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Notes
Skeletal muscle circulation
The skeletal muscle circulation normally receives about 15 – 20% of the cardiac output, but this may rise to > 80%
during exercise. Skeletal muscle provides a major contribution to the total peripheral resistance and sympathetic
regulation of muscle blood flow is important in the baroreceptor reflex. At rest most capillaries are not perfused as
their arterioles are constricted. Capillaries are recruited during exercise by metabolic hyperaemia, caused by release
of
+
K and CO2 from the muscle and adenosine. This overrides sympathetic vasoconstriction in working muscle; the latter
reduces flow in non-working muscle conserving cardiac output.
Pulmonary circulation
The pulmonary circulation is not controlled by either autonomic nerves or metabolic products, and the most
important mechanism regulating flow is hypoxic pulmonary vasoconstriction, in which small arteries constrict in
response to hypoxia (in contrast to elsewhere in the body).
If an area of lung is poorly ventilated and the alveolar partial pressure of oxygen is low, pulmonary blood vessels
are constricted and blood is diverted to areas of the lung that are better ventilated, thus maintaining optimal
ventilation- perfusion matching. This effect is accentuated by high alveolar PCO 2.
The response is unhelpful in the presence of global lung hypoxia, at altitude or in respiratory failure, where it may
contribute to the development of pulmonary hypertension and right-sided heart failure (cor pulmonale).
Cutaneous circulation
The main function of the cutaneous circulation is thermoregulation. Arteriovenous anastomoses (AVAs) directly
linked arterioles and venules, allowing a high blood flow into the venous plexus and thus radiation of heat. AVAs
are mostly found in the hands, feet and areas of the face.
Temperature is sensed by peripheral thermoreceptors and the hypothalamus coordinates the response.
Increased temperatures reduce sympathetic adrenergic stimulation, causing vasodilation and allowing more blood
to flow to the skin and radiate its heat to the environment, whereas activation of sympathetic cholinergic fibres
promotes sweating and the release of bradykinin, which also causes vasodilation.
Cerebral circulation
The brain receives around 15% of the total cardiac output and has a high capillary density.
The endothelial cells of the capillaries of the blood-brain barrier have very tight junctions, and contain membrane
transporters that control the movement of substances, such as ions, glucose and amino acids, and tightly regulate the
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composition of cerebrospinal fluid. This is continuous except where substances need to be absorbed or released e.g.
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pituitary gland, choroid plexus.
The autoregulation of cerebral blood flow can maintain a constant flow for blood pressures between 50 and 170
+
mmHg. CO2 and K are particularly important metabolic regulators in the brain, with increasing concentration
causing vasodilation and a functional hyperaemia.
Hyperventilation reduces blood PCO2 and can cause fainting due to cerebral vasoconstriction.
Coronary circulation
The heart has a high metabolic demand and its high capillary density allow it to extract an unusually large fraction
(about 70%) of oxygen from the blood.
In exercise, the reduced diastolic interval and increased oxygen consumption demand a greatly increased blood
+
flow which is achieved by metabolic hyperaemia mediated by adenosine, K and hypoxia. This overrides the
vasoconstriction mediated by sympathetic nerves acting at alpha-adrenergic receptors and is assisted by circulating
adrenaline which causes vasodilation by acting on beta-adrenergic receptors.
Answer
2+
Although Ca entry during the action potential (AP) is essential for contraction, it only accounts for about 25% of
2+ 2+
the rise in intracellular Ca . The rest is released from Ca stores in the sarcoplasmic reticulum (SR).
Notes
2+
Cardiac muscle contracts when intracellular Ca rises (> 100
2+
Although Ca entry during the action potential (AP) is essential for contraction, it only accounts for about 25% of
2+ 2+
the rise in intracellular Ca . The rest is released from Ca stores in the sarcoplasmic reticulum (SR).
APs travel down invaginations of the sarcolemma called T-tubules, which are close to, but do not touch, the
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2+ 2+ 2+
terminal cisternae of the SR. During the AP plateau, Ca enters the cell and activates Ca sensitive Ca release
channels in
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2+ 2+ 2+
the sarcoplasmic reticulum allowing stored Ca to flood into the cytosol; this is called Ca -induced Ca release.
2+ 2+
The amount of Ca released is dependent on how much is stored, and on the size of the initial Ca influx during
the AP.
2+ 2+
In relaxation, about 80% of Ca is rapidly pumped back into the SR (sequestered) by Ca ATPase pumps. The
2+ + 2+
Ca that entered the cell during the AP is transported out of the cell primarily by the Na /Ca exchanger in the
membrane
2+ + +
which pumps one Ca ion out in exchange for three Na ions in, using the Na electrochemical gradient as an
energy source. This is relatively slow and continues during diastole.
2+
Treppe effect: When more action potentials occur per unit time, more Ca enters the cell during the AP plateau,
2+ 2+ 2+
more Ca is stored in the SR, more Ca is released from the SR and thus more Ca is left inside the cell and
greater tension is produced during contraction. Increased heart rate increases the force of contraction in a
stepwise fashion as
2+
intracellular [Ca ] increases cumulatively over several beats.
Inotropic agents
2+
Factors that affect intracellular [Ca ] and hence cardiac contractility are called inotropes.
2+ +
Cardiac glycosides (e.g. digoxin) slow the removal of Ca from the cell by inhibiting the membrane Na pump which
+ 2+ 2+
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generates the Na gradient required for driving the export of Ca ; consequently the removal of Ca from
2+
the myocyte is slowed and more Ca is available for the next contraction.
+ 2+
Acidosis is negatively inotropic, largely because H competes for Ca binding sites.
Something wrong?
Answer
The wave of depolarisation through the heart causes local currents in surrounding fluid which are detected at the
body surface as small changes in voltage. This forms the basis of the ECG. The classical ECG records voltage
between the left and right arm (lead I), the right arm and left leg (lead II) and the left arm and left leg (lead III).
This is represented by Einthoven’s triangle. The size of the voltage at any time depends on the quantity of muscle
depolarisation and the direction in which the wave of depolarisation is travelling. Thus lead II normally shows the
largest deflection during ventricular depolarisation, as the muscle mass is greatest and depolarisation travels from
apex to base, more or less parallel to a line from the left hip to the right shoulder.
Notes
Myocytes
The myocardium is composed of cardiac muscle cells called myocytes. The cells are striated due to the
arrangement of the thick and thin filaments which make up the bulk of the muscle, although they are less
organised than in skeletal muscle. The myocytes are small and branched, with a single nucleus and are rich in
mitochondria. The normal pumping action of the heart is dependent on the synchronised contraction of all cardiac
cells.
Intercalated discs
The synchronicity between myocytes occurs because all the adjacent cells are connected by intercalated discs. The
intercalated discs provide both a structural attachment by ‘glueing’ cells together at desmosomes and an electrical
contact made up of proteins called connexons, called a gap junction, which essentially creates a low-resistance
pathway between cells. Gap junctions allow action potentials to spread rapidly from one cell to another and allows
the myocardium to act as a functional syncytium.
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Cardiac pacemaker
Cardiac myocyte contraction is not dependent on an external nerve supply but instead the heart generates its own
rhythm, demonstrating inherent rhythmicity.
The heartbeat is initiated by spontaneous depolarisation of the sinoatrial node (SAN), a region of specialised
myocytes in the right atrium, close to the coronary sinus. The rate is modulated by the autonomic nervous system.
Action potentials in the SAN activate adjacent atrial myocytes and a wave of depolarisation and contraction
therefore spreads through atrial muscle. This is prevented from reaching the ventricles directly by the annulus
fibrosis.
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This impulse is channelled through the atrioventricular node (AVN), located between the right atrium and ventricle
near the atrial septum. The AVN contains small cells and thus conducts slowly and delays the impulse for about 120
ms, allowing time for atrial contraction to complete ventricular filling.
Once complete, the impulse is then transmitted by specialised, wide, fast conducting myocytes in the bundle of His
and Purkinje fibres, by which it is distributed over the inner surface of both ventricles. From here a wave of
depolarisation and contraction moves from myocyte to myocyte across the endocardium until the whole ventricular
mass is activated.
Electrocardiogram (ECG)
The wave of depolarisation through the heart causes local currents in surrounding fluid which are detected at the
body surface as small changes in voltage. This forms the basis of the ECG. The classical ECG records voltage
between the left and right arm (lead I), the right arm and left leg (lead II) and the left arm and left leg (lead III).
This is represented by Einthoven’s triangle. The size of the voltage at any time depends on the quantity of muscle
depolarisation and the direction in which the wave of depolarisation is travelling. Thus lead II normally shows the
largest deflection during ventricular depolarisation, as the muscle mass is greatest and depolarisation travels from
apex to base, more or less parallel to a line from the left hip to the right shoulder.
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By Npatchett (Own work) [CC BY-SA 4.0 (], via Wikimedia Commons
a) Na+ influx
b) K+ influx
c) Ca2+ influx
d) K+ efflux
e) Ca2+ efflux
Something wrong?
Answer
The resting potential of ventricular myocytes is about -90 mV. An action potential (AP) is initiated when the
myocyte is depolarised to a threshold potential of about -65 mV, as a result of transmission from an adjacent
+ +
myocyte via gap junctions. Fast voltage-gated Na channels are activated and a Na influx depolarises the
membrane rapidly to about
+30 mV. This initial depolarisation is similar to that in nerve and skeletal muscle, and assists the transmission to
the next myocyte.
Notes
Cardiac myocyte action potential
The resting potential of ventricular myocytes is about -90 mV. An action potential (AP) is initiated when the
myocyte is depolarised to a threshold potential of about -65 mV, as a result of transmission from an adjacent
myocyte via gap junctions.
Depolarisation:
+ +
Fast voltage-gated Na channels are activated and a Na influx depolarises the membrane rapidly to about +30
mV. This initial depolarisation is similar to that in nerve and skeletal muscle, and assists the transmission to the
next myocyte.
+
Na channels and currents rapidly inactivate, but in cardiac myocytes, the initial depolarisation activates voltage-
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2+ 2+
gated Ca channels (slow L-type channels, threshold approximately – 45 mV) through which Ca floods into the
cell. The
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2+
resulting influx of Ca prevents the cell from repolarising and causes a plateau phase, that is maintained for about
250 ms until the L-type channels inactivate. The cardiac AP is thus much longer than that in nerve or skeletal
muscle.
Repolarisation:
+ +
Repolarisation occurs due to activation of voltage-gated K rectifier channels and a K efflux. As the AP lasts
almost as long as contraction, its refractory period prevents another AP being initiated until the muscle relaxes,
thus cardiac muscle cannot exhibit tetanus.
Image modified by FRCEM Success. [CC-BY-SA-3.0 (or GFDL (], via Wikimedia Commons
Atrial myocytes have a similar but more triangular AP compared to the ventricles (less plateau). Purkinje fibres in
the conduction system are also similar to ventricular myocytes, but have a spike at the peak of the upstroke
+
reflecting a larger Na current that contributes to their fast conduction velocity.
a) Na+
b) K+
c) Ca2+
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d) Mg2+
e) Cl-
Something wrong?
Answer
2+ 2+
Contractility of myocardial cells depends on the intracellular [Ca ], which is regulated by Ca entry across the
2+
cell membrane during the plateau of the action potential and by Ca uptake into and release from the
sarcoplasmic reticulum (SR).
Notes
2+
Cardiac muscle contracts when intracellular Ca rises (> 100
2+
Although Ca entry during the action potential (AP) is essential for contraction, it only accounts for about 25% of the
2+ 2+
rise in intracellular Ca . The rest is released from Ca stores in the sarcoplasmic reticulum (SR).
APs travel down invaginations of the sarcolemma called T-tubules, which are close to, but do not touch, the
2+ 2+ 2+
terminal cisternae of the SR. During the AP plateau, Ca enters the cell and activates Ca sensitive Ca release
2+ 2+
channels in the sarcoplasmic reticulum allowing stored Ca to flood into the cytosol; this is called Ca -induced
2+ 2+ 2+
Ca release. The amount of Ca released is dependent on how much is stored, and on the size of the initial Ca
influx during the AP.
2+ 2+
In relaxation, about 80% of Ca is rapidly pumped back into the SR (sequestered) by Ca ATPase pumps. The
2+ + 2+
Ca that entered the cell during the AP is transported out of the cell primarily by the Na /Ca exchanger in the
membrane
2+ + +
which pumps one Ca ion out in exchange for three Na ions in, using the Na electrochemical gradient as an
energy source. This is relatively slow and continues during diastole.
2+
Treppe effect: When more action potentials occur per unit time, more Ca enters the cell during the AP plateau,
2+ 2+ 2+
more Ca is stored in the SR, more Ca is released from the SR and thus more Ca is left inside the cell and
greater tension is produced during contraction. Increased heart rate increases the force of contraction in a
stepwise fashion as
2+
intracellular [Ca ] increases cumulatively over several beats.
Inotropic agents
2+
Factors that affect intracellular [Ca ] and hence cardiac contractility are called inotropes.
2+ +
Cardiac glycosides (e.g. digoxin) slow the removal of Ca from the cell by inhibiting the membrane Na pump which
+ 2+ 2+
generates the Na gradient required for driving the export of Ca ; consequently the removal of Ca from the
2+
myocyte is slowed and more Ca is available for the next contraction.
+ 2+
Acidosis is negatively inotropic, largely because H competes for Ca binding sites.
Answer
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Thromboxane A2 Prostacyclin
Angiotensin II Beta-agonists
Notes
The endothelium
The endothelium plays a vital role in regulation of vascular tone (as well as regulation of haemostasis, angiogenesis and
inflammatory response).
In response to substances in the blood, endothelial damage or changes in blood flow, it can synthesise several
important substances; nitric oxide and prostacyclin are important vasodilators and endothelin-1 and thromboxane
A2 are potent vasoconstrictors.
2+
Nitric oxide (NO) production by the endothelium is increased by factors that elevate intracellular Ca , including
local mediators such as bradykinin, histamine and serotonin, and some neurotransmitters (e.g. substance P). Increased
flow (shear stress) also stimulates NO production and additionally activates prostacyclin synthesis. The basal
production of NO continuously modulates vascular resistance. Nitric oxide also inhibits platelet activation and
thrombosis.
Endothelin-1 (ET-1) is an extremely potent vasoconstrictor peptide which is released from the endothelium in the
presence of many other vasoconstrictors, including angiotensin II, antidiuretic hormone (ADH) and noradrenaline,
and may be increased in disease and hypoxia.
The eicosanoids prostacyclin (PGI2) and thromboxane A2 (TXA2) are synthesised by the cyclooxygenase pathway from
arachidonic acid, which is made from membrane phospholipids by phospholipase A2.
Vasoconstriction
2+
Most vasoconstrictors bind to G-protein coupled receptors which mediate elevation in intracellular [Ca ], leading
to vascular smooth muscle contraction. Important vasoconstrictors include endothelin-1, angiotensin II and
noradrenaline.
2+ 2+
The increase in intracellular [Ca ] is brought about by release of Ca from the sarcoplasmic reticulum and by
2+ 2+
depolarisation and entry of Ca via L-type voltage-gated Ca channels. Most types of vascular smooth muscle do not
2+
generate action potentials, but instead depolarisation is graded, allowing graded entry of Ca .
Vasodilation
2+ 2+
Vasodilation occurs by decreasing intracellular [Ca ] by sequestration by the sarcoplasmic reticulum Ca
2+ + 2+
ATPase and by removal from the cell by a plasma membrane Ca ATPase and Na /Ca exchange.
Most endogenous vasodilators cause relaxation by increasing cyclic guanosine monophosphate (cGMP) (e.g. nitric
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oxide) or cyclic adenosine monophosphate (cAMP) (e.g. prostacyclin, beta-adrenergic receptor agonists), which
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2+
activate protein kinases causing substrate level phosphorylation. L-type Ca channel blocker drugs are clinically
effective vasodilators.
Thromboxane A2 Prostacyclin
Angiotensin II Beta-agonists
a) Mitochondria
b) Smooth endoplasmic reticulum
c) Golgi body
d) Rough endoplasmic reticulum
e) Sarcoplasmic reticulum
Something wrong?
Answer
2+
Although Ca entry during the action potential (AP) is essential for contraction, it only accounts for about 25% of
2+ 2+
the rise in intracellular Ca . The rest is released from Ca stores in the sarcoplasmic reticulum (SR). APs travel
down invaginations of the sarcolemma called T-tubules, which are close to, but do not touch, the terminal cisternae
of the SR.
2+ 2+ 2+
During the AP plateau, Ca enters the cell and activates Ca sensitive Ca release channels in the sarcoplasmic
2+ 2+ 2+
reticulum allowing stored Ca to flood into the cytosol; this is called Ca -induced Ca release. The amount of
2+ 2+
Ca released is dependent on how much is stored, and on the size of the initial Ca influx during the AP.
Notes
2+
Cardiac muscle contracts when intracellular Ca rises (> 100
2+
Although Ca entry during the action potential (AP) is essential for contraction, it only accounts for about 25% of the
2+ 2+
rise in intracellular Ca . The rest is released from Ca stores in the sarcoplasmic reticulum (SR).
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APs travel down invaginations of the sarcolemma called T-tubules, which are close to, but do not touch, the terminal
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2+ 2+ 2+
cisternae of the SR. During the AP plateau, Ca enters the cell and activates Ca sensitive Ca release channels
2+ 2+ 2+
in the sarcoplasmic reticulum allowing stored Ca to flood into the cytosol; this is called Ca -induced Ca
2+ 2+
release. The amount of Ca released is dependent on how much is stored, and on the size of the initial Ca
influx during the AP.
2+ 2+
In relaxation, about 80% of Ca is rapidly pumped back into the SR (sequestered) by Ca ATPase pumps. The
2+ + 2+
Ca that entered the cell during the AP is transported out of the cell primarily by the Na /Ca exchanger in the
membrane
2+ + +
which pumps one Ca ion out in exchange for three Na ions in, using the Na electrochemical gradient as an
energy source. This is relatively slow and continues during diastole.
2+
Treppe effect: When more action potentials occur per unit time, more Ca enters the cell during the AP plateau,
2+ 2+ 2+
more Ca is stored in the SR, more Ca is released from the SR and thus more Ca is left inside the cell and
greater tension is produced during contraction. Increased heart rate increases the force of contraction in a
stepwise fashion as
2+
intracellular [Ca ] increases cumulatively over several beats.
Inotropic agents
2+
Factors that affect intracellular [Ca ] and hence cardiac contractility are called inotropes.
2+ +
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Cardiac glycosides (e.g. digoxin) slow the removal of Ca from the cell by inhibiting the membrane Na pump
+ 2+ 2+
which generates the Na gradient required for driving the export of Ca ; consequently the removal of Ca
2+
from the myocyte is slowed and more Ca is available for the next contraction.
+ 2+
Acidosis is negatively inotropic, largely because H competes for Ca binding sites.
Answer
Diastole is usually twice the length of systole at rest, but decreases with increased heart rate. During systole,
contraction of the ventricles compresses the coronary arteries and suppresses blood flow. This is particularly evident
in the left ventricle, where during systole the ventricular pressure is the same as or greater than that in the arteries
and as a result more than 85% of left ventricular perfusion occurs during diastole. This becomes a problem if the
heart rate is increased as the diastolic interval is shorter and can result in ischaemia. The second heart sound,
caused by closure of the semilunar valves, marks the end of systole.
Notes
The cardiac cycle describes the events that occur during one beat of the heart.
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At the start of the cardiac cycle, towards the end of diastole, the whole of the heart is relaxed. The atrioventricular
(AV) valves are open because the atrial pressure is still slightly greater than the ventricular pressure. The semilunar
valves are closed, as the pressure in the pulmonary artery and aorta is greater than the ventricular pressures. The
cycle starts when the sinoatrial node (SAN) initiates atrial systole.
Atrial depolarisation causes the P wave on the ECG and initiates atrial contraction (atrial repolarisation is too
diffuse to be seen on the ECG).
As the atria contract, the atrial pressure increases which forces more blood flow across the open AV valves, leading
to rapid flow of blood into the ventricles. There are no valves between the veins and atria and atrial systole causes
a small pressure rise in the great veins (the a wave on the JVP waveform).
At rest, atrial contraction only contributes the last 15 – 20% of the final ventricular volume, as most of the
ventricular filling has occurred passively in diastole due to venous pressure. The proportion of atrial contribution
increases with heart rate as diastole shortens and there is less time for passive ventricular filling.
The end-diastolic volume (EDV) is usually about 120 – 140 mL, and the end-diastolic pressure is less than 10
mmHg (and higher in the left ventricle than the right due to the thicker and therefore stiffer left ventricle).
In ventricular hypertrophy, filling of the ‘stiff’ ventricle by atrial systole causes a fourth heart sound, which is not
audible in normal adults.
Ventricular depolarisation causes the QRS complex on the ECG, and triggers excitation-contraction coupling and
myocyte contraction.
