Cellular basis of cardiac

contraction
  The heart is composed of three Specialized excitatory and conductive
major types of cardiac muscle: fibers
 Contain few contractile fibrils
 Atrial muscle, ventricular
muscle, and specialized excitatory
 which Exhibit either automatic
and conductive muscle fibers
rhythmical electrical discharge in the
 The atrial and ventricular form of action potentials
types of muscle contract in  or conduction of the action potentials
much the same way as skeletal
through the heart
muscle except that the
duration of contraction is
much longer

cardiac muscle fibers

are arranged in a latticework,
with the fibers dividing recombining
and then spreading again

• Most of the ventricular mass is composed of cardiomyocytes, normally 60-140

micrometer inlength and 17–25 μm in diameter
• Each cell contains multiple myo brils that run the length of the cell and are
composed of series of repeating sarcomeres.
• The cytoplasm between the myo brils contains other cell constituents, including a
single centrally located nucleus, mitochondria, and the intracellular membrane
system, the SR.

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•The major function of cardiac muscle cells (cardiomyocytes or

myocytes)is to execute the cardiac contraction-relaxation cycle.
The contractile proteins of the heart lie within these myocytes.
A group of myocytes held together by surrounding collagen
connective tissue is a myofiber .

 Sarcolemma

The sarcolemma is composed of a lipid bilayer

The sarcolemma forms 2 specialized regions of the myocyte the
intercalated disks and the transverse tubular system
The intercalated disks are a specialized cellcell junction which
serves both as a strong mechanical linkage between myocytes and
as a path of low resistance that allows for rapid conduction of the
action potential between myocytes

 Sarcomere

The structural and functional unit of contraction

Lies between two Z lines which on transmission electron microscopy are seen as
dark repeating bands.
The distance between Z lines varies with the degree of contraction or stretch of the
muscle and ranges between 1.6 and 2.2 μm.
At the center of the sarcomere is a dark band of constant length (1.5 μm), the A
band, which is anked by two lighter bands, the I bands, which are of variable
length.
The sarcomere of heart muscle, like that of skeletal muscle, consists of
interdigitating thick and thin myo laments.
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 Thicker laments, composed principally of the protein myosin, traverse the A band; they
are about 10 nm (100 Å) in diameter, with tapered ends.
Thinner laments, composed primarily of actin, course from the Z lines through the I
band into the A band; they are ~5 nm (50 Å) in diameter and 1.0 μm in length
The thick and thin laments overlap only within the (dark) A band, whereas the (light) I
band contains only thin laments.
On electron-microscopic examination, bridges extend between the thick and thin
laments within the A band; these are myosin heads bound to actin laments.
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Sliding ilament theory
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The myosin molecule is a complex, asymmetric protein with a molecular mass of about 500,000
Da;
it has a rod-like portion that is about 150 nm (1500 Å) in length with a globular portion (head)
at its end.
The globular portions of myosin form the bridges to actin and are the site of ATPase activity.

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 Actin has a molecular mass of about 47,000 Da.
Thin laments consist of a double helix of two chains of actin molecules wound
about each other on a larger molecule, tropomyosin.
A group of regulatory proteins—troponins C, I, and T—localize at regular
intervals on this lament

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• Calcium activates the myosin ATPase, which breaks down ATP to supply the energy for
contraction.

• The activity of myosin ATPase determines the rate of actomyosin cross-bridge formation and
breakdown and ultimately determines contraction velocity.
• In relaxed muscle, tropomyosin inhibits this interaction.