The ventricular pressure rises sharply during contraction and the AV valves close as soon as this is greater than
the atrial pressure (causing the first heart sound). Because the mitral valve closes before the tricuspid valve, the first
heart sound may be split.
For a short period, as the forces are developing, both the AV and the semilunar valves are closed as the ventricular
pressure is still less than that in the pulmonary artery and aorta, and no ejection occurs. This is isovolumetric
contraction.
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The increasing pressure makes the AV valves bulge into the atria, causing a small atrial pressure wave (the c wave of
the JVP waveform).
When the ventricular pressure exceeds that in the pulmonary artery and the aorta, the semilunar valves open and
blood is ejected, initially rapidly (rapid ejection phase) and then more slowly (reduced ejection phase).
Atrial pressure initially decreases as the atrial base is pulled downward during ejection, expanding the atrial chamber
(the x descent of the JVP waveform). Atrial filling begins in the rapid ejection phase and continues during the
reduced ejection phase and atrial pressure begins to rise (the v wave of the JVP waveform).
During the second half of ejection, the ventricles stop actively contracting, the ventricular pressure starts to
decrease and the muscle starts to repolarise; this causes the T wave on the ECG, which marks the end of both
ventricular contraction and rapid ventricular ejection.
The ventricular pressure during the reduced ejection phase begins to decrease. Aortic pressure also decreases
because of the runoff of blood from large arteries into smaller arteries. The ventricular pressure falls slightly
below that in the aorta, but initially blood continues to flow out of the ventricle because of momentum;
eventually the ventricular pressure falls sufficiently and the semilunar valves close.
Closure of the semilunar valves causes a small increase in aortic pressure (the dicrotic notch on the arterial
waveform), and the second heart sound. Inspiration delays closure of the pulmonary valve and thus causes splitting of
the second heart sound.
The amount of blood ejected is the stroke volume (SV), and is usually about 70 mL (therefore about 50 mL is left;
this is the end-systolic volume). The proportion of EDV that is ejected (i.e. the SV/EDV) is the ejection fraction and
this is normally about 0.6.
Immediately after the closure of the semilunar valves, the ventricles rapidly relax and ventricular pressure
decreases rapidly but the AV valves remain closed as initially the ventricular pressure is still greater than atrial
pressure. This is isovolumetric relaxation.
Atrial pressure continues to rise because of venous return, with the v wave of the JVP waveform peaking during
this phase. As the ventricles continue to relax, the ventricular pressure falls below that of the atrial pressure and
the AV valves open.
When the AV valves open, the atrial pressure falls (the y descent of the JVP waveform) and the ventricles refill,
initially rapidly (the rapid filling phase) and then more slowly as the ventricles expand, become less complicant, and
ventricular pressures rise (the reduced filling phase). Rapid flow of blood from the atria into the ventricles causes
the third heart sound, which is normal in children but, in adults, is associated with disease such as ventricular
dilation.
Diastole is usually twice the length of systole at rest, but decreases with increased heart rate. During systole,
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contraction of the ventricles compresses the coronary arteries and suppresses blood flow. This is particularly
evident
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in the left ventricle, where during systole the ventricular pressure is the same as or greater than that in the arteries
and as a result more than 85% of left ventricular perfusion occurs during diastole. This becomes a problem if the
heart rate is increased as the diastolic interval is shorter and can result in ischaemia.
Atrial systole Open (atrial pressure > ventricular Closed (arterial pressure > ventricular
pressure) pressure)
Isovolumetric Closed (ventricular pressure > atrial Closed (arterial pressure > ventricular
contraction pressure) pressure)
Ventricular ejection Closed (ventricular pressure > atrial Open (ventricular pressure > arterial
pressure) pressure)
Isovolumetric Closed (ventricular pressure > atrial Closed (arterial pressure > ventricular
relaxation pressure) pressure)
Ventricular filling Open (atrial pressure > ventricular Closed (arterial pressure > ventricular
pressure) pressure)
c wave Isovolumetric Occurs due to the bulging of the tricuspid valve into the right atrium
contraction during right isovolumetric ventricular contraction
(early systole)
x descent Rapid ventricular Occurs due to a combination of right atrial relaxation, the downward
ejection (mid systole) displacement of the tricuspid valve during right ventricular contraction,
and the ejection of blood from both the ventricles
v wave Ventricular ejection Occurs due to right atrial filling from venous return
and isovolumetric
relaxation (late
systole)
y descent Ventricular filling Occurs due to opening of the tricuspid valve and the subsequent rapid
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(early diastole) inflow of blood from the right atrium to the right ventricle
First Start of systole Caused by closure of the atrioventricular (mitral & tricuspid) valves
heart
sound
Second heart End of systole Caused by closure of the semilunar (aortic and pulmonary) valves
sound
Third heart Early diastole Caused by rapid flow of blood from the atria into the ventricles during the
sound ventricular filling phase
Fourth heart Late diastole Caused by filling of an abnormally stiff ventricle in atrial systole
sound
ECG Event
a)
A decrease in mean arterial pressure is detected by the baroreceptors resulting in increased firing of afferent
sympathetic nerves.
b) Afferent nerves travel from the baroreceptors in the carotid sinus via the vagus nerve.
c) Sympathetic activity decreases total peripheral resistance.
d) The baroreceptors leads to venoconstriction which increases the central venous pressure.
e) The baroreceptor reflex leads to increased parasympathetic nerve activity.
Something wrong?
Answer
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Arterial baroreceptors are located in the carotid sinus and aortic arch, and detect the mean arterial pressure (MAP).
A decrease in MAP (such as in postural hypotension, or haemorrhage) reduces arterial stretch and decreases
baroreceptor activity, resulting in decreased firing in afferent nerves travelling via the glossopharyngeal nerve
(carotid sinus) and vagus nerve (aortic arch) to the medulla where the activity of the autonomic nervous system is
coordinated. Sympathetic nerve activity consequently increases, causing an increase in heart rate and cardiac
contractility, peripheral vasoconstriction with an increase in TPR, and venoconstriction with an increase in CVP and
thus an increase in cardiac output and blood pressure. Parasympathetic activity (vagal tone) decreases,
contributing to the rise in heart rate.
Notes
Mean arterial pressure (MAP) = Cardiac output (CO) x Total peripheral resistance (TPR).
Cardiac output is itself dependent on the central venous pressure (CVP), which in turn is highly dependent on the
blood volume. Alterations of any of these variables may change MAP.
Postural hypotension
On standing from a prone position, gravity causes blood to pool in veins in the legs. Central venous pressure (CVP)
falls, causing a fall in stroke volume and cardiac output (due to Starling’s law) and thus a fall in blood pressure.
Normally this fall in BP is rapidly corrected by the baroreceptor reflex which causes venoconstriction (partially
restoring CVP), and an increase in heart rate and contractility, so restoring cardiac output and blood pressure.
Impaired autonomic nervous activity in the elderly accounts for the greater likelihood of postural hypotension. Any
symptoms of dizziness, blurred vision or syncope is due to a transient fall in cerebral perfusion that occurs before
cardiac output and MAP can be corrected.
Baroreceptor reflex
Arterial baroreceptors are located in the carotid sinus and aortic arch, and detect the mean arterial pressure (MAP).
A decrease in MAP (such as in postural hypotension, or haemorrhage) reduces arterial stretch and decreases
baroreceptor activity, resulting in decreased firing in afferent nerves travelling via the glossopharyngeal nerve
(carotid sinus) and vagus nerve (aortic arch) to the medulla where the activity of the autonomic nervous system is
coordinated.
Sympathetic nerve activity consequently increases, causing an increase in heart rate and cardiac contractility,
peripheral vasoconstriction with an increase in TPR, and venoconstriction with an increase in CVP and thus an
increase in cardiac output and blood pressure. Parasympathetic activity (vagal tone) decreases, contributing to the
rise in heart rate. MAP therefore returns to normal. An increase in MAP has the opposite effect.
The baroreceptors are most sensitive between 80 and 150 mmHg and their sensitivity is increased by a large pulse
pressure. They also show adaptation; if a new pressure is maintained for a few hours, activity slowly moves
towards normal. The baroreceptor reflex is important for buffering short-term changes in MAP e.g. with postural
changes, or when muscle blood flow increases rapidly in exercise.
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A patient has a cardiac output of 4.8 L/min and a heart rate of 80 bpm, what is their
stroke volume:
a) 40 mL
b) 56 mL
c) 60 mL
d) 70 mL
e) 80 mL
Something wrong?
Answer
Cardiac output (CO) = Stroke volume (SV) x Heart rate (HR). Therefore SV = CO/HR = 4.8/80 = 0.06 L = 60 mL.
Notes
Total blood volume, cardiac output and stroke volume
The total blood volume in the circulatory system of a healthy adult is about 5 L.
The stroke volume is the volume of blood ejected per beat. It is usually about 70 mL/beat at
rest. The heart rate is the number of beats per minute. It is usually about 70 beats/minute
at rest.
The cardiac output is the volume of blood pumped out of heart via the aorta per minute.
Cardiac output (CO) = Stroke volume x Heart rate = 70 mL/beat x 70 beats/min = 4900
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mL/min
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During systole, the pressure in the left ventricle increases and blood is ejected into the aorta. The rise in pressure
stretches the elastic walls of the aorta and large arteries and drives blood flow. Systolic pressure is the maximum
arterial pressure during systole. During diastole, arterial blood flow is partly maintained by elastic recoil of the walls
of large arteries. The minimum pressure reached before the next systole is the diastolic pressure. The difference
between the systolic and diastolic pressure is the pulse pressure.
The mean arterial pressure (MAP) cannot be calculated by averaging these pressures, because for about 60% of
the time, the heart is in diastole. It is instead estimated as the diastolic + one-third of the pulse pressure, e.g. = 80
+ 1/3(110 – 80) = 90 mmHg where BP 110/80 mmHg.
The mean arterial pressure (MAP) at the start of the arterioles is about 65 mmHg. The pressure on the arterial side
of capillaries is about 25 mmHg, and on the venous side is about 15 mmHg. Venules converge into veins and finally
the vena cava. The pressure in the vena cava at the level of the heart (the central venous pressure) is usually close
to 0 mmHg.
a)
Stiffer arteries in atherosclerosis are better at damping out oscillations in pressure produced by pumping of the
heart.
b) Large arteries contain relatively more smooth muscle compared to smaller arterioles.
c) Veins have a smaller diameter than equivalent arteries.
d) Veins contain about 70% of the total blood volume at any one time.
e) Capillaries contain one-way valves to prevent backflow of blood.
Something wrong?
Answer
Veins have a larger diameter than equivalent arteries and provide less resistance. They have thin distensible walls
and contain about 70% of the total blood volume at any one time. Veins, not capillaries have unidirectional valves
to prevent backflow of blood. Large arteries are elastic and partially damp out oscillations in pressure produced by
pumping of the heart; stiff arteries (e.g. age, atherosclerosis) result in larger oscillations. Smaller arteries and
arterioles contain relatively more muscle and are resistance vessels, responsible for controlling tissue blood flow
through constriction.
Notes
The vascular system consists of arteries and arterioles that take blood from the heart to the tissues, thin-walled
capillaries and postcapillary venules that allow the diffusion of gases and metabolites, and venules and veins that
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return blood to the heart. The blood pressure, vessel diameter and wall thickness vary throughout the circulation.
Varying amounts of smooth muscle are contained within the vessel walls, allowing them to constrict and alter their
resistance to flow.
Large arteries are elastic and partially damp out oscillations in pressure produced by pumping of the heart; stiff
arteries (e.g. age, atherosclerosis) result in larger oscillations. The major arteries are conductance vessels and divide
repeatedly into smaller muscular arterioles. Smaller arteries and arterioles contain relatively more muscle and are
resistance vessels, responsible for controlling tissue blood flow through constriction.
The arterioles divide into dense networks of capillaries and these rejoin into small and then larger venules.
Capillaries and small venules are exchange vessels which have no smooth muscle or valves and which provide the
exchange surface between blood and tissues.
Veins
Veins have a larger diameter than equivalent arteries and provide less resistance. They have thin distensible walls
and contain about 70% of the total blood volume at any one time. Large veins are capacitance vessels and act as a
blood volume reservoir; when required they can constrict and increase the effective blood volume. Large veins in
the limbs contain one-way valves, and when muscle activity intermittently compresses these veins, they act as a
pump and assist venous return to the heart.
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Commons
The tendency for oedema to occur will be increased by which of the following:
a) Arteriolar constriction
b) Increased venous pressure
c) Venodilation
d) Muscular activity
e) Increased plasma protein concentration
Something wrong?
Answer
Oedema occurs when more fluid is filtered out of the capillaries than can be returned to the circulation by the
lymphatics. Filtration is increased by changes that increase capillary hydrostatic pressure or decrease plasma
oncotic pressure. Arteriolar constriction will reduce hydrostatic capillary pressure and transiently increase
absorption of fluid. Dehydration would increase plasma protein concentration and therefore increase plasma
oncotic pressure and absorption. Increased venous pressure would increase capillary hydrostatic pressure and
filtration.
Notes
Lymphatics
Normally, filtration of fluid out of the capillaries is slightly greater than absorption of fluid into the capillaries.
Fluid filtered by the microcirculation (about 8 L per day) is returned to the circulation by the lymphatic system.
Lymphatic capillaries are blind-ended tubes walled with endothelial cells which allow the entry of fluid, protein
and bacteria, but prevent their exit. Lymphatic capillaries drain into collecting lymphatics and then into larger
lymphatic vessels, both containing smooth muscle and unidirectional valves.
From here, lymph is propelled by smooth muscle constriction and compression of the vessels by body movements
into afferent lymphatics and then the lymph nodes, where bacteria and other foreign materials are removed by
phagocytes. Most fluid is reabsorbed here by capillaries, with the remainder returning via efferent lymphatics and
the thoracic duct into the subclavian veins.
The lymphatic system plays a major role in the body’s immune defence and is also important for absorption and
transport of fats.
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Oedema
Oedema is swelling of the tissues due to excess fluid in the interstitial space overwhelming the lymphatic system or
due to obstruction or dysfunction of the lymphatic system.
A reduction in plasma protein e.g. in starvation or a loss of endothelial integrity e.g. in inflammation or ischaemia
will reduce the oncotic pressure gradient and enhance filtration and loss of fluid into the tissues. An increase in
venous pressure e.g. in congestive heart failure or venous insufficiency will increase capillary hydrostatic pressure
with a similar effect.
Increased capillary Caused by increased venous pressures e.g. by gravitational forces, volume expanded
hydrostatic states, in heart failure or with venous obstruction
pressure
Decreased Caused by decreased protein concentration in blood e.g. nephrotic syndrome, protein
plasma oncotic malnutrition, liver failure
pressure
Lymphatic Caused by, for example, filariasis or following lymph node dissection, surgery or radiation
obstruction therapy
A patient’s ECG has no P wave, but has a normal QRS complex and normal T wave. Therefore,
his pacemaker must be located in:
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a) Sinoatrial node
b) Atrioventricular node
c) Bundle of His
d) Purkinje fibres
e) Ventricular muscle
Something wrong?
Answer
The absent P wave indicates that the atrium is not depolarising and, therefore, the pacemaker cannot be in the
sinoatrial (SA) node. Because the QRS and T waves are normal, depolarisation and repolarisation of the ventricle
must be proceeding in the normal sequence. This situation can occur if the pacemaker is located in the
atrioventricular (AV) node. If the pacemaker were located in the bundle of His or in the Purkinje system, the
ventricles would activate in an abnormal sequence (depending on the exact location of the pacemaker) and the
QRS wave would be abnormal.
Notes
Myocytes
The myocardium is composed of cardiac muscle cells called myocytes. The cells are striated due to the
arrangement of the thick and thin filaments which make up the bulk of the muscle, although they are less
organised than in skeletal muscle. The myocytes are small and branched, with a single nucleus and are rich in
mitochondria. The normal pumping action of the heart is dependent on the synchronised contraction of all cardiac
cells.
Intercalated discs
The synchronicity between myocytes occurs because all the adjacent cells are connected by intercalated discs. The
intercalated discs provide both a structural attachment by ‘glueing’ cells together at desmosomes and an electrical
contact made up of proteins called connexons, called a gap junction, which essentially creates a low-resistance
pathway between cells. Gap junctions allow action potentials to spread rapidly from one cell to another and allows
the myocardium to act as a functional syncytium.
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Cardiac pacemaker
Cardiac myocyte contraction is not dependent on an external nerve supply but instead the heart generates its own
rhythm, demonstrating inherent rhythmicity.
The heartbeat is initiated by spontaneous depolarisation of the sinoatrial node (SAN), a region of specialised
myocytes in the right atrium, close to the coronary sinus. The rate is modulated by the autonomic nervous system.
Action potentials in the SAN activate adjacent atrial myocytes and a wave of depolarisation and contraction
therefore spreads through atrial muscle. This is prevented from reaching the ventricles directly by the annulus
fibrosis.
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By OpenStax College [CC BY 3.0 (], via Wikimedia Commons
This impulse is channelled through the atrioventricular node (AVN), located between the right atrium and ventricle
near the atrial septum. The AVN contains small cells and thus conducts slowly and delays the impulse for about 120
ms, allowing time for atrial contraction to complete ventricular filling.
Once complete, the impulse is then transmitted by specialised, wide, fast conducting myocytes in the bundle of His
and Purkinje fibres, by which it is distributed over the inner surface of both ventricles. From here a wave of
depolarisation and contraction moves from myocyte to myocyte across the endocardium until the whole ventricular
mass is activated.
Electrocardiogram (ECG)
The wave of depolarisation through the heart causes local currents in surrounding fluid which are detected at the
body surface as small changes in voltage. This forms the basis of the ECG. The classical ECG records voltage
between the left and right arm (lead I), the right arm and left leg (lead II) and the left arm and left leg (lead III).
This is represented by Einthoven’s triangle. The size of the voltage at any time depends on the quantity of muscle
depolarisation and the direction in which the wave of depolarisation is travelling. Thus lead II normally shows the
largest deflection during ventricular depolarisation, as the muscle mass is greatest and depolarisation travels from
apex to base, more or less parallel to a line from the left hip to the right shoulder.
By Npatchett (Own work) [CC BY-SA 4.0 (], via Wikimedia Commons
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a) Na+ influx
b) Ca2+ efflux
c) K+ influx
d) K+ efflux
e) Ca2+ influx
Something wrong?
Answer
2+
Although Ca entry during the action potential (AP) is essential for contraction, it only accounts for about 25% of
2+ 2+
the rise in intracellular Ca . The rest is released from Ca stores in the sarcoplasmic reticulum (SR). APs travel
down invaginations of the sarcolemma called T-tubules, which are close to, but do not touch, the terminal cisternae
of the SR.
2+ 2+ 2+
During the AP plateau, Ca enters the cell and activates Ca sensitive Ca release channels in the sarcoplasmic
2+ 2+ 2+
reticulum allowing stored Ca to flood into the cytosol; this is called Ca -induced Ca release. The amount of
2+ 2+
Ca released is dependent on how much is stored, and on the size of the initial Ca influx during the AP.
Notes
2+
Cardiac muscle contracts when intracellular Ca rises (> 100
2+
Although Ca entry during the action potential (AP) is essential for contraction, it only accounts for about 25% of the
2+ 2+
rise in intracellular Ca . The rest is released from Ca stores in the sarcoplasmic reticulum (SR).
APs travel down invaginations of the sarcolemma called T-tubules, which are close to, but do not touch, the
2+ 2+ 2+
terminal cisternae of the SR. During the AP plateau, Ca enters the cell and activates Ca sensitive Ca release
2+ 2+
channels in the sarcoplasmic reticulum allowing stored Ca to flood into the cytosol; this is called Ca -induced
2+ 2+ 2+
Ca release. The amount of Ca released is dependent on how much is stored, and on the size of the initial Ca
influx during the AP.
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2+ 2+
In relaxation, about 80% of Ca is rapidly pumped back into the SR (sequestered) by Ca ATPase pumps. The
2+ + 2+
Ca that entered the cell during the AP is transported out of the cell primarily by the Na /Ca exchanger in the
membrane
2+ + +
which pumps one Ca ion out in exchange for three Na ions in, using the Na electrochemical gradient as an
energy source. This is relatively slow and continues during diastole.
2+
Treppe effect: When more action potentials occur per unit time, more Ca enters the cell during the AP plateau,
2+ 2+ 2+
more Ca is stored in the SR, more Ca is released from the SR and thus more Ca is left inside the cell and
greater tension is produced during contraction. Increased heart rate increases the force of contraction in a
stepwise fashion as
2+
intracellular [Ca ] increases cumulatively over several beats.
Inotropic agents
2+
Factors that affect intracellular [Ca ] and hence cardiac contractility are called inotropes.
2+ +
Cardiac glycosides (e.g. digoxin) slow the removal of Ca from the cell by inhibiting the membrane Na pump which
+ 2+ 2+
generates the Na gradient required for driving the export of Ca ; consequently the removal of Ca from the
2+
myocyte is slowed and more Ca is available for the next contraction.
+ 2+
Acidosis is negatively inotropic, largely because H competes for Ca binding sites.
a) The a wave
b) The c wave
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c) The v wave
d) The x descent
e) The y descent
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Something wrong?
Answer
c wave Isovolumetric Occurs due to the bulging of the tricuspid valve into the right atrium
contraction during right isovolumetric ventricular contraction
(early systole)
x descent Rapid ventricular Occurs due to a combination of right atrial relaxation, the downward
ejection (mid systole) displacement of the tricuspid valve during right ventricular contraction,
and the ejection of blood from both the ventricles
v wave Ventricular ejection Occurs due to right atrial filling from venous return
and isovolumetric
relaxation (late
systole)
y descent Ventricular filling Occurs due to opening of the tricuspid valve and the subsequent rapid
(early diastole) inflow of blood from the right atrium to the right ventricle
Notes
The cardiac cycle describes the events that occur during one beat of the heart.
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At the start of the cardiac cycle, towards the end of diastole, the whole of the heart is relaxed. The atrioventricular
(AV) valves are open because the atrial pressure is still slightly greater than the ventricular pressure. The semilunar
valves are closed, as the pressure in the pulmonary artery and aorta is greater than the ventricular pressures. The
cycle starts when the sinoatrial node (SAN) initiates atrial systole.
Atrial depolarisation causes the P wave on the ECG and initiates atrial contraction (atrial repolarisation is too
diffuse to be seen on the ECG).
As the atria contract, the atrial pressure increases which forces more blood flow across the open AV valves, leading
to rapid flow of blood into the ventricles. There are no valves between the veins and atria and atrial systole causes
a small pressure rise in the great veins (the a wave on the JVP waveform).
At rest, atrial contraction only contributes the last 15 – 20% of the final ventricular volume, as most of the
ventricular filling has occurred passively in diastole due to venous pressure. The proportion of atrial contribution
increases with heart rate as diastole shortens and there is less time for passive ventricular filling.
The end-diastolic volume (EDV) is usually about 120 – 140 mL, and the end-diastolic pressure is less than 10
mmHg (and higher in the left ventricle than the right due to the thicker and therefore stiffer left ventricle).
In ventricular hypertrophy, filling of the ‘stiff’ ventricle by atrial systole causes a fourth heart sound, which is not
audible in normal adults.
Ventricular depolarisation causes the QRS complex on the ECG, and triggers excitation-contraction coupling and
myocyte contraction.
The ventricular pressure rises sharply during contraction and the AV valves close as soon as this is greater than
the atrial pressure (causing the first heart sound). Because the mitral valve closes before the tricuspid valve, the first
heart sound may be split.
For a short period, as the forces are developing, both the AV and the semilunar valves are closed as the ventricular
pressure is still less than that in the pulmonary artery and aorta, and no ejection occurs. This is isovolumetric
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contraction.
The increasing pressure makes the AV valves bulge into the atria, causing a small atrial pressure wave (the c wave of
the JVP waveform).
When the ventricular pressure exceeds that in the pulmonary artery and the aorta, the semilunar valves open and
blood is ejected, initially rapidly (rapid ejection phase) and then more slowly (reduced ejection phase).
Atrial pressure initially decreases as the atrial base is pulled downward during ejection, expanding the atrial chamber
(the x descent of the JVP waveform). Atrial filling begins in the rapid ejection phase and continues during the
reduced ejection phase and atrial pressure begins to rise (the v wave of the JVP waveform).
During the second half of ejection, the ventricles stop actively contracting, the ventricular pressure starts to
decrease and the muscle starts to repolarise; this causes the T wave on the ECG, which marks the end of both
ventricular contraction and rapid ventricular ejection.
The ventricular pressure during the reduced ejection phase begins to decrease. Aortic pressure also decreases
because of the runoff of blood from large arteries into smaller arteries. The ventricular pressure falls slightly
below that in the aorta, but initially blood continues to flow out of the ventricle because of momentum;
eventually the ventricular pressure falls sufficiently and the semilunar valves close.
Closure of the semilunar valves causes a small increase in aortic pressure (the dicrotic notch on the arterial
waveform), and the second heart sound. Inspiration delays closure of the pulmonary valve and thus causes splitting of
the second heart sound.
The amount of blood ejected is the stroke volume (SV), and is usually about 70 mL (therefore about 50 mL is left;
this is the end-systolic volume). The proportion of EDV that is ejected (i.e. the SV/EDV) is the ejection fraction and
this is normally about 0.6.
Immediately after the closure of the semilunar valves, the ventricles rapidly relax and ventricular pressure
decreases rapidly but the AV valves remain closed as initially the ventricular pressure is still greater than atrial
pressure. This is isovolumetric relaxation.
Atrial pressure continues to rise because of venous return, with the v wave of the JVP waveform peaking during
this phase. As the ventricles continue to relax, the ventricular pressure falls below that of the atrial pressure and
the AV valves open.
When the AV valves open, the atrial pressure falls (the y descent of the JVP waveform) and the ventricles refill,
initially rapidly (the rapid filling phase) and then more slowly as the ventricles expand, become less complicant, and
ventricular pressures rise (the reduced filling phase). Rapid flow of blood from the atria into the ventricles causes
the third heart sound, which is normal in children but, in adults, is associated with disease such as ventricular
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dilation.
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Diastole is usually twice the length of systole at rest, but decreases with increased heart rate. During systole,
contraction of the ventricles compresses the coronary arteries and suppresses blood flow. This is particularly evident
in the left ventricle, where during systole the ventricular pressure is the same as or greater than that in the arteries
and as a result more than 85% of left ventricular perfusion occurs during diastole. This becomes a problem if the
heart rate is increased as the diastolic interval is shorter and can result in ischaemia.
Atrial systole Open (atrial pressure > ventricular Closed (arterial pressure > ventricular
pressure) pressure)
Isovolumetric Closed (ventricular pressure > atrial Closed (arterial pressure > ventricular
contraction pressure) pressure)
Ventricular ejection Closed (ventricular pressure > atrial Open (ventricular pressure > arterial
pressure) pressure)
Isovolumetric Closed (ventricular pressure > atrial Closed (arterial pressure > ventricular
relaxation pressure) pressure)
Ventricular filling Open (atrial pressure > ventricular Closed (arterial pressure > ventricular
pressure) pressure)
c wave Isovolumetric Occurs due to the bulging of the tricuspid valve into the right atrium
contraction during right isovolumetric ventricular contraction
(early systole)
x descent Rapid ventricular Occurs due to a combination of right atrial relaxation, the downward
ejection (mid systole) displacement of the tricuspid valve during right ventricular contraction,
and the ejection of blood from both the ventricles
v wave Ventricular ejection Occurs due to right atrial filling from venous return
and isovolumetric
relaxation (late
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systole)
y descent Ventricular filling Occurs due to opening of the tricuspid valve and the subsequent rapid
(early diastole) inflow of blood from the right atrium to the right ventricle
First Start of systole Caused by closure of the atrioventricular (mitral & tricuspid) valves
heart
sound
Second heart End of systole Caused by closure of the semilunar (aortic and pulmonary) valves
sound
Third heart Early diastole Caused by rapid flow of blood from the atria into the ventricles during the
sound ventricular filling phase
Fourth heart Late diastole Caused by filling of an abnormally stiff ventricle in atrial systole
sound
ECG Event
a) Blood flow through the skin is controlled by both sympathetic and parasympathetic nerve fibres.
b) The main function of the cutaneous circulation is contributing to total peripheral resistance.
c) Arteriovenous anastomoses are mostly found in the scalp and groin.
d) Cutaneous vessels are dilated by the baroreceptor reflex.
e)
When temperature is low, sympathetic stimulation of alpha-adrenergic receptors causes vasoconstriction of
cutaneous vessels.
Something wrong?
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Answer
The main function of the cutaneous circulation is thermoregulation. Arteriovenous anastomoses (AVAs) directly
linked arterioles and venules, allowing a high blood flow into the venous plexus and thus radiation of heat. AVAs
are mostly found in the hands, feet and areas of the face. Temperature is sensed by peripheral thermoreceptors
and the hypothalamus coordinates the response. When temperature is low, sympathetic stimulation of alpha-
adrenergic receptors causes vasoconstriction of cutaneous vessels minimising loss of body heat (a similar response
occurs in the baroreceptor reflex). Piloerection traps insulating air. Increased temperatures reduce sympathetic
adrenergic stimulation, causing vasodilation and allowing more blood to flow to the skin and radiate its heat to the
environment, whereas activation of sympathetic cholinergic fibres promotes sweating and the release of bradykinin,
which also causes vasodilation.
Notes
Skeletal muscle circulation
The skeletal muscle circulation normally receives about 15 – 20% of the cardiac output, but this may rise to > 80%
during exercise. Skeletal muscle provides a major contribution to the total peripheral resistance and sympathetic
regulation of muscle blood flow is important in the baroreceptor reflex. At rest most capillaries are not perfused as
their arterioles are constricted. Capillaries are recruited during exercise by metabolic hyperaemia, caused by release
of
+
K and CO2 from the muscle and adenosine. This overrides sympathetic vasoconstriction in working muscle; the latter
reduces flow in non-working muscle conserving cardiac output.
Pulmonary circulation
The pulmonary circulation is not controlled by either autonomic nerves or metabolic products, and the most
important mechanism regulating flow is hypoxic pulmonary vasoconstriction, in which small arteries constrict in
response to hypoxia (in contrast to elsewhere in the body).
If an area of lung is poorly ventilated and the alveolar partial pressure of oxygen is low, pulmonary blood vessels
are constricted and blood is diverted to areas of the lung that are better ventilated, thus maintaining optimal
ventilation- perfusion matching. This effect is accentuated by high alveolar PCO 2.
The response is unhelpful in the presence of global lung hypoxia, at altitude or in respiratory failure, where it may
contribute to the development of pulmonary hypertension and right-sided heart failure (cor pulmonale).
Cutaneous circulation
The main function of the cutaneous circulation is thermoregulation. Arteriovenous anastomoses (AVAs) directly
linked arterioles and venules, allowing a high blood flow into the venous plexus and thus radiation of heat. AVAs
are mostly found in the hands, feet and areas of the face.
Temperature is sensed by peripheral thermoreceptors and the hypothalamus coordinates the response.
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When temperature is low, sympathetic stimulation of alpha-adrenergic receptors causes vasoconstriction of
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cutaneous vessels minimising loss of body heat (a similar response occurs in the baroreceptor reflex).
Piloerection traps insulating air.
Increased temperatures reduce sympathetic adrenergic stimulation, causing vasodilation and allowing more blood
to flow to the skin and radiate its heat to the environment, whereas activation of sympathetic cholinergic fibres
promotes sweating and the release of bradykinin, which also causes vasodilation.
Cerebral circulation
The brain receives around 15% of the total cardiac output and has a high capillary density.
The endothelial cells of the capillaries of the blood-brain barrier have very tight junctions, and contain membrane
transporters that control the movement of substances, such as ions, glucose and amino acids, and tightly regulate
the composition of cerebrospinal fluid. This is continuous except where substances need to be absorbed or released
e.g. pituitary gland, choroid plexus.
The autoregulation of cerebral blood flow can maintain a constant flow for blood pressures between 50 and 170
+
mmHg. CO2 and K are particularly important metabolic regulators in the brain, with increasing concentration
causing vasodilation and a functional hyperaemia.
Hyperventilation reduces blood PCO2 and can cause fainting due to cerebral vasoconstriction.
Coronary circulation
The heart has a high metabolic demand and its high capillary density allow it to extract an unusually large fraction
(about 70%) of oxygen from the blood.
In exercise, the reduced diastolic interval and increased oxygen consumption demand a greatly increased blood
+
flow which is achieved by metabolic hyperaemia mediated by adenosine, K and hypoxia. This overrides the
vasoconstriction mediated by sympathetic nerves acting at alpha-adrenergic receptors and is assisted by circulating
adrenaline which causes vasodilation by acting on beta-adrenergic receptors.
a) +40 mV
b) -20 mV
c) -40 mV
d) -60 mV
e) -90 mV
Something wrong?
Answer
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The resting potential of the SAN is about – 60 mV, and it decays steadily with time until it reaches a threshold
potential of about – 40 mV, when an action potential is initiated.
Notes
Sinoatrial node action potential
The action potential (AP) of the sinoatrial node (SAN) differs from that in ventricular muscle.
The resting potential of the SAN is about – 60 mV, and it decays steadily with time until it reaches a threshold
potential of about – 40 mV, when an action potential is initiated.
+
The upstroke of the AP is slow, as it is not due to activation of fast Na channels like cardiac myocytes, but instead
2+ +
slow L-type Ca channels; the SA node contains no functional fast Na channels. The slow upstroke means that
conduction
between nodal myocytes is slow, which is particularly important at the atrioventricular node (which has a similar AP
to the SAN).
The rate of decay of the SAN resting potential determines the rate of AP and therefore of heart rate, it is therefore
+
called the pacemaker potential. The pacemaker potential decays because of a slowly reducing outward K current
set
against inward currents. Factors that affect these currents alter the rate of decay and the time to reach threshold
and thus heart rate and are called chronotropic agents.
Noradrenaline (the sympathetic neurotransmitter) is a positive chronotrope and causes a faster rate of decay and thus
heart rate whereas acetylcholine (the parasympathetic neurotransmitter) is a negative chronotrope and lengthens the
time to reach threshold and decreases heart rate.
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Other atrial cells, the AV node, the bundle of His and Purkinje system may also exhibit decaying resting potentials
that can act as pacemakers. However the SAN is normally fastest and predominates – this is called overdrive
suppression.
a) Blood-brain barrier
b) Renal glomeruli
c) Reticuloendothelial system
d) Skin
e) Lungs
Something wrong?
Answer
Fenestrated capillaries, found in renal glomeruli, endocrine glands and intestinal villi, are more permeable than
continuous capillaries with less tight junctions, and the endothelial cells are also punctured by pores which allow
large amounts of fluids or metabolites to pass.
Notes
Capillaries and the smallest venules are formed from a single layer of endothelial cells supported on the outside by
a basal lamina containing collagen. The luminal surface is covered by the glycoprotein network called the
glycocalyx.
Capillary permeability
Capillaries throughout the body vary in their permeability based on the size of their pores. There are three basic types:
Continuous capillaries, found in the skin, lungs, muscles and CNS, are the most selective with low permeability,
as junctions between the endothelial cells are very tight, restricting the flow of molecules with MW >
10,000. Fenestrated capillaries, found in renal glomeruli, endocrine glands and intestinal villi, are more
permeable with less tight junctions, and the endothelial cells are also punctured by pores which allow large
amounts of fluids or metabolites to pass.
Discontinuous capillaries, found in the reticuloendothelial system (bone marrow, liver and spleen), have large
gaps between endothelial cells and are permeable to red blood cells.
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Transcapillary exchange
Water, gases and other substances cross the capillary wall mainly by diffusion down their concentration gradients.
Non-polar lipophilic substances e.g. CO2 and O2 can cross the endothelial lipid bilayer membrane easily. The
membrane is however more impermeable to hydrophilic molecules such as glucose and polar molecules and ions.
Such substances mainly cross the wall of continuous capillaries through the gaps between endothelial cells, slowed
down by tight junctions between cells and by the glycocalyx so that diffusion is much slower than for lipophilic
substances.
This small pore system also prevents the diffusion of substances greater than 10,000 Da such as plasma proteins.
Plasma proteins can cross the capillary wall, but extremely slowly; this may involve large pores through endothelial
cells, such as in fenestrated capillaries or large spaces between endothelial cells, such as in discontinuous
capillaries.
In the ventricular ejection phase of the cardiac cycle, all of the following statements are
true EXCEPT for:
Answer
When the ventricular pressure exceeds that in the pulmonary artery and the aorta, the semilunar valves open
and blood is ejected, initially rapidly (rapid ejection phase) and then more slowly (reduced ejection phase). The AV
valves which closed at the beginning of isovolumetric contraction, remain closed in the ventricular ejection phase.
Atrial pressure initially decreases as the atrial base is pulled downward during ejection, expanding the atrial
chamber (the x descent of the JVP waveform). During the second half of ejection, the ventricles stop actively
contracting, the ventricular pressure starts to decrease and the muscle starts to repolarise; this causes the T wave on
the ECG, which marks the end of both ventricular contraction and rapid ventricular ejection.
Notes
The cardiac cycle describes the events that occur during one beat of the heart.
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At the start of the cardiac cycle, towards the end of diastole, the whole of the heart is relaxed. The atrioventricular
(AV) valves are open because the atrial pressure is still slightly greater than the ventricular pressure. The semilunar
valves are closed, as the pressure in the pulmonary artery and aorta is greater than the ventricular pressures. The
cycle starts when the sinoatrial node (SAN) initiates atrial systole.
Atrial depolarisation causes the P wave on the ECG and initiates atrial contraction (atrial repolarisation is too
diffuse to be seen on the ECG).
As the atria contract, the atrial pressure increases which forces more blood flow across the open AV valves, leading
to rapid flow of blood into the ventricles. There are no valves between the veins and atria and atrial systole causes
a small pressure rise in the great veins (the a wave on the JVP waveform).
At rest, atrial contraction only contributes the last 15 – 20% of the final ventricular volume, as most of the
ventricular filling has occurred passively in diastole due to venous pressure. The proportion of atrial contribution
increases with heart rate as diastole shortens and there is less time for passive ventricular filling.
The end-diastolic volume (EDV) is usually about 120 – 140 mL, and the end-diastolic pressure is less than 10
mmHg (and higher in the left ventricle than the right due to the thicker and therefore stiffer left ventricle).
In ventricular hypertrophy, filling of the ‘stiff’ ventricle by atrial systole causes a fourth heart sound, which is not
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audible in normal adults.
Ventricular depolarisation causes the QRS complex on the ECG, and triggers excitation-contraction coupling and
myocyte contraction.
The ventricular pressure rises sharply during contraction and the AV valves close as soon as this is greater than
the atrial pressure (causing the first heart sound). Because the mitral valve closes before the tricuspid valve, the first
heart sound may be split.
For a short period, as the forces are developing, both the AV and the semilunar valves are closed as the ventricular
pressure is still less than that in the pulmonary artery and aorta, and no ejection occurs. This is isovolumetric
contraction.
The increasing pressure makes the AV valves bulge into the atria, causing a small atrial pressure wave (the c wave of
the JVP waveform).
When the ventricular pressure exceeds that in the pulmonary artery and the aorta, the semilunar valves open and
blood is ejected, initially rapidly (rapid ejection phase) and then more slowly (reduced ejection phase).
Atrial pressure initially decreases as the atrial base is pulled downward during ejection, expanding the atrial chamber
(the x descent of the JVP waveform). Atrial filling begins in the rapid ejection phase and continues during the
reduced ejection phase and atrial pressure begins to rise (the v wave of the JVP waveform).
During the second half of ejection, the ventricles stop actively contracting, the ventricular pressure starts to
decrease and the muscle starts to repolarise; this causes the T wave on the ECG, which marks the end of both
ventricular contraction and rapid ventricular ejection.
The ventricular pressure during the reduced ejection phase begins to decrease. Aortic pressure also decreases
because of the runoff of blood from large arteries into smaller arteries. The ventricular pressure falls slightly
below that in the aorta, but initially blood continues to flow out of the ventricle because of momentum;
eventually the ventricular pressure falls sufficiently and the semilunar valves close.
Closure of the semilunar valves causes a small increase in aortic pressure (the dicrotic notch on the arterial
waveform), and the second heart sound. Inspiration delays closure of the pulmonary valve and thus causes splitting of
the second heart sound.
The amount of blood ejected is the stroke volume (SV), and is usually about 70 mL (therefore about 50 mL is left;
this is the end-systolic volume). The proportion of EDV that is ejected (i.e. the SV/EDV) is the ejection fraction and
this is normally about 0.6.
Immediately after the closure of the semilunar valves, the ventricles rapidly relax and ventricular pressure decreases
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rapidly but the AV valves remain closed as initially the ventricular pressure is still greater than atrial pressure.
This is isovolumetric relaxation.
Atrial pressure continues to rise because of venous return, with the v wave of the JVP waveform peaking during
this phase. As the ventricles continue to relax, the ventricular pressure falls below that of the atrial pressure and
the AV valves open.
When the AV valves open, the atrial pressure falls (the y descent of the JVP waveform) and the ventricles refill,
initially rapidly (the rapid filling phase) and then more slowly as the ventricles expand, become less complicant, and
ventricular pressures rise (the reduced filling phase). Rapid flow of blood from the atria into the ventricles causes
the third heart sound, which is normal in children but, in adults, is associated with disease such as ventricular
dilation.