• The arrival of Ca2+ at the contractile proteins is a crucial link in excitationcontraction

Coupling

• Binding of Ca2+ to troponin C shifts the troponin tropomyosin complex on the actin
filament which permits the myosin heads to form strong binding cross bridges with
actin molecules

• Repetitive interaction between myosin heads and actin laments is termed cross-
bridge cycling and results in sliding of the actin along the myosin laments, with
muscle shortening and or the development of tension.
• The splitting of ATP then dissociates the myosin cross-bridge from actin.
• In the presence of ATP , actin and myosin laments bind and dissociate cyclically
if suf cient Ca2+ is present;
• These processes cease when [Ca2+] falls below a critical level,and the troponin-
tropomyosin complex once more inhibits actin-myosin interactions
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 Titin an enormous, exible, myo brillar protein, connects myosin to the Z line; its elasticity
contributes to the passive mechanical characteristics of the heart.
Tethers the myosin molecule to the Z-line thereby stabilizing the contractile proteins
Stretches and relaxes its elasticity contributes to the stress-strain relationship of cardiac
muscle
Increased diastolic stretch of titin as the length of the sarcomere in cardiac muscle is
increased causes the enfolded part of the titin molecule to straighten.
This stretched molecular spring then contracts more vigorously in systole.
Dystrophin is a cytoskeletal protein binds to the dystroglycan complex at membrane adherens
junctions,tethers the sarcomere to the cell membrane at these regions of tight coupling to
adjacent myocytes .
Mutations in multiple sarcomeric and cytoskeletal proteins cause different Mendelian
disorders involving theheart and skeletal muscle
And also sensitize individuals to toxic cardiomyopathies (e.g., due to alcohol or
chemotherapy).
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Titin
Cytoplasmic [Ca2+] is a principal determinant of the inotropic state of the heart.

Most agents that stimulate myocardial contractility (positive inotropic stimuli),

including digitalis glycosides and β-adrenergic agonists, increase cytoplasmic
[Ca2+], triggering cross-bridge cycling.

During excitement or exercise an increased number of adrenergic impulses

liberate an increased amount of norepinephrine from the terminals into the
synaptic cleft.

Interacts with both alpha- and beta-adrenergic receptors on myocytes and also
alpha-adrenergic receptors in arterioles.
G proteins are a superfamily of proteins that bind guanine triphosphate (GTP)
and other guanine nucleotides.
 crucial in carrying the signal onward from the agonist and its receptor to the
activity of the membrane-bound enzyme system that produces the second
messenger cAMP
Cyclic AMP in turn activates protein kinase A (PKA), which phosphorylates
sarcolemmal Ca channels, thereby enhancing the in ux of Ca into the myocyte.
2+ 2+

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 CARDIAC ACTIVATION
In the inactive state, the cardiac cell is electrically polarized; i.e., the interior has a
negative charge relative to the outside of the cell, with a transmembrane potential of –
80 to –100 mV .
The sarcolemma, which in the resting state is largely impermeable to Na , and a
+

Na - and K -pump energized by ATP that extrudes Na from the cell and maintain the
+ + +

resting potential.
In this resting state, intracellular [K ] is relatively high and [Na ] is far lower;
+ +

conversely, extracellular [Na ] is high and [K ] is low.

+ +

At the same time, extracellular [Ca ] greatly exceeds free intracellular [Ca ].
2+ 2+
Sarcoplasmic reticulum
 An intracellular membrane network is a highly efficient Ca2+ handling organelle specialized for the
regulation of cytosolic Ca2+ concentration.
Contains three important components that participate Ca2+ homeostasis:
 Sarcoplasmic reticulum Ca2+ATPase (SERCA-2)
 Regulatory protein of SERCA-2 -phospholamban
 Ca2+ release channel


SERCA-ATP-dependent Ca2+ pump distinct from that found in the sarcolemma

Fundamental determinant of Ca2+ accumulation within the myocyte
For every 1 mol of ATP hydrolyzed, 2 mol of Ca2+ is transported back into the
sarcoplasmic reticulum, thereby decreasing cytosolic Ca2+
In conjunction with the Na+/Ca2+ exchanger and sarcolemmal Ca2+ ATPase, the uptake
of Ca2+ bySERCA-2 forms the basis by which cytosolic Ca2+ can be altered by more than 100-fold
during the excitationcontraction coupling process

 Phospholamban

co localized with SERCA-2 is an important regulatory protein for SERCA-2 function

When phosphorylated, phospholamban facilitates SERCA-2 uptake into the sarcoplasmic

reticulum whereas dephosphorylation of phospholamban results in decreased sensitivity of
SERCA-2 to cytosolic Ca2+.