Diastole is usually twice the length of systole at rest, but decreases with increased heart rate. During systole,
contraction of the ventricles compresses the coronary arteries and suppresses blood flow. This is particularly evident
in the left ventricle, where during systole the ventricular pressure is the same as or greater than that in the arteries
and as a result more than 85% of left ventricular perfusion occurs during diastole. This becomes a problem if the
heart rate is increased as the diastolic interval is shorter and can result in ischaemia.
Atrial systole Open (atrial pressure > ventricular Closed (arterial pressure > ventricular
pressure) pressure)
Isovolumetric Closed (ventricular pressure > atrial Closed (arterial pressure > ventricular
contraction pressure) pressure)
Ventricular ejection Closed (ventricular pressure > atrial Open (ventricular pressure > arterial
pressure) pressure)
Isovolumetric Closed (ventricular pressure > atrial Closed (arterial pressure > ventricular
relaxation pressure) pressure)
Ventricular filling Open (atrial pressure > ventricular Closed (arterial pressure > ventricular
pressure) pressure)
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diastole)
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c wave Isovolumetric Occurs due to the bulging of the tricuspid valve into the right atrium
contraction during right isovolumetric ventricular contraction
(early systole)
x descent Rapid ventricular Occurs due to a combination of right atrial relaxation, the downward
ejection (mid systole) displacement of the tricuspid valve during right ventricular contraction,
and the ejection of blood from both the ventricles
v wave Ventricular ejection Occurs due to right atrial filling from venous return
and isovolumetric
relaxation (late
systole)
y descent Ventricular filling Occurs due to opening of the tricuspid valve and the subsequent rapid
(early diastole) inflow of blood from the right atrium to the right ventricle
First Start of systole Caused by closure of the atrioventricular (mitral & tricuspid) valves
heart
sound
Second heart End of systole Caused by closure of the semilunar (aortic and pulmonary) valves
sound
Third heart Early diastole Caused by rapid flow of blood from the atria into the ventricles during the
sound ventricular filling phase
Fourth heart Late diastole Caused by filling of an abnormally stiff ventricle in atrial systole
sound
ECG Event
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Answer
Contractility (inotropy) is the intrinsic ability of cardiac muscle to develop force at a given muscle length. It is
2+
determined by the intracellular [Ca ] and can be estimated by the ejection fraction. Increases in contractility
(positive
inotropy) cause an increase in stroke volume/cardiac output for any level of right atrial pressure or end-diastolic
volume, and hence shift the Starling curve upwards.
Notes
Cardiac output is determined by the heart rate and stroke volume. Stroke volume is dependent on the filling
pressure (the preload), the cardiac muscle force (the contractility) and the pressure against which the heart has to
pump (the afterload).
Frank-Starling relationship
The volume of blood in the ventricle at the start of systole, the end-diastolic volume (EDV), depends on the end-
diastolic pressure (EDP) and the compliance of the ventricular wall. Right ventricular EDP is dependent on right
atrial and hence central venous pressure (CVP). If EDP (and thus EDV) is increased, the force of the following
contraction, and thus stroke volume increases; this is known as the Frank-Starling relationship.
Starling’s law of the heart states that ‘the energy released during contraction depends on the initial fibre length’. An
increase in EDV causes an increase in ventricular fibre length, which produces an increase in developed tension and
results in an increased force of systolic contraction. As muscle is stretched, more myosin cross-bridges can form,
increasing force. However, cardiac muscle has a much steeper relationship between stretch and force than skeletal
2+
muscle, because in the heart stretch also increases the Ca sensitivity of troponin, so more force is generated for the
2+
same intracellular Ca .
The most important consequence of Starling’s law is that output is matched between the right and left ventricles.
It thus explains how CVP, although only perceived by the right ventricle, also influences left ventricular function
and cardiac output, and why postural hypotension and haemorrhage reduce cardiac output. It also allows the
heart to sustain output when afterload is increased, or contractility is reduced, as both lead to accumulation of
venous blood and a raised EDP, which increases ventricular force and restores stroke volume.
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Factors affecting the Frank-Starling curve
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Preload
Increases in preload cause a rightward shift along the
curve Decreases in preload cause a leftward shift along the
curve
Contractility
Increases in contractility shift the curve upward
Decreases in contractility shift the curve downwards
Afterload
Increases in afterload shift the curve downwards and to the
right Decreases in afterload shift the curve upwards and to the
left
Preload can be defined as the initial stretching of the cardiac myocytes prior to contraction. Preload, therefore, is
related to muscle sarcomere length. Because sarcomere length cannot be determined in the intact heart, other
indices of preload are used such as ventricular end-diastolic volume or pressure. When venous return to the heart is
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increased,
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the end-diastolic pressure and volume of the ventricles are increased, which stretches the sarcomeres, thereby
increasing their preload.
Contractility
Contractility (inotropy) is the intrinsic ability of cardiac muscle to develop force at a given muscle length. It is
2+
determined by the intracellular [Ca ] and can be estimated by the ejection fraction. Increases in contractility
cause an
increase in stroke volume/cardiac output for any level of right atrial pressure or end-diastolic volume, and hence
shift the Starling curve upwards. Decreases in contractility cause a decrease in stroke volume/cardiac output for
any level of right atrial pressure or end-diastolic volume and hence shift the Starling curve downwards.
Afterload
Afterload is determined by the resistance to outflow from the ventricle, which for the left ventricle is mainly
determined by the aortic pressure, and for the right, the pulmonary artery pressure.
An increase in afterload (e.g. hypertension, valve stenosis) means that the ventricles must eject blood against a
higher pressure, resulting in a decrease in stroke volume and a downward shift of the Starling curve.
This decrease in stroke volume however results in an increase in end-systolic volume. As a result, blood
accumulates on the venous side and filling pressure rises. This will result in a secondary increase in preload and
a rightward shift along the Starling curve; cardiac output is restored at the expense of an increased EDP.
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a) Stroke volume and heart rate
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Answer
Mean arterial pressure (MAP) = Cardiac output (CO) x Total peripheral resistance (TPR).
Cardiac output is itself dependent on the central venous pressure (CVP), which in turn is highly dependent on the
blood volume. Alterations of any of these variables may change MAP.
Notes
Mean arterial pressure (MAP) = Cardiac output (CO) x Total peripheral resistance (TPR).
Cardiac output is itself dependent on the central venous pressure (CVP), which in turn is highly dependent on the
blood volume. Alterations of any of these variables may change MAP.
Postural hypotension
On standing from a prone position, gravity causes blood to pool in veins in the legs. Central venous pressure (CVP)
falls, causing a fall in stroke volume and cardiac output (due to Starling’s law) and thus a fall in blood pressure.
Normally this fall in BP is rapidly corrected by the baroreceptor reflex which causes venoconstriction (partially
restoring CVP), and an increase in heart rate and contractility, so restoring cardiac output and blood pressure.
Impaired autonomic nervous activity in the elderly accounts for the greater likelihood of postural hypotension. Any
symptoms of dizziness, blurred vision or syncope is due to a transient fall in cerebral perfusion that occurs before
cardiac output and MAP can be corrected.
Baroreceptor reflex
Arterial baroreceptors are located in the carotid sinus and aortic arch, and detect the mean arterial pressure (MAP).
A decrease in MAP (such as in postural hypotension, or haemorrhage) reduces arterial stretch and decreases
baroreceptor activity, resulting in decreased firing in afferent nerves travelling via the glossopharyngeal nerve
(carotid sinus) and vagus nerve (aortic arch) to the medulla where the activity of the autonomic nervous system is
coordinated.
Sympathetic nerve activity consequently increases, causing an increase in heart rate and cardiac contractility,
peripheral vasoconstriction with an increase in TPR, and venoconstriction with an increase in CVP and thus an
increase in cardiac output and blood pressure. Parasympathetic activity (vagal tone) decreases, contributing to the
rise in heart rate. MAP therefore returns to normal. An increase in MAP has the opposite effect.
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The baroreceptors are most sensitive between 80 and 150 mmHg and their sensitivity is increased by a large pulse
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pressure. They also show adaptation; if a new pressure is maintained for a few hours, activity slowly moves towards
normal. The baroreceptor reflex is important for buffering short-term changes in MAP e.g. with postural changes, or
when muscle blood flow increases rapidly in exercise.
In the atrial systolic phase of the cardiac cycle, all of the following statements are true
EXCEPT for:
Answer
The semilunar valves are closed during atrial systole. Atrial depolarisation causes the P wave on the ECG and initiates
atrial contraction (atrial repolarisation is too diffuse to be seen on the ECG). As the atria contract, the atrial
pressure increases which forces more blood flow across the open AV valves, leading to rapid flow of blood into the
ventricles. There are no valves between the veins and atria and atrial systole causes a small pressure rise in the
great veins (the a wave on the JVP waveform). At rest, atrial contraction only contributes the last 15 – 20% of
the final ventricular volume, as most of the ventricular filling has occurred passively in diastole due to venous
pressure. The proportion of atrial contribution increases with heart rate as diastole shortens and there is less time
for passive ventricular filling. In ventricular hypertrophy, filling of the ‘stiff’ ventricle by atrial systole causes a fourth
heart sound, which is not audible in normal adults.
Notes
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The cardiac cycle describes the events that occur during one beat of the heart.
At the start of the cardiac cycle, towards the end of diastole, the whole of the heart is relaxed. The atrioventricular
(AV) valves are open because the atrial pressure is still slightly greater than the ventricular pressure. The semilunar
valves are closed, as the pressure in the pulmonary artery and aorta is greater than the ventricular pressures. The
cycle starts when the sinoatrial node (SAN) initiates atrial systole.
Atrial depolarisation causes the P wave on the ECG and initiates atrial contraction (atrial repolarisation is too
diffuse to be seen on the ECG).
As the atria contract, the atrial pressure increases which forces more blood flow across the open AV valves, leading
to rapid flow of blood into the ventricles. There are no valves between the veins and atria and atrial systole causes
a small pressure rise in the great veins (the a wave on the JVP waveform).
At rest, atrial contraction only contributes the last 15 – 20% of the final ventricular volume, as most of the
ventricular filling has occurred passively in diastole due to venous pressure. The proportion of atrial contribution
increases with heart rate as diastole shortens and there is less time for passive ventricular filling.
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The end-diastolic volume (EDV) is usually about 120 – 140 mL, and the end-diastolic pressure is less than 10
mmHg (and higher in the left ventricle than the right due to the thicker and therefore stiffer left ventricle).
In ventricular hypertrophy, filling of the ‘stiff’ ventricle by atrial systole causes a fourth heart sound, which is not
audible in normal adults.
Ventricular depolarisation causes the QRS complex on the ECG, and triggers excitation-contraction coupling and
myocyte contraction.
The ventricular pressure rises sharply during contraction and the AV valves close as soon as this is greater than
the atrial pressure (causing the first heart sound). Because the mitral valve closes before the tricuspid valve, the first
heart sound may be split.
For a short period, as the forces are developing, both the AV and the semilunar valves are closed as the ventricular
pressure is still less than that in the pulmonary artery and aorta, and no ejection occurs. This is isovolumetric
contraction.
The increasing pressure makes the AV valves bulge into the atria, causing a small atrial pressure wave (the c wave of
the JVP waveform).
When the ventricular pressure exceeds that in the pulmonary artery and the aorta, the semilunar valves open and
blood is ejected, initially rapidly (rapid ejection phase) and then more slowly (reduced ejection phase).
Atrial pressure initially decreases as the atrial base is pulled downward during ejection, expanding the atrial chamber
(the x descent of the JVP waveform). Atrial filling begins in the rapid ejection phase and continues during the
reduced ejection phase and atrial pressure begins to rise (the v wave of the JVP waveform).
During the second half of ejection, the ventricles stop actively contracting, the ventricular pressure starts to
decrease and the muscle starts to repolarise; this causes the T wave on the ECG, which marks the end of both
ventricular contraction and rapid ventricular ejection.
The ventricular pressure during the reduced ejection phase begins to decrease. Aortic pressure also decreases
because of the runoff of blood from large arteries into smaller arteries. The ventricular pressure falls slightly
below that in the aorta, but initially blood continues to flow out of the ventricle because of momentum;
eventually the ventricular pressure falls sufficiently and the semilunar valves close.
Closure of the semilunar valves causes a small increase in aortic pressure (the dicrotic notch on the arterial
waveform), and the second heart sound. Inspiration delays closure of the pulmonary valve and thus causes splitting of
the second heart sound.
The amount of blood ejected is the stroke volume (SV), and is usually about 70 mL (therefore about 50 mL is left;
this is the end-systolic volume). The proportion of EDV that is ejected (i.e. the SV/EDV) is the ejection fraction and
this is normally about 0.6.
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Immediately after the closure of the semilunar valves, the ventricles rapidly relax and ventricular pressure
decreases rapidly but the AV valves remain closed as initially the ventricular pressure is still greater than atrial
pressure. This is isovolumetric relaxation.
Atrial pressure continues to rise because of venous return, with the v wave of the JVP waveform peaking during
this phase. As the ventricles continue to relax, the ventricular pressure falls below that of the atrial pressure and
the AV valves open.
When the AV valves open, the atrial pressure falls (the y descent of the JVP waveform) and the ventricles refill,
initially rapidly (the rapid filling phase) and then more slowly as the ventricles expand, become less complicant, and
ventricular pressures rise (the reduced filling phase). Rapid flow of blood from the atria into the ventricles causes
the third heart sound, which is normal in children but, in adults, is associated with disease such as ventricular
dilation.
Diastole is usually twice the length of systole at rest, but decreases with increased heart rate. During systole,
contraction of the ventricles compresses the coronary arteries and suppresses blood flow. This is particularly evident
in the left ventricle, where during systole the ventricular pressure is the same as or greater than that in the arteries
and as a result more than 85% of left ventricular perfusion occurs during diastole. This becomes a problem if the
heart rate is increased as the diastolic interval is shorter and can result in ischaemia.
Atrial systole Open (atrial pressure > ventricular Closed (arterial pressure > ventricular
pressure) pressure)
Isovolumetric Closed (ventricular pressure > atrial Closed (arterial pressure > ventricular
contraction pressure) pressure)
Ventricular ejection Closed (ventricular pressure > atrial Open (ventricular pressure > arterial
pressure) pressure)
Isovolumetric Closed (ventricular pressure > atrial Closed (arterial pressure > ventricular
relaxation pressure) pressure)
Ventricular filling Open (atrial pressure > ventricular Closed (arterial pressure > ventricular
pressure) pressure)
c wave Isovolumetric Occurs due to the bulging of the tricuspid valve into the right atrium
contraction during right isovolumetric ventricular contraction
(early systole)
x descent Rapid ventricular Occurs due to a combination of right atrial relaxation, the downward
ejection (mid systole) displacement of the tricuspid valve during right ventricular contraction,
and the ejection of blood from both the ventricles
v wave Ventricular ejection Occurs due to right atrial filling from venous return
and isovolumetric
relaxation (late
systole)
y descent Ventricular filling Occurs due to opening of the tricuspid valve and the subsequent rapid
(early diastole) inflow of blood from the right atrium to the right ventricle
First Start of systole Caused by closure of the atrioventricular (mitral & tricuspid) valves
heart
sound
Second heart End of systole Caused by closure of the semilunar (aortic and pulmonary) valves
sound
Third heart Early diastole Caused by rapid flow of blood from the atria into the ventricles during the
sound ventricular filling phase
Fourth heart Late diastole Caused by filling of an abnormally stiff ventricle in atrial systole
sound
ECG Event
Nitric oxide release from endothelium is stimulated by all of the following EXCEPT for:
a) Substance P
b) Shear stress
c) Histamine
d) Bradykinin
e) Noradrenaline
Something wrong?
Answer
2+
Nitric oxide (NO) production by the endothelium is increased by factors that elevate intracellular Ca , including
local mediators such as bradykinin, histamine and serotonin, and some neurotransmitters (e.g. substance P). Increased
flow (shear stress) also stimulates NO production and additionally activates prostacyclin synthesis. The basal
production of NO continuously modulates vascular resistance. Nitric oxide also inhibits platelet activation and
thrombosis.
Notes
The endothelium
The endothelium plays a vital role in regulation of vascular tone (as well as regulation of haemostasis, angiogenesis and
inflammatory response).
In response to substances in the blood, endothelial damage or changes in blood flow, it can synthesise several
important substances; nitric oxide and prostacyclin are important vasodilators and endothelin-1 and thromboxane
A2 are potent vasoconstrictors.
2+
Nitric oxide (NO) production by the endothelium is increased by factors that elevate intracellular Ca , including
local mediators such as bradykinin, histamine and serotonin, and some neurotransmitters (e.g. substance P). Increased
flow (shear stress) also stimulates NO production and additionally activates prostacyclin synthesis. The basal
production of NO continuously modulates vascular resistance. Nitric oxide also inhibits platelet activation and
thrombosis.
Endothelin-1 (ET-1) is an extremely potent vasoconstrictor peptide which is released from the endothelium in the
presence of many other vasoconstrictors, including angiotensin II, antidiuretic hormone (ADH) and noradrenaline,
and may be increased in disease and hypoxia.
The eicosanoids prostacyclin (PGI2) and thromboxane A2 (TXA2) are synthesised by the cyclooxygenase pathway from
arachidonic acid, which is made from membrane phospholipids by phospholipase A2.
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Vasoconstriction
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2+
Most vasoconstrictors bind to G-protein coupled receptors which mediate elevation in intracellular [Ca ], leading
to vascular smooth muscle contraction. Important vasoconstrictors include endothelin-1, angiotensin II and
noradrenaline.
2+ 2+
The increase in intracellular [Ca ] is brought about by release of Ca from the sarcoplasmic reticulum and by
2+ 2+
depolarisation and entry of Ca via L-type voltage-gated Ca channels. Most types of vascular smooth muscle do not
2+
generate action potentials, but instead depolarisation is graded, allowing graded entry of Ca .
Vasodilation
2+ 2+
Vasodilation occurs by decreasing intracellular [Ca ] by sequestration by the sarcoplasmic reticulum Ca
2+ + 2+
ATPase and by removal from the cell by a plasma membrane Ca ATPase and Na /Ca exchange.
Most endogenous vasodilators cause relaxation by increasing cyclic guanosine monophosphate (cGMP) (e.g. nitric
oxide) or cyclic adenosine monophosphate (cAMP) (e.g. prostacyclin, beta-adrenergic receptor agonists), which
2+
activate protein kinases causing substrate level phosphorylation. L-type Ca channel blocker drugs are clinically
effective vasodilators.
Thromboxane A2 Prostacyclin
Angiotensin II Beta-agonists
Which of the following structures prevents a direct electrical pathway from the atria to the
ventricles:
a) Intercalated discs
b) Connexons
c) Annulus fibrosus
d) Purkinje fibres
e) Chordae tendineae
Something wrong?
Answer
The atria are separated from the ventricles by a band of fibrous connective tissue called the annulus fibrosus, which
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provides a skeleton for the attachment of muscle and cardiac valves, and prevents electrical conduction between
the atria and ventricles (except at the atrioventricular node).
Notes
Myocytes
The myocardium is composed of cardiac muscle cells called myocytes. The cells are striated due to the
arrangement of the thick and thin filaments which make up the bulk of the muscle, although they are less
organised than in skeletal muscle. The myocytes are small and branched, with a single nucleus and are rich in
mitochondria. The normal pumping action of the heart is dependent on the synchronised contraction of all cardiac
cells.
Intercalated discs
The synchronicity between myocytes occurs because all the adjacent cells are connected by intercalated discs. The
intercalated discs provide both a structural attachment by ‘glueing’ cells together at desmosomes and an electrical
contact made up of proteins called connexons, called a gap junction, which essentially creates a low-resistance
pathway between cells. Gap junctions allow action potentials to spread rapidly from one cell to another and allows
the myocardium to act as a functional syncytium.
Cardiac pacemaker
Cardiac myocyte contraction is not dependent on an external nerve supply but instead the heart generates its own
rhythm, demonstrating inherent rhythmicity.
The heartbeat is initiated by spontaneous depolarisation of the sinoatrial node (SAN), a region of specialised
myocytes in the right atrium, close to the coronary sinus. The rate is modulated by the autonomic nervous system.
Action potentials in the SAN activate adjacent atrial myocytes and a wave of depolarisation and contraction
therefore spreads through atrial muscle. This is prevented from reaching the ventricles directly by the annulus
fibrosis.
This impulse is channelled through the atrioventricular node (AVN), located between the right atrium and ventricle
near the atrial septum. The AVN contains small cells and thus conducts slowly and delays the impulse for about 120
ms, allowing time for atrial contraction to complete ventricular filling.
Once complete, the impulse is then transmitted by specialised, wide, fast conducting myocytes in the bundle of His
and Purkinje fibres, by which it is distributed over the inner surface of both ventricles. From here a wave of
depolarisation and contraction moves from myocyte to myocyte across the endocardium until the whole ventricular
mass is activated.
Electrocardiogram (ECG)
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The wave of depolarisation through the heart causes local currents in surrounding fluid which are detected at the
body surface as small changes in voltage. This forms the basis of the ECG. The classical ECG records voltage
between the left and right arm (lead I), the right arm and left leg (lead II) and the left arm and left leg (lead III).