Thus the phosphorylated state of phospholamban plays a critical role in the rate and extent of
Ca2+ removal from the cytosolic compartment.

 The calcium release channel(ryanodine receptor channel)

Found in dense populations at the interface between the sarcoplasmic

reticulum and the T-tubular system
A small but rapid influx of Ca2+ through the Ltype Ca2+ channel will
result in an immediate release of a large bolus of Ca2+ into the myocyte
cytosolic space.
This large release of Ca2+ from the calcium release channel is
responsible for engaging the contractile apparatus.

 During the action potential plateau (phase 2), there is a slow inward current through
sarcolemmal L-type Ca2+ channels .
Depolarizing current spreads across the cell membrane, penetrating deeply into the
cell via the T tubular system. The absolute quantity of Ca2+ traversing sarcolemmal
and T tubular membranes is modest and insuf cient to fully activate contraction.
However, this initial Ca2+ current, through Ca2+-induced Ca2+ release, triggers
substantial Ca2+ release from the SR, inducing contraction.
Ca2+ is released from the SR through a Ca2+ release channel, a cardiac isoform of
the ryanodine receptor (RyR2).
Several regulatory proteins, including calstabin 2, inhibit RyR2 and thus SR Ca2+
release.

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The Ca2+ released from the SR diffuses to interact with myo brillar troponin C ,
repressing this protein’s inhibition of contraction, and so activating myo laments to
shorten.
During repolarization, the activity of the SR Ca2+ ATPase (SERCA2A) leads to Ca2+
uptake against a concentration gradient into the SR where it complexes with another
specialized protein, calsequestrin .
The uptake of Ca2+ is ATP (energy)-dependent and lowers cytoplasmic [Ca2+] to a level
where actomyosin interaction is inhibited and myocardial relaxation occurs.
There is also a sarcolemmal exchange of Ca2+ for Na+ , reducing the cytoplasmic
[Ca2+].
Additional control of calcium compartmentalization results from cyclic AMP–
dependent PKA phosphorylation of the SR protein phospholamban, permitting
SERCA2A activation, increasing SR Ca2+ uptake, and so accelerating relaxation rates
and loading the SR with Ca2+ for subsequent cycles of release and contraction.

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 Thus, the combination of the cell membrane, transverse tubules, and SR, which transmit the action
potential, release and then reaccumulate Ca2+, controls the cyclic contraction and relaxation of
heart muscle.
Genetic or pharmacologic alterations of any component can disturb any of the functions of this
nely tuned system.
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Energy is derived mainly from oxidative metabolism of fatty acids.

During contraction most of the expended chemical energy is converted into

heat and a much smaller portion into work Output.

During contraction most of the expended chemical energy is converted into

heat and a much smaller portion into work Output

Maximum efficiency of the normal heart is between 20 and 25 %.

In heart failure, this can decrease to as low as 5 to 10 per cent.

FRANK Starling LAW- Within physiologic limits the larger the volume of the
heart the greater the energy of its contraction and the amount of chemical
change at each contraction.
The greater the initial LV volume the more rapid the rate of rise the greater
the peak pressure reached and the faster the rate of relaxation

 CONTRACTILITY

Contractility or the inotropic state is the inherent capacity of the myocardium

to contract independently of changes in preload or afterload
Means a greater rate of contraction to reach a greater peak force.
Increased contractile function is associated with enhanced rates of relaxation
or a lusitropic effect.
Factors that increase contractility include exercise, adrenergic stimulation,
digitalis, and other inotropic agents.