This is represented by Einthoven’s triangle. The size of the voltage at any time depends on the quantity of muscle
depolarisation and the direction in which the wave of depolarisation is travelling. Thus lead II normally shows the
largest deflection during ventricular depolarisation, as the muscle mass is greatest and depolarisation travels from
apex to base, more or less parallel to a line from the left hip to the right shoulder.
By Npatchett (Own work) [CC BY-SA 4.0 (], via Wikimedia Commons
a) T wave
b) Q wave
c) P wave
d) PR interval
e) ST segment
Something wrong?
Answer
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ECG Event
Notes
The cardiac cycle describes the events that occur during one beat of the heart.
At the start of the cardiac cycle, towards the end of diastole, the whole of the heart is relaxed. The atrioventricular
(AV) valves are open because the atrial pressure is still slightly greater than the ventricular pressure. The semilunar
valves are closed, as the pressure in the pulmonary artery and aorta is greater than the ventricular pressures. The
cycle starts when the sinoatrial node (SAN) initiates atrial systole.
Atrial depolarisation causes the P wave on the ECG and initiates atrial contraction (atrial repolarisation is too
diffuse to be seen on the ECG).
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As the atria contract, the atrial pressure increases which forces more blood flow across the open AV valves, leading
to rapid flow of blood into the ventricles. There are no valves between the veins and atria and atrial systole causes
a small pressure rise in the great veins (the a wave on the JVP waveform).
At rest, atrial contraction only contributes the last 15 – 20% of the final ventricular volume, as most of the
ventricular filling has occurred passively in diastole due to venous pressure. The proportion of atrial contribution
increases with heart rate as diastole shortens and there is less time for passive ventricular filling.
The end-diastolic volume (EDV) is usually about 120 – 140 mL, and the end-diastolic pressure is less than 10
mmHg (and higher in the left ventricle than the right due to the thicker and therefore stiffer left ventricle).
In ventricular hypertrophy, filling of the ‘stiff’ ventricle by atrial systole causes a fourth heart sound, which is not
audible in normal adults.
Ventricular depolarisation causes the QRS complex on the ECG, and triggers excitation-contraction coupling and
myocyte contraction.
The ventricular pressure rises sharply during contraction and the AV valves close as soon as this is greater than
the atrial pressure (causing the first heart sound). Because the mitral valve closes before the tricuspid valve, the first
heart sound may be split.
For a short period, as the forces are developing, both the AV and the semilunar valves are closed as the ventricular
pressure is still less than that in the pulmonary artery and aorta, and no ejection occurs. This is isovolumetric
contraction.
The increasing pressure makes the AV valves bulge into the atria, causing a small atrial pressure wave (the c wave of
the JVP waveform).
When the ventricular pressure exceeds that in the pulmonary artery and the aorta, the semilunar valves open and
blood is ejected, initially rapidly (rapid ejection phase) and then more slowly (reduced ejection phase).
Atrial pressure initially decreases as the atrial base is pulled downward during ejection, expanding the atrial chamber
(the x descent of the JVP waveform). Atrial filling begins in the rapid ejection phase and continues during the
reduced ejection phase and atrial pressure begins to rise (the v wave of the JVP waveform).
During the second half of ejection, the ventricles stop actively contracting, the ventricular pressure starts to
decrease and the muscle starts to repolarise; this causes the T wave on the ECG, which marks the end of both
ventricular contraction and rapid ventricular ejection.
The ventricular pressure during the reduced ejection phase begins to decrease. Aortic pressure also decreases
because of the runoff of blood from large arteries into smaller arteries. The ventricular pressure falls slightly
below that in the aorta, but initially blood continues to flow out of the ventricle because of momentum;
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eventually the
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ventricular pressure falls sufficiently and the semilunar valves close.
Closure of the semilunar valves causes a small increase in aortic pressure (the dicrotic notch on the arterial
waveform), and the second heart sound. Inspiration delays closure of the pulmonary valve and thus causes splitting of
the second heart sound.
The amount of blood ejected is the stroke volume (SV), and is usually about 70 mL (therefore about 50 mL is left;
this is the end-systolic volume). The proportion of EDV that is ejected (i.e. the SV/EDV) is the ejection fraction and
this is normally about 0.6.
Immediately after the closure of the semilunar valves, the ventricles rapidly relax and ventricular pressure
decreases rapidly but the AV valves remain closed as initially the ventricular pressure is still greater than atrial
pressure. This is isovolumetric relaxation.
Atrial pressure continues to rise because of venous return, with the v wave of the JVP waveform peaking during
this phase. As the ventricles continue to relax, the ventricular pressure falls below that of the atrial pressure and
the AV valves open.
When the AV valves open, the atrial pressure falls (the y descent of the JVP waveform) and the ventricles refill,
initially rapidly (the rapid filling phase) and then more slowly as the ventricles expand, become less complicant, and
ventricular pressures rise (the reduced filling phase). Rapid flow of blood from the atria into the ventricles causes
the third heart sound, which is normal in children but, in adults, is associated with disease such as ventricular
dilation.
Diastole is usually twice the length of systole at rest, but decreases with increased heart rate. During systole,
contraction of the ventricles compresses the coronary arteries and suppresses blood flow. This is particularly evident
in the left ventricle, where during systole the ventricular pressure is the same as or greater than that in the arteries
and as a result more than 85% of left ventricular perfusion occurs during diastole. This becomes a problem if the
heart rate is increased as the diastolic interval is shorter and can result in ischaemia.
Atrial systole Open (atrial pressure > ventricular Closed (arterial pressure > ventricular
pressure) pressure)
Isovolumetric Closed (ventricular pressure > atrial Closed (arterial pressure > ventricular
contraction pressure) pressure)
Ventricular ejection Closed (ventricular pressure > atrial Open (ventricular pressure > arterial
pressure) pressure)
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Isovolumetric Closed (ventricular pressure > atrial Closed (arterial pressure > ventricular
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relaxation pressure) pressure)
Ventricular filling Open (atrial pressure > ventricular Closed (arterial pressure > ventricular
pressure) pressure)
c wave Isovolumetric Occurs due to the bulging of the tricuspid valve into the right atrium
contraction during right isovolumetric ventricular contraction
(early systole)
x descent Rapid ventricular Occurs due to a combination of right atrial relaxation, the downward
ejection (mid systole) displacement of the tricuspid valve during right ventricular contraction,
and the ejection of blood from both the ventricles
v wave Ventricular ejection Occurs due to right atrial filling from venous return
and isovolumetric
relaxation (late
systole)
y descent Ventricular filling Occurs due to opening of the tricuspid valve and the subsequent rapid
(early diastole) inflow of blood from the right atrium to the right ventricle
First Start of systole Caused by closure of the atrioventricular (mitral & tricuspid) valves
heart
sound
Second heart End of systole Caused by closure of the semilunar (aortic and pulmonary) valves
sound
Third heart Early diastole Caused by rapid flow of blood from the atria into the ventricles during the
sound ventricular filling phase
Fourth heart Late diastole Caused by filling of an abnormally stiff ventricle in atrial systole
sound
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ECG Event
Regarding pressures in the peripheral vascular system, which of the following statements is
CORRECT:
a) The mean arterial pressure (MAP) at the start of the arterioles is about 90 mmHg.
b) The pressure on the arterial side of the capillaries is about 65 mmHg.
c) The pressure on the venous side of the capillaries is about 5 mmHg.
d) The pressure in the vena cava at the level of the heart is usually close to 0 mmHg.
e) There is about a 25 mmHg drop in pressure over the capillary bed.
Something wrong?
Answer
The mean arterial pressure (MAP) at the start of the arterioles is about 65 mmHg. The pressure on the arterial side
of capillaries is about 25 mmHg, and on the venous side is about 15 mmHg (thus a drop of about 10 mmHg over
the capillary bed). Venules converge into veins and finally the vena cava. The pressure in the vena cava at the level
of the heart (the central venous pressure) is usually close to 0 mmHg.
Notes
Total blood volume, cardiac output and stroke volume
The total blood volume in the circulatory system of a healthy adult is about 5 L.
The stroke volume is the volume of blood ejected per beat. It is usually about 70 mL/beat at
rest. The heart rate is the number of beats per minute. It is usually about 70 beats/minute
at rest.
The cardiac output is the volume of blood pumped out of heart via the aorta per minute.
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Cardiac output (CO) = Stroke volume x Heart rate = 70 mL/beat x 70 beats/min = 4900
mL/min
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Therefore cardiac output is usually about 5 L/minute at rest in humans.
During systole, the pressure in the left ventricle increases and blood is ejected into the aorta. The rise in pressure
stretches the elastic walls of the aorta and large arteries and drives blood flow. Systolic pressure is the maximum
arterial pressure during systole. During diastole, arterial blood flow is partly maintained by elastic recoil of the walls
of large arteries. The minimum pressure reached before the next systole is the diastolic pressure. The difference
between the systolic and diastolic pressure is the pulse pressure.
The mean arterial pressure (MAP) cannot be calculated by averaging these pressures, because for about 60% of
the time, the heart is in diastole. It is instead estimated as the diastolic + one-third of the pulse pressure, e.g. = 80
+ 1/3(110 – 80) = 90 mmHg where BP 110/80 mmHg.
The mean arterial pressure (MAP) at the start of the arterioles is about 65 mmHg. The pressure on the arterial side
of capillaries is about 25 mmHg, and on the venous side is about 15 mmHg. Venules converge into veins and finally
the vena cava. The pressure in the vena cava at the level of the heart (the central venous pressure) is usually close
to 0 mmHg.
Answer
Normally overall the hydrostatic pressure along the length of the capillary is greater than plasma oncotic pressure
and thus there is a small net filtration of fluid from the capillary into the interstitial space. Blood flow into the
microcirculation is regulated by the vasoconstriction of small arterioles, activated by the sympathetic nervous
system through numerous nerve endings in their walls. Across capillary walls, unlike proteins, most ions and small
molecules diffuse easily and thus the crystalloid osmotic pressure they exert is roughly the same on either side of
the capillary wall. Plasma colloidal osmotic pressure is higher than interstitial colloidal osmotic pressure and tends
to draw fluid intravascularly. Arteriolar constriction will reduce hydrostatic capillary pressure and transiently
increase absorption of fluid.
Notes
Overview of microcirculation
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The microcirculation consists of the smallest terminal arterioles and the exchange vessels – the capillaries and small
postcapillary venules.
Blood flow into the microcirculation is regulated by the vasoconstriction of small arterioles, activated by the
sympathetic nervous system through numerous nerve endings in their walls. Each small arteriole feeds many
capillaries via several terminal arterioles. Terminal arterioles are not innervated and vasoconstriction is instead
mediated by local metabolites, allowing perfusion to be matched to metabolism.
Starling equation
The capillary wall is very permeable to water. Water tends to flow from a low to a high osmotic pressure, but from
a high to a low hydrostatic pressure. The net flow of water across the capillary wall is therefore determined by the
balance between the hydrostatic pressure which tends to drive water out of the capillaries and the oncotic pressure
which tends to draw water into the capillaries from the interstitial space.
Starling’s equation tells us that the net flow of water across the capillary wall is proportional to (Pc – Pi) – (πp –
πi), where (Pc – Pi) is the difference in hydrostatic pressure between the capillary and interstitial space and (πp –
πi) is the difference in osmotic pressure between plasma and interstitial fluid. A positive value means there is a net
fluid movement out of the capillary (filtration), a negative value means there is a net fluid movement into the
capillary (absorption).
Oncotic pressure:
Across capillary walls, unlike proteins, most ions and small molecules diffuse easily and thus the crystalloid osmotic
pressure they exert is roughly the same on either side of the capillary wall; for this reason, the osmotic force across
the capillary wall is largely determined by protein concentration in the blood. Plasma protein concentration is
normally much higher than interstitial protein concentration because very little protein is filtered; plasma colloidal
osmotic pressure is therefore higher than interstitial colloidal osmotic pressure and tends to draw fluid
intravascularly.
Hydrostatic pressure:
Capillary hydrostatic pressure normally varies from about 35 mmHg at the arteriolar end to about 15 mmHg at the
venous end, whereas the interstitial hydrostatic pressure is normally close to 0 mmHg (or is slightly negative). The
greater hydrostatic pressure inside the capillary tends to drive filtration of water out of the capillary into the
tissues.
Net filtration:
Normally overall the hydrostatic pressure along the length of the capillary is greater than plasma oncotic pressure
and thus there is a small net filtration of fluid from the capillary into the interstitial space; of about 4000 L of
plasma entering the capillaries daily as the blood recirculates, a net filtration of 8 L occurs. Although arteriolar
constriction will reduce capillary hydrostatic pressure and therefore lead to the reabsorption of fluid, this will
normally be transient due to the concentration of interstitial fluid, i.e. the increased interstitial oncotic pressure.
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Factors increasing Causes
filtration
Increased capillary Caused by increased venous pressures e.g. by gravitational forces, volume expanded
hydrostatic states, in heart failure or with venous obstruction
pressure
Decreased Caused by decreased protein concentration in blood e.g. nephrotic syndrome, protein
capillary oncotic malnutrition, liver failure
pressure
Lymphatic Caused by, for example, filariasis or following lymph node dissection, surgery or radiation
obstruction therapy
Regarding the skeletal muscle circulation, which of the following statements is INCORRECT:
Answer
The skeletal muscle circulation normally receives about 15 – 20% of the cardiac output, but this may rise to > 80%
during exercise. Skeletal muscle provides a major contribution to the total peripheral resistance and sympathetic
regulation of muscle blood flow is important in the baroreceptor reflex. At rest most capillaries are not perfused as
their arterioles are constricted. Capillaries are recruited during exercise by metabolic hyperaemia, caused by release
of
+
K and CO2 from the muscle and adenosine. This overrides sympathetic vasoconstriction in working muscle; the latter
reduces flow in non-working muscle conserving cardiac output.
Notes
Skeletal muscle circulation
The skeletal muscle circulation normally receives about 15 – 20% of the cardiac output, but this may rise to > 80%
during exercise. Skeletal muscle provides a major contribution to the total peripheral resistance and sympathetic
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regulation of muscle blood flow is important in the baroreceptor reflex. At rest most capillaries are not perfused as
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their arterioles are constricted. Capillaries are recruited during exercise by metabolic hyperaemia, caused by release
+
of K and CO2 from the muscle and adenosine. This overrides sympathetic vasoconstriction in working muscle; the
latter reduces flow in non-working muscle conserving cardiac output.
Pulmonary circulation
The pulmonary circulation is not controlled by either autonomic nerves or metabolic products, and the most
important mechanism regulating flow is hypoxic pulmonary vasoconstriction, in which small arteries constrict in
response to hypoxia (in contrast to elsewhere in the body).
If an area of lung is poorly ventilated and the alveolar partial pressure of oxygen is low, pulmonary blood vessels
are constricted and blood is diverted to areas of the lung that are better ventilated, thus maintaining optimal
ventilation- perfusion matching. This effect is accentuated by high alveolar PCO 2.
The response is unhelpful in the presence of global lung hypoxia, at altitude or in respiratory failure, where it may
contribute to the development of pulmonary hypertension and right-sided heart failure (cor pulmonale).
Cutaneous circulation
The main function of the cutaneous circulation is thermoregulation. Arteriovenous anastomoses (AVAs) directly
linked arterioles and venules, allowing a high blood flow into the venous plexus and thus radiation of heat. AVAs
are mostly found in the hands, feet and areas of the face.
Temperature is sensed by peripheral thermoreceptors and the hypothalamus coordinates the response.
Increased temperatures reduce sympathetic adrenergic stimulation, causing vasodilation and allowing more blood
to flow to the skin and radiate its heat to the environment, whereas activation of sympathetic cholinergic fibres
promotes sweating and the release of bradykinin, which also causes vasodilation.
Cerebral circulation
The brain receives around 15% of the total cardiac output and has a high capillary density.
The endothelial cells of the capillaries of the blood-brain barrier have very tight junctions, and contain membrane
transporters that control the movement of substances, such as ions, glucose and amino acids, and tightly regulate
the composition of cerebrospinal fluid. This is continuous except where substances need to be absorbed or released
e.g. pituitary gland, choroid plexus.
The autoregulation of cerebral blood flow can maintain a constant flow for blood pressures between 50 and 170
+
mmHg. CO2 and K are particularly important metabolic regulators in the brain, with increasing concentration
causing vasodilation and a functional hyperaemia.
Hyperventilation reduces blood PCO2 and can cause fainting due to cerebral vasoconstriction.
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Coronary circulation
The heart has a high metabolic demand and its high capillary density allow it to extract an unusually large fraction
(about 70%) of oxygen from the blood.
In exercise, the reduced diastolic interval and increased oxygen consumption demand a greatly increased blood
+
flow which is achieved by metabolic hyperaemia mediated by adenosine, K and hypoxia. This overrides the
vasoconstriction mediated by sympathetic nerves acting at alpha-adrenergic receptors and is assisted by circulating
adrenaline which causes vasodilation by acting on beta-adrenergic receptors.
In the cardiac myocyte action potential, the plateau phase of the action potential occurs due
to a:
a) Na+ influx
b) K+ influx
c) Ca2+ influx
d) K+ efflux
e) Ca2+ efflux
Something wrong?
Answer
+
After the intial upstroke of the action potential, Na channels and currents rapidly inactivate, but in cardiac
2+
myocytes, the initial depolarisation activates voltage-gated Ca channels (slow L-type channels, threshold
approximately – 45
2+ 2+
mV) through which Ca floods into the cell. The resulting influx of Ca prevents the cell from repolarising and
causes a plateau phase, that is maintained for about 250 ms until the L-type channels inactivate. The cardiac AP is
thus much longer than that in nerve or skeletal muscle.
Notes
Cardiac myocyte action potential
The resting potential of ventricular myocytes is about -90 mV. An action potential (AP) is initiated when the
myocyte is depolarised to a threshold potential of about -65 mV, as a result of transmission from an adjacent
myocyte via gap junctions.
Depolarisation:
+ +
Fast voltage-gated Na channels are activated and a Na influx depolarises the membrane rapidly to about +30
mV. This initial depolarisation is similar to that in nerve and skeletal muscle, and assists the transmission to the
next myocyte.
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+
Na channels and currents rapidly inactivate, but in cardiac myocytes, the initial depolarisation activates voltage-
2+ 2+
gated Ca channels (slow L-type channels, threshold approximately – 45 mV) through which Ca floods into the
cell. The
2+
resulting influx of Ca prevents the cell from repolarising and causes a plateau phase, that is maintained for about
250 ms until the L-type channels inactivate. The cardiac AP is thus much longer than that in nerve or skeletal
muscle.
Repolarisation:
+ +
Repolarisation occurs due to activation of voltage-gated K rectifier channels and a K efflux. As the AP lasts
almost as long as contraction, its refractory period prevents another AP being initiated until the muscle relaxes,
thus cardiac muscle cannot exhibit tetanus.
Image modified by FRCEM Success. [CC-BY-SA-3.0 (or GFDL (], via Wikimedia Commons
Atrial myocytes have a similar but more triangular AP compared to the ventricles (less plateau). Purkinje fibres in
the conduction system are also similar to ventricular myocytes, but have a spike at the peak of the upstroke
+
reflecting a larger Na current that contributes to their fast conduction velocity.
a) Normally absorption of fluid into the capillaries is greater than filtration out of the capillaries.
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b) About 2 L is filtered by the microcirculation per day.
c) Lymphatic vessels contain both smooth muscle and unidirectional valves.
d) The lymphatic system empties into the thoracic duct, which in turn empties into the jugular vein.
e) The lymphatic system is also important for absorption and transport of carbohydrate.
Something wrong?
Answer
Normally, filtration of fluid out of the capillaries is slightly greater than absorption of fluid into the capillaries. Fluid
filtered by the microcirculation (about 8 L per day) is returned to the circulation by the lymphatic system.
Lymphatic capillaries drain into collecting lymphatics and then into larger lymphatic vessels, both containing
smooth muscle and unidirectional valves. From here, lymph is propelled by smooth muscle constriction and
compression of the vessels by body movements into afferent lymphatics and then the lymph nodes, where bacteria
and other foreign materials are removed by phagocytes. Most fluid is reabsorbed here by capillaries, with the
remainder returning via efferent lymphatics and the thoracic duct into the subclavian veins. The lymphatic system
plays a major role in the body’s immune defence and is also important for absorption and transport of fats.
Notes
Lymphatics
Normally, filtration of fluid out of the capillaries is slightly greater than absorption of fluid into the capillaries.
Fluid filtered by the microcirculation (about 8 L per day) is returned to the circulation by the lymphatic system.
Lymphatic capillaries are blind-ended tubes walled with endothelial cells which allow the entry of fluid, protein
and bacteria, but prevent their exit. Lymphatic capillaries drain into collecting lymphatics and then into larger
lymphatic vessels, both containing smooth muscle and unidirectional valves.
From here, lymph is propelled by smooth muscle constriction and compression of the vessels by body movements
into afferent lymphatics and then the lymph nodes, where bacteria and other foreign materials are removed by
phagocytes. Most fluid is reabsorbed here by capillaries, with the remainder returning via efferent lymphatics and
the thoracic duct into the subclavian veins.
The lymphatic system plays a major role in the body’s immune defence and is also important for absorption and
transport of fats.
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Oedema
Oedema is swelling of the tissues due to excess fluid in the interstitial space overwhelming the lymphatic system or
due to obstruction or dysfunction of the lymphatic system.
A reduction in plasma protein e.g. in starvation or a loss of endothelial integrity e.g. in inflammation or ischaemia
will reduce the oncotic pressure gradient and enhance filtration and loss of fluid into the tissues. An increase in
venous pressure e.g. in congestive heart failure or venous insufficiency will increase capillary hydrostatic pressure
with a similar effect.
Increased capillary Caused by increased venous pressures e.g. by gravitational forces, volume expanded
hydrostatic states, in heart failure or with venous obstruction
pressure
Decreased plasma Caused by decreased protein concentration in blood e.g. nephrotic syndrome, protein
oncotic pressure malnutrition, liver failure
Lymphatic Caused by, for example, filariasis or following lymph node dissection, surgery or radiation
obstruction therapy
When an elderly dehydrated patient is moved from a supine to a standing position, her
heart rate increases. Which of the following accounts for the increase in heart rate upon
standing:
Answer
On standing from a prone position, gravity causes blood to pool in veins in the legs with a decrease in venous
return. Central venous pressure (CVP) falls, causing a fall in stroke volume and cardiac output (due to Starling’s
law) and thus a fall in blood pressure. Normally this fall in BP is rapidly corrected by the baroreceptor reflex which
causes venoconstriction (partially restoring CVP), and an increase in heart rate and contractility, so restoring
cardiac output and blood pressure.
Notes
Mean arterial pressure (MAP) = Cardiac output (CO) x Total peripheral resistance (TPR).
Cardiac output is itself dependent on the central venous pressure (CVP), which in turn is highly dependent on the
blood volume. Alterations of any of these variables may change MAP.
Postural hypotension
On standing from a prone position, gravity causes blood to pool in veins in the legs. Central venous pressure (CVP)
falls, causing a fall in stroke volume and cardiac output (due to Starling’s law) and thus a fall in blood pressure.
Normally this fall in BP is rapidly corrected by the baroreceptor reflex which causes venoconstriction (partially
restoring CVP), and an increase in heart rate and contractility, so restoring cardiac output and blood pressure.
Impaired autonomic nervous activity in the elderly accounts for the greater likelihood of postural hypotension. Any
symptoms of dizziness, blurred vision or syncope is due to a transient fall in cerebral perfusion that occurs before
cardiac output and MAP can be corrected.
Baroreceptor reflex
Arterial baroreceptors are located in the carotid sinus and aortic arch, and detect the mean arterial pressure (MAP).
A decrease in MAP (such as in postural hypotension, or haemorrhage) reduces arterial stretch and decreases
baroreceptor activity, resulting in decreased firing in afferent nerves travelling via the glossopharyngeal nerve
(carotid sinus) and vagus nerve (aortic arch) to the medulla where the activity of the autonomic nervous system is
coordinated.
Sympathetic nerve activity consequently increases, causing an increase in heart rate and cardiac contractility,
peripheral vasoconstriction with an increase in TPR, and venoconstriction with an increase in CVP and thus an
increase in cardiac output and blood pressure. Parasympathetic activity (vagal tone) decreases, contributing to the
rise in heart rate. MAP therefore returns to normal. An increase in MAP has the opposite effect.
The baroreceptors are most sensitive between 80 and 150 mmHg and their sensitivity is increased by a large pulse
pressure. They also show adaptation; if a new pressure is maintained for a few hours, activity slowly moves
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towards normal. The baroreceptor reflex is important for buffering short-term changes in MAP e.g. with postural
changes, or
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a) Endothelin-1
b) Thromboxane A2
c) Prostacyclin
d) Angiotensin II
e) Noradrenaline
Something wrong?
Answer
Thromboxane A2 Prostacyclin
Angiotensin II Beta-agonists
Notes
The endothelium
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The endothelium plays a vital role in regulation of vascular tone (as well as regulation of haemostasis, angiogenesis and
inflammatory response).
In response to substances in the blood, endothelial damage or changes in blood flow, it can synthesise several
important substances; nitric oxide and prostacyclin are important vasodilators and endothelin-1 and thromboxane
A2 are potent vasoconstrictors.
2+
Nitric oxide (NO) production by the endothelium is increased by factors that elevate intracellular Ca , including
local mediators such as bradykinin, histamine and serotonin, and some neurotransmitters (e.g. substance P). Increased
flow (shear stress) also stimulates NO production and additionally activates prostacyclin synthesis. The basal
production of NO continuously modulates vascular resistance. Nitric oxide also inhibits platelet activation and
thrombosis.
Endothelin-1 (ET-1) is an extremely potent vasoconstrictor peptide which is released from the endothelium in the
presence of many other vasoconstrictors, including angiotensin II, antidiuretic hormone (ADH) and noradrenaline,
and may be increased in disease and hypoxia.
The eicosanoids prostacyclin (PGI2) and thromboxane A2 (TXA2) are synthesised by the cyclooxygenase pathway from
arachidonic acid, which is made from membrane phospholipids by phospholipase A2.
Vasoconstriction
2+
Most vasoconstrictors bind to G-protein coupled receptors which mediate elevation in intracellular [Ca ], leading
to vascular smooth muscle contraction. Important vasoconstrictors include endothelin-1, angiotensin II and
noradrenaline.
2+ 2+
The increase in intracellular [Ca ] is brought about by release of Ca from the sarcoplasmic reticulum and by
2+ 2+
depolarisation and entry of Ca via L-type voltage-gated Ca channels. Most types of vascular smooth muscle do not
2+
generate action potentials, but instead depolarisation is graded, allowing graded entry of Ca .
Vasodilation
2+ 2+
Vasodilation occurs by decreasing intracellular [Ca ] by sequestration by the sarcoplasmic reticulum Ca
2+ + 2+
ATPase and by removal from the cell by a plasma membrane Ca ATPase and Na /Ca exchange.
Most endogenous vasodilators cause relaxation by increasing cyclic guanosine monophosphate (cGMP) (e.g. nitric
oxide) or cyclic adenosine monophosphate (cAMP) (e.g. prostacyclin, beta-adrenergic receptor agonists), which
2+
activate protein kinases causing substrate level phosphorylation. L-type Ca channel blocker drugs are clinically
effective vasodilators.
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Thromboxane A2 Prostacyclin
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Angiotensin II Beta-agonists
a) Right atrium
b) Carotid sinus and aortic arch
c) Ascending aorta
d) Internal jugular vein
e) Carotid sinus and right atrium
Something wrong?
Answer
Arterial baroreceptors are located in the carotid sinus and aortic arch, and detect the mean arterial pressure (MAP).
Notes
Mean arterial pressure (MAP) = Cardiac output (CO) x Total peripheral resistance (TPR).
Cardiac output is itself dependent on the central venous pressure (CVP), which in turn is highly dependent on the
blood volume. Alterations of any of these variables may change MAP.
Postural hypotension
On standing from a prone position, gravity causes blood to pool in veins in the legs. Central venous pressure (CVP)
falls, causing a fall in stroke volume and cardiac output (due to Starling’s law) and thus a fall in blood pressure.
Normally this fall in BP is rapidly corrected by the baroreceptor reflex which causes venoconstriction (partially
restoring CVP), and an increase in heart rate and contractility, so restoring cardiac output and blood pressure.
Impaired autonomic nervous activity in the elderly accounts for the greater likelihood of postural hypotension. Any
symptoms of dizziness, blurred vision or syncope is due to a transient fall in cerebral perfusion that occurs before
cardiac output and MAP can be corrected.
Baroreceptor reflex
Arterial baroreceptors are located in the carotid sinus and aortic arch, and detect the mean arterial pressure (MAP).
A decrease in MAP (such as in postural hypotension, or haemorrhage) reduces arterial stretch and decreases
baroreceptor activity, resulting in decreased firing in afferent nerves travelling via the glossopharyngeal nerve
(carotid sinus) and vagus nerve (aortic arch) to the medulla where the activity of the autonomic nervous system is
coordinated.
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Sympathetic nerve activity consequently increases, causing an increase in heart rate and cardiac contractility,
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peripheral vasoconstriction with an increase in TPR, and venoconstriction with an increase in CVP and thus an
increase in cardiac output and blood pressure. Parasympathetic activity (vagal tone) decreases, contributing to the
rise in heart rate. MAP therefore returns to normal. An increase in MAP has the opposite effect.
The baroreceptors are most sensitive between 80 and 150 mmHg and their sensitivity is increased by a large pulse
pressure. They also show adaptation; if a new pressure is maintained for a few hours, activity slowly moves
towards normal. The baroreceptor reflex is important for buffering short-term changes in MAP e.g. with postural
changes, or when muscle blood flow increases rapidly in exercise.
a) -35mV
b) -40mV
c) -65mV
d) -70mV
e) -90mV
Something wrong?
Answer
The resting potential of ventricular myocytes is about -90 mV. An action potential (AP) is initiated when the
myocyte is depolarised to a threshold potential of about -65 mV, as a result of transmission from an adjacent
myocyte via gap junctions.
Notes
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The resting potential of ventricular myocytes is about -90 mV. An action potential (AP) is initiated when the
myocyte is depolarised to a threshold potential of about -65 mV, as a result of transmission from an adjacent
myocyte via gap junctions.
Depolarisation:
+ +
Fast voltage-gated Na channels are activated and a Na influx depolarises the membrane rapidly to about +30
mV. This initial depolarisation is similar to that in nerve and skeletal muscle, and assists the transmission to the
next myocyte.
+
Na channels and currents rapidly inactivate, but in cardiac myocytes, the initial depolarisation activates voltage-
2+ 2+
gated Ca channels (slow L-type channels, threshold approximately – 45 mV) through which Ca floods into the
cell. The
2+
resulting influx of Ca prevents the cell from repolarising and causes a plateau phase, that is maintained for about
250 ms until the L-type channels inactivate. The cardiac AP is thus much longer than that in nerve or skeletal
muscle.
Repolarisation:
+ +
Repolarisation occurs due to activation of voltage-gated K rectifier channels and a K efflux. As the AP lasts
almost as long as contraction, its refractory period prevents another AP being initiated until the muscle relaxes,
thus cardiac muscle cannot exhibit tetanus.
Image modified by FRCEM Success. [CC-BY-SA-3.0 (or GFDL (], via Wikimedia Commons
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Atrial myocytes have a similar but more triangular AP compared to the ventricles (less plateau). Purkinje fibres in
the conduction system are also similar to ventricular myocytes, but have a spike at the peak of the upstroke
+
reflecting a larger Na current that contributes to their fast conduction velocity.
In ventricular myocytes, the plateau phase of the action potential comes about through which
of the following:
Answer
+
After the intial upstroke of the action potential, Na channels and currents rapidly inactivate, but in cardiac
2+
myocytes, the initial depolarisation activates voltage-gated Ca channels (slow L-type channels, threshold
approximately – 45
2+ 2+
mV) through which Ca floods into the cell. The resulting influx of Ca prevents the cell from repolarising and
causes a plateau phase, that is maintained for about 250 ms until the L-type channels inactivate. The cardiac AP is
thus much longer than that in nerve or skeletal muscle.
Notes
Cardiac myocyte action potential
The resting potential of ventricular myocytes is about -90 mV. An action potential (AP) is initiated when the
myocyte is depolarised to a threshold potential of about -65 mV, as a result of transmission from an adjacent
myocyte via gap junctions.
Depolarisation:
+ +
Fast voltage-gated Na channels are activated and a Na influx depolarises the membrane rapidly to about +30
mV. This initial depolarisation is similar to that in nerve and skeletal muscle, and assists the transmission to the
next myocyte.
+
Na channels and currents rapidly inactivate, but in cardiac myocytes, the initial depolarisation activates voltage-
2+ 2+
gated Ca channels (slow L-type channels, threshold approximately – 45 mV) through which Ca floods into the
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cell. The
2+
resulting influx of Ca prevents the cell from repolarising and causes a plateau phase, that is maintained for about
250 ms until the L-type channels inactivate. The cardiac AP is thus much longer than that in nerve or skeletal
muscle.
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Repolarisation:
+ +
Repolarisation occurs due to activation of voltage-gated K rectifier channels and a K efflux. As the AP lasts
almost as long as contraction, its refractory period prevents another AP being initiated until the muscle relaxes,
thus cardiac muscle cannot exhibit tetanus.
Image modified by FRCEM Success. [CC-BY-SA-3.0 (or GFDL (], via Wikimedia Commons
Atrial myocytes have a similar but more triangular AP compared to the ventricles (less plateau). Purkinje fibres in
the conduction system are also similar to ventricular myocytes, but have a spike at the peak of the upstroke
+
reflecting a larger Na current that contributes to their fast conduction velocity.
a) Blood-brain barrier
b) Renal glomeruli
c) Reticuloendothelial system
d) Skin
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e) Lungs
Something wrong?
Answer
Discontinuous capillaries, found in the reticuloendothelial system (bone marrow, liver and spleen), have large gaps
between endothelial cells and are permeable to red blood cells.
Notes
Capillaries and the smallest venules are formed from a single layer of endothelial cells supported on the outside by
a basal lamina containing collagen. The luminal surface is covered by the glycoprotein network called the
glycocalyx.
Capillary permeability
Capillaries throughout the body vary in their permeability based on the size of their pores. There are three basic types:
Continuous capillaries, found in the skin, lungs, muscles and CNS, are the most selective with low permeability,
as junctions between the endothelial cells are very tight, restricting the flow of molecules with MW >
10,000. Fenestrated capillaries, found in renal glomeruli, endocrine glands and intestinal villi, are more
permeable with less tight junctions, and the endothelial cells are also punctured by pores which allow large
amounts of fluids or metabolites to pass.
Discontinuous capillaries, found in the reticuloendothelial system (bone marrow, liver and spleen), have large
gaps between endothelial cells and are permeable to red blood cells.
Water, gases and other substances cross the capillary wall mainly by diffusion down their concentration gradients.
Non-polar lipophilic substances e.g. CO2 and O2 can cross the endothelial lipid bilayer membrane easily. The
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membrane is however more impermeable to hydrophilic molecules such as glucose and polar molecules and ions.
Such substances mainly cross the wall of continuous capillaries through the gaps between endothelial cells, slowed
down by tight junctions between cells and by the glycocalyx so that diffusion is much slower than for lipophilic
substances.
This small pore system also prevents the diffusion of substances greater than 10,000 Da such as plasma proteins.
Plasma proteins can cross the capillary wall, but extremely slowly; this may involve large pores through endothelial
cells, such as in fenestrated capillaries or large spaces between endothelial cells, such as in discontinuous
capillaries.
Answer
Noradrenaline (the sympathetic neurotransmitter) is a positive inotrope; it binds to β1-adrenoceptors on the
2+ 2+
membrane and causes increased Ca entry via L-type channels during the AP and thus increases Ca release
2+ 2+
from the SR. Noradrenaline also increases Ca sequestration into the SR and thus more Ca is available for the
2+
next contraction. Cardiac glycosides (e.g. digoxin) slow the removal of Ca from the cell by inhibiting the
+ + 2+
membrane Na pump which generates the Na gradient required for driving the export of Ca ; consequently the
2+ 2+
removal of Ca from the myocyte is slowed and more Ca is available for the next contraction. Acidosis is
+ 2+
negatively inotropic, largely because H competes for Ca binding sites.
Notes
2+
Cardiac muscle contracts when intracellular Ca rises (> 100
2+
Although Ca entry during the action potential (AP) is essential for contraction, it only accounts for about 25% of the
2+ 2+
rise in intracellular Ca . The rest is released from Ca stores in the sarcoplasmic reticulum (SR).
APs travel down invaginations of the sarcolemma called T-tubules, which are close to, but do not touch, the
2+ 2+ 2+
terminal cisternae of the SR. During the AP plateau, Ca enters the cell and activates Ca sensitive Ca release
2+ 2+
channels in the sarcoplasmic reticulum allowing stored Ca to flood into the cytosol; this is called Ca -induced
2+ 2+ 2+
Ca release. The amount of Ca released is dependent on how much is stored, and on the size of the initial Ca
influx during the AP.
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2+ 2+
In relaxation, about 80% of Ca is rapidly pumped back into the SR (sequestered) by Ca ATPase pumps. The
2+ + 2+
Ca that entered the cell during the AP is transported out of the cell primarily by the Na /Ca exchanger in the
membrane
2+ + +
which pumps one Ca ion out in exchange for three Na ions in, using the Na electrochemical gradient as an
energy source. This is relatively slow and continues during diastole.
2+
Treppe effect: When more action potentials occur per unit time, more Ca enters the cell during the AP plateau,
2+ 2+ 2+
more Ca is stored in the SR, more Ca is released from the SR and thus more Ca is left inside the cell and
greater tension is produced during contraction. Increased heart rate increases the force of contraction in a
stepwise fashion as
2+
intracellular [Ca ] increases cumulatively over several beats.
Inotropic agents
2+
Factors that affect intracellular [Ca ] and hence cardiac contractility are called inotropes.
2+ +
Cardiac glycosides (e.g. digoxin) slow the removal of Ca from the cell by inhibiting the membrane Na pump which
+ 2+ 2+
generates the Na gradient required for driving the export of Ca ; consequently the removal of Ca from the
2+
myocyte is slowed and more Ca is available for the next contraction.
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+ 2+
Acidosis is negatively inotropic, largely because H competes for Ca binding sites.
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Which of the following represents ventricular repolarisation on the ECG:
a) T wave
b) QRS complex
c) P wave
d) PR interval
e) ST segment
Something wrong?
Answer
ECG Event
Notes
The cardiac cycle describes the events that occur during one beat of the heart.
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At the start of the cardiac cycle, towards the end of diastole, the whole of the heart is relaxed. The atrioventricular
(AV) valves are open because the atrial pressure is still slightly greater than the ventricular pressure. The semilunar
valves are closed, as the pressure in the pulmonary artery and aorta is greater than the ventricular pressures. The
cycle starts when the sinoatrial node (SAN) initiates atrial systole.
Atrial depolarisation causes the P wave on the ECG and initiates atrial contraction (atrial repolarisation is too
diffuse to be seen on the ECG).
As the atria contract, the atrial pressure increases which forces more blood flow across the open AV valves, leading
to rapid flow of blood into the ventricles. There are no valves between the veins and atria and atrial systole causes
a small pressure rise in the great veins (the a wave on the JVP waveform).
At rest, atrial contraction only contributes the last 15 – 20% of the final ventricular volume, as most of the
ventricular filling has occurred passively in diastole due to venous pressure. The proportion of atrial contribution
increases with heart rate as diastole shortens and there is less time for passive ventricular filling.
The end-diastolic volume (EDV) is usually about 120 – 140 mL, and the end-diastolic pressure is less than 10
mmHg (and higher in the left ventricle than the right due to the thicker and therefore stiffer left ventricle).
In ventricular hypertrophy, filling of the ‘stiff’ ventricle by atrial systole causes a fourth heart sound, which is not
audible in normal adults.
Ventricular depolarisation causes the QRS complex on the ECG, and triggers excitation-contraction coupling and
myocyte contraction.
The ventricular pressure rises sharply during contraction and the AV valves close as soon as this is greater than
the atrial pressure (causing the first heart sound). Because the mitral valve closes before the tricuspid valve, the first
heart sound may be split.
For a short period, as the forces are developing, both the AV and the semilunar valves are closed as the ventricular
pressure is still less than that in the pulmonary artery and aorta, and no ejection occurs. This is isovolumetric
contraction.
The increasing pressure makes the AV valves bulge into the atria, causing a small atrial pressure wave (the c wave of
the JVP waveform).
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When the ventricular pressure exceeds that in the pulmonary artery and the aorta, the semilunar valves open and
blood is ejected, initially rapidly (rapid ejection phase) and then more slowly (reduced ejection phase).
Atrial pressure initially decreases as the atrial base is pulled downward during ejection, expanding the atrial chamber
(the x descent of the JVP waveform). Atrial filling begins in the rapid ejection phase and continues during the
reduced ejection phase and atrial pressure begins to rise (the v wave of the JVP waveform).
During the second half of ejection, the ventricles stop actively contracting, the ventricular pressure starts to
decrease and the muscle starts to repolarise; this causes the T wave on the ECG, which marks the end of both
ventricular contraction and rapid ventricular ejection.
The ventricular pressure during the reduced ejection phase begins to decrease. Aortic pressure also decreases
because of the runoff of blood from large arteries into smaller arteries. The ventricular pressure falls slightly
below that in the aorta, but initially blood continues to flow out of the ventricle because of momentum;
eventually the ventricular pressure falls sufficiently and the semilunar valves close.
Closure of the semilunar valves causes a small increase in aortic pressure (the dicrotic notch on the arterial
waveform), and the second heart sound. Inspiration delays closure of the pulmonary valve and thus causes splitting of
the second heart sound.
The amount of blood ejected is the stroke volume (SV), and is usually about 70 mL (therefore about 50 mL is left;
this is the end-systolic volume). The proportion of EDV that is ejected (i.e. the SV/EDV) is the ejection fraction and
this is normally about 0.6.
Immediately after the closure of the semilunar valves, the ventricles rapidly relax and ventricular pressure
decreases rapidly but the AV valves remain closed as initially the ventricular pressure is still greater than atrial
pressure. This is isovolumetric relaxation.
Atrial pressure continues to rise because of venous return, with the v wave of the JVP waveform peaking during
this phase. As the ventricles continue to relax, the ventricular pressure falls below that of the atrial pressure and
the AV valves open.
When the AV valves open, the atrial pressure falls (the y descent of the JVP waveform) and the ventricles refill,
initially rapidly (the rapid filling phase) and then more slowly as the ventricles expand, become less complicant, and
ventricular pressures rise (the reduced filling phase). Rapid flow of blood from the atria into the ventricles causes
the third heart sound, which is normal in children but, in adults, is associated with disease such as ventricular
dilation.
Diastole is usually twice the length of systole at rest, but decreases with increased heart rate. During systole,
contraction of the ventricles compresses the coronary arteries and suppresses blood flow. This is particularly evident
in the left ventricle, where during systole the ventricular pressure is the same as or greater than that in the arteries
and as a result more than 85% of left ventricular perfusion occurs during diastole. This becomes a problem if the
heart rate is increased as the diastolic interval is shorter and can result in ischaemia.
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Valves during cardiac cycle
Atrial systole Open (atrial pressure > ventricular Closed (arterial pressure > ventricular
pressure) pressure)
Isovolumetric Closed (ventricular pressure > atrial Closed (arterial pressure > ventricular
contraction pressure) pressure)
Ventricular ejection Closed (ventricular pressure > atrial Open (ventricular pressure > arterial
pressure) pressure)
Isovolumetric Closed (ventricular pressure > atrial Closed (arterial pressure > ventricular
relaxation pressure) pressure)
Ventricular filling Open (atrial pressure > ventricular Closed (arterial pressure > ventricular
pressure) pressure)
c wave Isovolumetric Occurs due to the bulging of the tricuspid valve into the right atrium
contraction during right isovolumetric ventricular contraction
(early systole)
x descent Rapid ventricular Occurs due to a combination of right atrial relaxation, the downward
ejection (mid systole) displacement of the tricuspid valve during right ventricular contraction,
and the ejection of blood from both the ventricles
v wave Ventricular ejection Occurs due to right atrial filling from venous return
and isovolumetric
relaxation (late
systole)
y descent Ventricular filling Occurs due to opening of the tricuspid valve and the subsequent rapid
(early diastole) inflow of blood from the right atrium to the right ventricle
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First Start of systole Caused by closure of the atrioventricular (mitral & tricuspid) valves
heart
sound
Second heart End of systole Caused by closure of the semilunar (aortic and pulmonary) valves
sound
Third heart Early diastole Caused by rapid flow of blood from the atria into the ventricles during the
sound ventricular filling phase
Fourth heart Late diastole Caused by filling of an abnormally stiff ventricle in atrial systole
sound
ECG Event
Which of the following best describes the mean arterial pressure (MAP):
Answer
The difference between the systolic and diastolic pressure is the pulse pressure.
The mean arterial pressure (MAP) cannot be calculated by averaging these pressures, because for about 60% of
the time, the heart is in diastole. It is instead estimated as the diastolic + one-third of the pulse pressure, e.g. = 80
+ 1/3(110 – 80) = 90 mmHg where BP 110/80 mmHg.
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Notes
Total blood volume, cardiac output and stroke volume
The total blood volume in the circulatory system of a healthy adult is about 5 L.
The stroke volume is the volume of blood ejected per beat. It is usually about 70 mL/beat at
rest. The heart rate is the number of beats per minute. It is usually about 70 beats/minute
at rest.
The cardiac output is the volume of blood pumped out of heart via the aorta per minute.
Cardiac output (CO) = Stroke volume x Heart rate = 70 mL/beat x 70 beats/min = 4900
During systole, the pressure in the left ventricle increases and blood is ejected into the aorta. The rise in pressure
stretches the elastic walls of the aorta and large arteries and drives blood flow. Systolic pressure is the maximum
arterial pressure during systole. During diastole, arterial blood flow is partly maintained by elastic recoil of the walls
of large arteries. The minimum pressure reached before the next systole is the diastolic pressure. The difference
between the systolic and diastolic pressure is the pulse pressure.
The mean arterial pressure (MAP) cannot be calculated by averaging these pressures, because for about 60% of
the time, the heart is in diastole. It is instead estimated as the diastolic + one-third of the pulse pressure, e.g. = 80
+ 1/3(110 – 80) = 90 mmHg where BP 110/80 mmHg.
The mean arterial pressure (MAP) at the start of the arterioles is about 65 mmHg. The pressure on the arterial side
of capillaries is about 25 mmHg, and on the venous side is about 15 mmHg. Venules converge into veins and finally
the vena cava. The pressure in the vena cava at the level of the heart (the central venous pressure) is usually close
to 0 mmHg.
Regarding the skeletal muscle circulation, which of the following statements is CORRECT:
a)
Blood flow through skeletal muscle involves arteriovenous anastomoses which directly link arterioles and venules.
b) Capillaries are recruited during exercise by metabolic hyperaemia caused by release of Ca2+.
c) Sympathetic activity causes vasodilation of the arterioles in working skeletal muscle.
d) The skeletal muscle circulation usually receives around 10% of the cardiac output.
e)
The skeletal muscle circulation plays a significant role in increasing total peripheral resistance in the baroreceptor
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reflex.
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Something wrong?
Answer
The skeletal muscle circulation normally receives about 15 – 20% of the cardiac output, but this may rise to > 80%
during exercise. Skeletal muscle provides a major contribution to the total peripheral resistance and sympathetic
regulation of muscle blood flow is important in the baroreceptor reflex. At rest most capillaries are not perfused as
their arterioles are constricted. Capillaries are recruited during exercise by metabolic hyperaemia, caused by release
of
+
K and CO2 from the muscle and adenosine. This overrides sympathetic vasoconstriction in working muscle; the latter
reduces flow in non-working muscle conserving cardiac output.
Notes
Skeletal muscle circulation
The skeletal muscle circulation normally receives about 15 – 20% of the cardiac output, but this may rise to > 80%
during exercise. Skeletal muscle provides a major contribution to the total peripheral resistance and sympathetic
regulation of muscle blood flow is important in the baroreceptor reflex. At rest most capillaries are not perfused as
their arterioles are constricted. Capillaries are recruited during exercise by metabolic hyperaemia, caused by release
of
+
K and CO2 from the muscle and adenosine. This overrides sympathetic vasoconstriction in working muscle; the latter
reduces flow in non-working muscle conserving cardiac output.
Pulmonary circulation
The pulmonary circulation is not controlled by either autonomic nerves or metabolic products, and the most
important mechanism regulating flow is hypoxic pulmonary vasoconstriction, in which small arteries constrict in
response to hypoxia (in contrast to elsewhere in the body).
If an area of lung is poorly ventilated and the alveolar partial pressure of oxygen is low, pulmonary blood vessels
are constricted and blood is diverted to areas of the lung that are better ventilated, thus maintaining optimal
ventilation- perfusion matching. This effect is accentuated by high alveolar PCO 2.
The response is unhelpful in the presence of global lung hypoxia, at altitude or in respiratory failure, where it may
contribute to the development of pulmonary hypertension and right-sided heart failure (cor pulmonale).
Cutaneous circulation
The main function of the cutaneous circulation is thermoregulation. Arteriovenous anastomoses (AVAs) directly
linked arterioles and venules, allowing a high blood flow into the venous plexus and thus radiation of heat. AVAs
are mostly found in the hands, feet and areas of the face.
Temperature is sensed by peripheral thermoreceptors and the hypothalamus coordinates the response.
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When temperature is low, sympathetic stimulation of alpha-adrenergic receptors causes vasoconstriction of
cutaneous vessels minimising loss of body heat (a similar response occurs in the baroreceptor reflex). Piloerection
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traps insulating air.
Increased temperatures reduce sympathetic adrenergic stimulation, causing vasodilation and allowing more blood
to flow to the skin and radiate its heat to the environment, whereas activation of sympathetic cholinergic fibres
promotes sweating and the release of bradykinin, which also causes vasodilation.
Cerebral circulation
The brain receives around 15% of the total cardiac output and has a high capillary density.
The endothelial cells of the capillaries of the blood-brain barrier have very tight junctions, and contain membrane
transporters that control the movement of substances, such as ions, glucose and amino acids, and tightly regulate
the composition of cerebrospinal fluid. This is continuous except where substances need to be absorbed or released
e.g. pituitary gland, choroid plexus.
The autoregulation of cerebral blood flow can maintain a constant flow for blood pressures between 50 and 170
+
mmHg. CO2 and K are particularly important metabolic regulators in the brain, with increasing concentration
causing vasodilation and a functional hyperaemia.
Hyperventilation reduces blood PCO2 and can cause fainting due to cerebral vasoconstriction.
Coronary circulation
The heart has a high metabolic demand and its high capillary density allow it to extract an unusually large fraction
(about 70%) of oxygen from the blood.
In exercise, the reduced diastolic interval and increased oxygen consumption demand a greatly increased blood
+
flow which is achieved by metabolic hyperaemia mediated by adenosine, K and hypoxia. This overrides the
vasoconstriction mediated by sympathetic nerves acting at alpha-adrenergic receptors and is assisted by circulating
adrenaline which causes vasodilation by acting on beta-adrenergic receptors.
a) Tight junctions
b) Intercalated discs
c) Sarcolemma
d) T-tubules
e) Microglia
Something wrong?
Answer
Adjacent cardiac myocytes are connected to each other by intercalated discs. The intercalated discs provide both a
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structural attachment by ‘glueing’ cells together at desmosomes and an electrical contact made up of proteins called
connexons, called a gap junction, which essentially creates a low-resistance pathway between cells.
Notes
Myocytes
The myocardium is composed of cardiac muscle cells called myocytes. The cells are striated due to the
arrangement of the thick and thin filaments which make up the bulk of the muscle, although they are less
organised than in skeletal muscle. The myocytes are small and branched, with a single nucleus and are rich in
mitochondria. The normal pumping action of the heart is dependent on the synchronised contraction of all cardiac
cells.
Intercalated discs
The synchronicity between myocytes occurs because all the adjacent cells are connected by intercalated discs. The
intercalated discs provide both a structural attachment by ‘glueing’ cells together at desmosomes and an electrical
contact made up of proteins called connexons, called a gap junction, which essentially creates a low-resistance
pathway between cells. Gap junctions allow action potentials to spread rapidly from one cell to another and allows
the myocardium to act as a functional syncytium.
Cardiac pacemaker
Cardiac myocyte contraction is not dependent on an external nerve supply but instead the heart generates its own
rhythm, demonstrating inherent rhythmicity.
The heartbeat is initiated by spontaneous depolarisation of the sinoatrial node (SAN), a region of specialised
myocytes in the right atrium, close to the coronary sinus. The rate is modulated by the autonomic nervous system.
Action potentials in the SAN activate adjacent atrial myocytes and a wave of depolarisation and contraction
therefore spreads through atrial muscle. This is prevented from reaching the ventricles directly by the annulus
fibrosis.
This impulse is channelled through the atrioventricular node (AVN), located between the right atrium and ventricle
near the atrial septum. The AVN contains small cells and thus conducts slowly and delays the impulse for about 120
ms, allowing time for atrial contraction to complete ventricular filling.
Once complete, the impulse is then transmitted by specialised, wide, fast conducting myocytes in the bundle of His
and Purkinje fibres, by which it is distributed over the inner surface of both ventricles. From here a wave of
depolarisation and contraction moves from myocyte to myocyte across the endocardium until the whole ventricular
mass is activated.
Electrocardiogram (ECG)
The wave of depolarisation through the heart causes local currents in surrounding fluid which are detected at the body
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surface as small changes in voltage. This forms the basis of the ECG. The classical ECG records voltage between
the left and right arm (lead I), the right arm and left leg (lead II) and the left arm and left leg (lead III). This is
represented by Einthoven’s triangle. The size of the voltage at any time depends on the quantity of muscle
depolarisation and the direction in which the wave of depolarisation is travelling. Thus lead II normally shows the
largest deflection during ventricular depolarisation, as the muscle mass is greatest and depolarisation travels from
apex to base, more or less parallel to a line from the left hip to the right shoulder.
By Npatchett (Own work) [CC BY-SA 4.0 (], via Wikimedia Commons
Something wrong?
Answer
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2+
Most vasoconstrictors bind to G-protein coupled receptors which mediate elevation in intracellular [Ca ], leading
to vascular smooth muscle contraction. Important vasoconstrictors include endothelin-1, angiotensin II and
2+ 2+
noradrenaline. The increase in intracellular [Ca ] is brought about by release of Ca from the sarcoplasmic
reticulum
2+ 2+
and by depolarisation and entry of Ca via L-type voltage-gated Ca channels. Most types of vascular smooth muscle
2+
do not generate action potentials, but instead depolarisation is graded, allowing graded entry of Ca .
2+ 2+
Vasodilation occurs by decreasing intracellular [Ca ] by sequestration by the sarcoplasmic reticulum Ca
2+ + 2+
ATPase and by removal from the cell by a plasma membrane Ca ATPase and Na /Ca exchange. Most
endogenous
vasodilators cause relaxation by increasing cyclic guanosine monophosphate (cGMP) (e.g. nitric oxide) or cyclic
adenosine monophosphate (cAMP) (e.g. prostacyclin, beta-adrenergic receptor agonists), which activate protein
2+
kinases causing substrate level phosphorylation. L-type Ca channel blocker drugs are clinically effective
vasodilators.
Notes
The endothelium
The endothelium plays a vital role in regulation of vascular tone (as well as regulation of haemostasis, angiogenesis and
inflammatory response).
In response to substances in the blood, endothelial damage or changes in blood flow, it can synthesise several
important substances; nitric oxide and prostacyclin are important vasodilators and endothelin-1 and thromboxane
A2 are potent vasoconstrictors.
2+
Nitric oxide (NO) production by the endothelium is increased by factors that elevate intracellular Ca , including
local mediators such as bradykinin, histamine and serotonin, and some neurotransmitters (e.g. substance P). Increased
flow (shear stress) also stimulates NO production and additionally activates prostacyclin synthesis. The basal
production of NO continuously modulates vascular resistance. Nitric oxide also inhibits platelet activation and
thrombosis.
Endothelin-1 (ET-1) is an extremely potent vasoconstrictor peptide which is released from the endothelium in the
presence of many other vasoconstrictors, including angiotensin II, antidiuretic hormone (ADH) and noradrenaline,
and may be increased in disease and hypoxia.
The eicosanoids prostacyclin (PGI2) and thromboxane A2 (TXA2) are synthesised by the cyclooxygenase pathway from
arachidonic acid, which is made from membrane phospholipids by phospholipase A2.
Vasoconstriction
2+
Most vasoconstrictors bind to G-protein coupled receptors which mediate elevation in intracellular [Ca ], leading
to vascular smooth muscle contraction. Important vasoconstrictors include endothelin-1, angiotensin II and
noradrenaline.
2+ 2+
The increase in intracellular [Ca ] is brought about by release of Ca from the sarcoplasmic reticulum and by
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2+ 2+
depolarisation and entry of Ca via L-type voltage-gated Ca channels. Most types of vascular smooth muscle do not
2+
generate action potentials, but instead depolarisation is graded, allowing graded entry of Ca .
Vasodilation
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2+ 2+
Vasodilation occurs by decreasing intracellular [Ca ] by sequestration by the sarcoplasmic reticulum Ca
2+ + 2+
ATPase and by removal from the cell by a plasma membrane Ca ATPase and Na /Ca exchange.
Most endogenous vasodilators cause relaxation by increasing cyclic guanosine monophosphate (cGMP) (e.g. nitric
oxide) or cyclic adenosine monophosphate (cAMP) (e.g. prostacyclin, beta-adrenergic receptor agonists), which
2+
activate protein kinases causing substrate level phosphorylation. L-type Ca channel blocker drugs are clinically
effective vasodilators.
Thromboxane A2 Prostacyclin
Angiotensin II Beta-agonists
Conduction of impulses between the atria and the ventricles is channelled through:
Answer
This impulse is channelled through the atrioventricular node (AVN), located between the right atrium and ventricle
near the atrial septum. The AVN contains small cells and thus conducts slowly and delays the impulse for about 120
ms, allowing time for atrial contraction to complete ventricular filling.
Notes
Myocytes
The myocardium is composed of cardiac muscle cells called myocytes. The cells are striated due to the
arrangement of the thick and thin filaments which make up the bulk of the muscle, although they are less
organised than in skeletal muscle. The myocytes are small and branched, with a single nucleus and are rich in
mitochondria. The normal pumping action of the heart is dependent on the synchronised contraction of all cardiac
cells.
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Intercalated discs
The synchronicity between myocytes occurs because all the adjacent cells are connected by intercalated discs. The
intercalated discs provide both a structural attachment by ‘glueing’ cells together at desmosomes and an electrical
contact made up of proteins called connexons, called a gap junction, which essentially creates a low-resistance
pathway between cells. Gap junctions allow action potentials to spread rapidly from one cell to another and allows
the myocardium to act as a functional syncytium.
Cardiac pacemaker
Cardiac myocyte contraction is not dependent on an external nerve supply but instead the heart generates its own
rhythm, demonstrating inherent rhythmicity.
The heartbeat is initiated by spontaneous depolarisation of the sinoatrial node (SAN), a region of specialised
myocytes in the right atrium, close to the coronary sinus. The rate is modulated by the autonomic nervous system.
Action potentials in the SAN activate adjacent atrial myocytes and a wave of depolarisation and contraction
therefore spreads
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through atrial muscle. This is prevented from reaching the ventricles directly by the annulus fibrosis.
This impulse is channelled through the atrioventricular node (AVN), located between the right atrium and ventricle
near the atrial septum. The AVN contains small cells and thus conducts slowly and delays the impulse for about 120
ms, allowing time for atrial contraction to complete ventricular filling.
Once complete, the impulse is then transmitted by specialised, wide, fast conducting myocytes in the bundle of His
and Purkinje fibres, by which it is distributed over the inner surface of both ventricles. From here a wave of
depolarisation and contraction moves from myocyte to myocyte across the endocardium until the whole ventricular
mass is activated.
Electrocardiogram (ECG)
The wave of depolarisation through the heart causes local currents in surrounding fluid which are detected at the
body surface as small changes in voltage. This forms the basis of the ECG. The classical ECG records voltage
between the left and right arm (lead I), the right arm and left leg (lead II) and the left arm and left leg (lead III).
This is represented by Einthoven’s triangle. The size of the voltage at any time depends on the quantity of muscle
depolarisation and the direction in which the wave of depolarisation is travelling. Thus lead II normally shows the
largest deflection during ventricular depolarisation, as the muscle mass is greatest and depolarisation travels from
apex to base, more or less parallel to a line from the left hip to the right shoulder.
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By Npatchett (Own work) [CC BY-SA 4.0 (], via Wikimedia Commons
a) Autoregulation is the ability to maintain a constant blood flow at very high blood pressures (> 170 SBP).
b) In the myogenic mechanism, arterial vasodilation occurs in response to stretching of the vessel wall.
c) An increase in blood flow dilutes locally produced vasodilating factors causing vasoconstriction.
d) Autoregulation is particularly important in the pulmonary circulation.
e) The myogenic mechanism involves activation of smooth muscle stretch-activated Na+ channels.
Something wrong?
Answer
Autoregulation is the ability to maintain a constant blood flow despite variations in blood pressure (between 50 –
170 mmHg). It is particularly important in the brain, kidney and heart. There are two main methods contributing to
autoregulation.
The myogenic mechanism involves arterial constriction in response to stretching of the vessel wall,
2+ 2+
probably due to activation of smooth muscle stretch-activated Ca channels and Ca entry. A reduction
in pressure and stretch closes these channels, causing vasodilatation.
The second mechanism of autoregulation is due to locally produced vasodilating factors; an increase in blood
flow dilutes these factors causing vasoconstriction, whereas decreased blood flow has the opposite
effect.
Notes
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In addition to central control of blood pressure, tissues can regulate their own blood flow to match their
requirements via autoregulation, metabolic factors and local hormones (autocoids).
Autoregulation
Autoregulation is the ability to maintain a constant blood flow despite variations in blood pressure (between 50 –
170 mmHg). It is particularly important in the brain, kidney and heart. There are two main methods contributing to
autoregulation.
The myogenic mechanism involves arterial constriction in response to stretching of the vessel wall,
2+ 2+
probably due to activation of smooth muscle stretch-activated Ca channels and Ca entry. A reduction
in pressure and stretch closes these channels, causing vasodilatation.
The second mechanism of autoregulation is due to locally produced vasodilating factors; an increase in blood
flow dilutes these factors causing vasoconstriction, whereas decreased blood flow has the opposite
effect.
Metabolic factors
+
Many factors may contribute to metabolic hyperaemia (increased blood flow), with the most important being K ,
CO2 and adenosine, and in some cases hypoxia itself.
+ +
K , released from active tissues and in ischaemia, causes vasodilation partly by stimulating the Na pump, thus
2+
increasing Ca removal from smooth muscle cells and hyperpolarising the cell.
CO2 and acidosis cause vasodilation largely through increased nitric oxide production and inhibition of smooth
2+
muscle Ca entry.
Adenosine, released from the heart, skeletal muscle and brain during increased metabolism and
hypoxia, causes vasodilation by stimulating the production of cAMP in smooth muscle.
+
Hypoxia may reduce ATP sufficiently for K channels to activate causing hyperpolarisation.
Autocoids
In inflammation, local inflammatory mediators such as histamine and bradykinin cause vasodilation
and increased permeability of exchange vessels, leading to swelling but allowing access by immune
cells to damaged tissues.
In clotting, serotonin and thromboxane A2 released from activated platelets cause vasoconstriction to help
reduce bleeding.
The upstroke of the action potential of the sinoatrial node occurs due to which of the
following:
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Something wrong?
Answer
+
The upstroke of the AP is slow, as it is not due to activation of fast Na channels like cardiac myocytes, but instead
2+ +
slow L-type Ca channels; the SA node contains no functional fast Na channels. The slow upstroke means that
conduction
between nodal myocytes is slow, which is particularly important at the atrioventricular node (which has a similar AP
to the SAN).
Notes
Sinoatrial node action potential
The action potential (AP) of the sinoatrial node (SAN) differs from that in ventricular muscle.
The resting potential of the SAN is about – 60 mV, and it decays steadily with time until it reaches a threshold
potential of about – 40 mV, when an action potential is initiated.
+
The upstroke of the AP is slow, as it is not due to activation of fast Na channels like cardiac myocytes, but instead
2+ +
slow L-type Ca channels; the SA node contains no functional fast Na channels. The slow upstroke means that
conduction
between nodal myocytes is slow, which is particularly important at the atrioventricular node (which has a similar AP
to the SAN).
The rate of decay of the SAN resting potential determines the rate of AP and therefore of heart rate, it is therefore
+
called the pacemaker potential. The pacemaker potential decays because of a slowly reducing outward K current
set
against inward currents. Factors that affect these currents alter the rate of decay and the time to reach threshold
and thus heart rate and are called chronotropic agents.
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Chronotropic agents
Noradrenaline (the sympathetic neurotransmitter) is a positive chronotrope and causes a faster rate of decay and thus
heart rate whereas acetylcholine (the parasympathetic neurotransmitter) is a negative chronotrope and lengthens the
time to reach threshold and decreases heart rate.
Other atrial cells, the AV node, the bundle of His and Purkinje system may also exhibit decaying resting potentials
that can act as pacemakers. However the SAN is normally fastest and predominates – this is called overdrive
suppression.
a) It is located between the right atrium and ventricle near the atrial septum.
b) It is a region of specialised nerve cells that can initiate an impulse.
c) Rate of depolarisation is increased by sympathetic stimulation.
d) Rate of depolarisation is not affected by parasympathetic stimulation.
e) Initiation of depolarisation is mediated by the sympathetic nervous system.
Something wrong?
Answer
Cardiac myocyte contraction is not dependent on an external nerve supply but instead the heart generates its own
rhythm, demonstrating inherent rhythmicity.
The heartbeat is initiated by spontaneous depolarisation of the sinoatrial node (SAN), a region of specialised
myocytes in the right atrium, close to the coronary sinus. The rate is modulated by the autonomic nervous system:
increased by the sympathetic nervous system and decreased by the parasympathetic nervous system. Action
potentials in the SAN activate adjacent atrial myocytes and a wave of depolarisation and contraction therefore
spreads through atrial muscle. This is prevented from reaching the ventricles directly by the annulus fibrosis.
Notes
Myocytes
The myocardium is composed of cardiac muscle cells called myocytes. The cells are striated due to the
arrangement of the thick and thin filaments which make up the bulk of the muscle, although they are less
organised than in skeletal muscle. The myocytes are small and branched, with a single nucleus and are rich in
mitochondria. The normal pumping action of the heart is dependent on the synchronised contraction of all cardiac
cells.
Intercalated discs
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The synchronicity between myocytes occurs because all the adjacent cells are connected by intercalated discs. The
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intercalated discs provide both a structural attachment by ‘glueing’ cells together at desmosomes and an electrical
contact made up of proteins called connexons, called a gap junction, which essentially creates a low-resistance
pathway between cells. Gap junctions allow action potentials to spread rapidly from one cell to another and allows
the myocardium to act as a functional syncytium.
Cardiac pacemaker
Cardiac myocyte contraction is not dependent on an external nerve supply but instead the heart generates its own
rhythm, demonstrating inherent rhythmicity.
The heartbeat is initiated by spontaneous depolarisation of the sinoatrial node (SAN), a region of specialised
myocytes in the right atrium, close to the coronary sinus. The rate is modulated by the autonomic nervous system.
Action potentials in the SAN activate adjacent atrial myocytes and a wave of depolarisation and contraction
therefore spreads through atrial muscle. This is prevented from reaching the ventricles directly by the annulus
fibrosis.
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This impulse is channelled through the atrioventricular node (AVN), located between the right atrium and ventricle
near the atrial septum. The AVN contains small cells and thus conducts slowly and delays the impulse for about 120
ms, allowing time for atrial contraction to complete ventricular filling.
Once complete, the impulse is then transmitted by specialised, wide, fast conducting myocytes in the bundle of His
and Purkinje fibres, by which it is distributed over the inner surface of both ventricles. From here a wave of
depolarisation and contraction moves from myocyte to myocyte across the endocardium until the whole ventricular
mass is activated.
Electrocardiogram (ECG)
The wave of depolarisation through the heart causes local currents in surrounding fluid which are detected at the
body surface as small changes in voltage. This forms the basis of the ECG. The classical ECG records voltage
between the left and right arm (lead I), the right arm and left leg (lead II) and the left arm and left leg (lead III).
This is represented by Einthoven’s triangle. The size of the voltage at any time depends on the quantity of muscle
depolarisation and the direction in which the wave of depolarisation is travelling. Thus lead II normally shows the
largest deflection during ventricular depolarisation, as the muscle mass is greatest and depolarisation travels from
apex to base, more or less parallel to a line from the left hip to the right shoulder.
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Answer
2+ 2+ 2+
During the AP plateau, Ca enters the cell and activates Ca sensitive Ca release channels in the sarcoplasmic
2+ 2+ 2+
reticulum allowing stored Ca to flood into the cytosol; this is called Ca -induced Ca release. In relaxation,
2+ 2+ 2+
about 80% of Ca is rapidly pumped back into the SR (sequestered) by Ca ATPase pumps. The Ca that
+ 2+
entered the cell during the AP is transported out of the cell primarily by the Na /Ca exchanger in the membrane
2+ + +
which pumps one Ca ion out in exchange for three Na ions in, using the Na electrochemical gradient as an
2+
energy source. Increased heart rate increases the force of contraction in a stepwise fashion as intracellular [Ca ]
increases cumulatively over
2+
several beats; this is the Treppe effect. Factors that affect intracellular [Ca ] and hence cardiac contractility are called
inotropes.
Notes
2+
Cardiac muscle contracts when intracellular Ca rises (> 100
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2+
Although Ca entry during the action potential (AP) is essential for contraction, it only accounts for about 25% of
2+ 2+
the rise in intracellular Ca . The rest is released from Ca stores in the sarcoplasmic reticulum (SR).
APs travel down invaginations of the sarcolemma called T-tubules, which are close to, but do not touch, the
2+ 2+ 2+
terminal cisternae of the SR. During the AP plateau, Ca enters the cell and activates Ca sensitive Ca release
2+ 2+
channels in the sarcoplasmic reticulum allowing stored Ca to flood into the cytosol; this is called Ca -induced
2+ 2+ 2+
Ca release. The amount of Ca released is dependent on how much is stored, and on the size of the initial Ca
influx during the AP.
2+ 2+
In relaxation, about 80% of Ca is rapidly pumped back into the SR (sequestered) by Ca ATPase pumps. The
2+ + 2+
Ca that entered the cell during the AP is transported out of the cell primarily by the Na /Ca exchanger in the
membrane
2+ + +
which pumps one Ca ion out in exchange for three Na ions in, using the Na electrochemical gradient as an
energy source. This is relatively slow and continues during diastole.
2+
Treppe effect: When more action potentials occur per unit time, more Ca enters the cell during the AP plateau,
2+ 2+ 2+
more Ca is stored in the SR, more Ca is released from the SR and thus more Ca is left inside the cell and
greater tension is produced during contraction. Increased heart rate increases the force of contraction in a
stepwise fashion as
2+
intracellular [Ca ] increases cumulatively over several beats.
Inotropic agents
2+
Factors that affect intracellular [Ca ] and hence cardiac contractility are called inotropes.
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2+ 2+
membrane and causes increased Ca entry via L-type channels during the AP and thus increases Ca release
2+ 2+
from the SR. Noradrenaline also increases Ca sequestration into the SR and thus more Ca is available for the
next contraction.
2+ +
Cardiac glycosides (e.g. digoxin) slow the removal of Ca from the cell by inhibiting the membrane Na pump which
+ 2+ 2+
generates the Na gradient required for driving the export of Ca ; consequently the removal of Ca from the
2+
myocyte is slowed and more Ca is available for the next contraction.
+ 2+
Acidosis is negatively inotropic, largely because H competes for Ca binding sites.
Which of the following JVP waveforms corresponds with rapid ventricular filling:
a) The a wave
b) The c wave
c) The v wave
d) The x descent
e) The y descent
Something wrong?
Answer
c wave Isovolumetric Occurs due to the bulging of the tricuspid valve into the right atrium
contraction during right isovolumetric ventricular contraction
(early systole)
x descent Rapid ventricular Occurs due to a combination of right atrial relaxation, the downward
ejection (mid systole) displacement of the tricuspid valve during right ventricular contraction,
and the ejection of blood from both the ventricles
v wave Ventricular ejection Occurs due to right atrial filling from venous return
and isovolumetric
relaxation (late
systole)
y descent Ventricular filling Occurs due to opening of the tricuspid valve and the subsequent rapid
(early diastole) inflow of blood from the right atrium to the right ventricle
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Notes
The cardiac cycle describes the events that occur during one beat of the heart.
At the start of the cardiac cycle, towards the end of diastole, the whole of the heart is relaxed. The atrioventricular
(AV) valves are open because the atrial pressure is still slightly greater than the ventricular pressure. The semilunar
valves are closed, as the pressure in the pulmonary artery and aorta is greater than the ventricular pressures. The
cycle starts when the sinoatrial node (SAN) initiates atrial systole.
Atrial depolarisation causes the P wave on the ECG and initiates atrial contraction (atrial repolarisation is too
diffuse to be seen on the ECG).
As the atria contract, the atrial pressure increases which forces more blood flow across the open AV valves, leading
to rapid flow of blood into the ventricles. There are no valves between the veins and atria and atrial systole causes
a small pressure rise in the great veins (the a wave on the JVP waveform).
At rest, atrial contraction only contributes the last 15 – 20% of the final ventricular volume, as most of the
ventricular filling has occurred passively in diastole due to venous pressure. The proportion of atrial contribution
increases with
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heart rate as diastole shortens and there is less time for passive ventricular filling.
The end-diastolic volume (EDV) is usually about 120 – 140 mL, and the end-diastolic pressure is less than 10
mmHg (and higher in the left ventricle than the right due to the thicker and therefore stiffer left ventricle).
In ventricular hypertrophy, filling of the ‘stiff’ ventricle by atrial systole causes a fourth heart sound, which is not
audible in normal adults.
Ventricular depolarisation causes the QRS complex on the ECG, and triggers excitation-contraction coupling and
myocyte contraction.
The ventricular pressure rises sharply during contraction and the AV valves close as soon as this is greater than
the atrial pressure (causing the first heart sound). Because the mitral valve closes before the tricuspid valve, the first
heart sound may be split.
For a short period, as the forces are developing, both the AV and the semilunar valves are closed as the ventricular
pressure is still less than that in the pulmonary artery and aorta, and no ejection occurs. This is isovolumetric
contraction.
The increasing pressure makes the AV valves bulge into the atria, causing a small atrial pressure wave (the c wave of
the JVP waveform).
When the ventricular pressure exceeds that in the pulmonary artery and the aorta, the semilunar valves open and
blood is ejected, initially rapidly (rapid ejection phase) and then more slowly (reduced ejection phase).
Atrial pressure initially decreases as the atrial base is pulled downward during ejection, expanding the atrial chamber
(the x descent of the JVP waveform). Atrial filling begins in the rapid ejection phase and continues during the
reduced ejection phase and atrial pressure begins to rise (the v wave of the JVP waveform).
During the second half of ejection, the ventricles stop actively contracting, the ventricular pressure starts to
decrease and the muscle starts to repolarise; this causes the T wave on the ECG, which marks the end of both
ventricular contraction and rapid ventricular ejection.
The ventricular pressure during the reduced ejection phase begins to decrease. Aortic pressure also decreases
because of the runoff of blood from large arteries into smaller arteries. The ventricular pressure falls slightly
below that in the aorta, but initially blood continues to flow out of the ventricle because of momentum;
eventually the ventricular pressure falls sufficiently and the semilunar valves close.
Closure of the semilunar valves causes a small increase in aortic pressure (the dicrotic notch on the arterial
waveform), and the second heart sound. Inspiration delays closure of the pulmonary valve and thus causes splitting of
the second heart sound.
The amount of blood ejected is the stroke volume (SV), and is usually about 70 mL (therefore about 50 mL is left; this is
the end-systolic volume). The proportion of EDV that is ejected (i.e. the SV/EDV) is the ejection fraction and this is
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Immediately after the closure of the semilunar valves, the ventricles rapidly relax and ventricular pressure
decreases rapidly but the AV valves remain closed as initially the ventricular pressure is still greater than atrial
pressure. This is isovolumetric relaxation.
Atrial pressure continues to rise because of venous return, with the v wave of the JVP waveform peaking during
this phase. As the ventricles continue to relax, the ventricular pressure falls below that of the atrial pressure and
the AV valves open.
When the AV valves open, the atrial pressure falls (the y descent of the JVP waveform) and the ventricles refill,
initially rapidly (the rapid filling phase) and then more slowly as the ventricles expand, become less complicant, and
ventricular pressures rise (the reduced filling phase). Rapid flow of blood from the atria into the ventricles causes
the third heart sound, which is normal in children but, in adults, is associated with disease such as ventricular
dilation.
Diastole is usually twice the length of systole at rest, but decreases with increased heart rate. During systole,
contraction of the ventricles compresses the coronary arteries and suppresses blood flow. This is particularly evident
in the left ventricle, where during systole the ventricular pressure is the same as or greater than that in the arteries
and as a result more than 85% of left ventricular perfusion occurs during diastole. This becomes a problem if the
heart rate is increased as the diastolic interval is shorter and can result in ischaemia.
Atrial systole Open (atrial pressure > ventricular Closed (arterial pressure > ventricular
pressure) pressure)
Isovolumetric Closed (ventricular pressure > atrial Closed (arterial pressure > ventricular
contraction pressure) pressure)
Ventricular ejection Closed (ventricular pressure > atrial Open (ventricular pressure > arterial
pressure) pressure)
Isovolumetric Closed (ventricular pressure > atrial Closed (arterial pressure > ventricular
relaxation pressure) pressure)
Ventricular filling Open (atrial pressure > ventricular Closed (arterial pressure > ventricular
pressure) pressure)
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c wave Isovolumetric Occurs due to the bulging of the tricuspid valve into the right atrium
contraction during right isovolumetric ventricular contraction
(early systole)
x descent Rapid ventricular Occurs due to a combination of right atrial relaxation, the downward
ejection (mid systole) displacement of the tricuspid valve during right ventricular contraction,
and the ejection of blood from both the ventricles
v wave Ventricular ejection Occurs due to right atrial filling from venous return
and isovolumetric
relaxation (late
systole)
y descent Ventricular filling Occurs due to opening of the tricuspid valve and the subsequent rapid
(early diastole) inflow of blood from the right atrium to the right ventricle
First Start of systole Caused by closure of the atrioventricular (mitral & tricuspid) valves
heart
sound
Second heart End of systole Caused by closure of the semilunar (aortic and pulmonary) valves
sound
Third heart Early diastole Caused by rapid flow of blood from the atria into the ventricles during the
sound ventricular filling phase
Fourth heart Late diastole Caused by filling of an abnormally stiff ventricle in atrial systole
sound
ECG Event
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Answer
The heart has a high metabolic demand and its high capillary density allow it to extract an unusually large fraction
(about 70%) of oxygen from the blood. In exercise, the reduced diastolic interval and increased oxygen consumption
+
demand a greatly increased blood flow which is achieved by metabolic hyperaemia mediated by adenosine, K and
hypoxia. This overrides the vasoconstriction mediated by sympathetic nerves acting at alpha-adrenergic receptors
and is assisted by circulating adrenaline which causes vasodilation by acting on beta-adrenergic receptors.
Notes
Skeletal muscle circulation
The skeletal muscle circulation normally receives about 15 – 20% of the cardiac output, but this may rise to > 80%
during exercise. Skeletal muscle provides a major contribution to the total peripheral resistance and sympathetic
regulation of muscle blood flow is important in the baroreceptor reflex. At rest most capillaries are not perfused as
their arterioles are constricted. Capillaries are recruited during exercise by metabolic hyperaemia, caused by release
of
+
K and CO2 from the muscle and adenosine. This overrides sympathetic vasoconstriction in working muscle; the latter
reduces flow in non-working muscle conserving cardiac output.
Pulmonary circulation
The pulmonary circulation is not controlled by either autonomic nerves or metabolic products, and the most
important mechanism regulating flow is hypoxic pulmonary vasoconstriction, in which small arteries constrict in
response to hypoxia (in contrast to elsewhere in the body).
If an area of lung is poorly ventilated and the alveolar partial pressure of oxygen is low, pulmonary blood vessels
are constricted and blood is diverted to areas of the lung that are better ventilated, thus maintaining optimal
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ventilation- perfusion matching. This effect is accentuated by high alveolar PCO 2.
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The response is unhelpful in the presence of global lung hypoxia, at altitude or in respiratory failure, where it may
contribute to the development of pulmonary hypertension and right-sided heart failure (cor pulmonale).
Cutaneous circulation
The main function of the cutaneous circulation is thermoregulation. Arteriovenous anastomoses (AVAs) directly
linked arterioles and venules, allowing a high blood flow into the venous plexus and thus radiation of heat. AVAs
are mostly found in the hands, feet and areas of the face.
Temperature is sensed by peripheral thermoreceptors and the hypothalamus coordinates the response.
Increased temperatures reduce sympathetic adrenergic stimulation, causing vasodilation and allowing more blood
to flow to the skin and radiate its heat to the environment, whereas activation of sympathetic cholinergic fibres
promotes sweating and the release of bradykinin, which also causes vasodilation.
Cerebral circulation
The brain receives around 15% of the total cardiac output and has a high capillary density.
The endothelial cells of the capillaries of the blood-brain barrier have very tight junctions, and contain membrane
transporters that control the movement of substances, such as ions, glucose and amino acids, and tightly regulate
the composition of cerebrospinal fluid. This is continuous except where substances need to be absorbed or released
e.g. pituitary gland, choroid plexus.
The autoregulation of cerebral blood flow can maintain a constant flow for blood pressures between 50 and 170
+
mmHg. CO2 and K are particularly important metabolic regulators in the brain, with increasing concentration
causing vasodilation and a functional hyperaemia.
Hyperventilation reduces blood PCO2 and can cause fainting due to cerebral vasoconstriction.
Coronary circulation
The heart has a high metabolic demand and its high capillary density allow it to extract an unusually large fraction
(about 70%) of oxygen from the blood.
In exercise, the reduced diastolic interval and increased oxygen consumption demand a greatly increased blood
+
flow which is achieved by metabolic hyperaemia mediated by adenosine, K and hypoxia. This overrides the
vasoconstriction mediated by sympathetic nerves acting at alpha-adrenergic receptors and is assisted by circulating
adrenaline which causes vasodilation by acting on beta-adrenergic receptors.
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