THE NORMAL HEART
Biochemistry and physiology
of cardiac muscle
Alex Sirker
Ajay M Shah
Abstract
The heart is composed of muscle cells (cardiomyocytes) that account for most
of the heart mass and generate its pumping force. Other cell types (fibro-
blasts, vascular endothelial cells, vascular smooth muscle cells) and the
extracellular matrix also play key roles in cardiac function, both in health
and in disease. Excitationecontraction coupling links the electrical activation
of cardiomyocytes to cellular contraction. Calcium is a key second messenger
in this process; its entry into the cell triggers further calcium release from the
sarcoplasmic reticulum, which then activates the contractile machinery.
Subsequent reduction in calcium concentration brings about cardiac relaxa-
tion, which is necessary for the heart to re-fill. Calcium also regulates other
critical processes in the heart including transcription of genes and the match-
ing of energy supply from the mitochondria with cellular demand. In health,
the contractile function of the heart is regulated by several factors, including
its loading conditions, autonomic influences and many locally produced
autocrine/paracrine agents. These factors alter contractile strength through
two main mechanisms, namely the modulation of the calcium transient within
cardiomyocytes and/or changes in myofilament sensitivity to calcium.
Keywords calcium; cardiomyocyte; contractile function; excitatione
contraction coupling; fibroblasts; myofilament
The synchronous contraction of cardiomyocytes during ventricular
systole generates the power required to pump blood out of the heart.
Conversely, active myocyte relaxation and passive mechanical
properties of the ventricles (the latter largely dependent on the
extracellular matrix) determine filling of the heart during diastole.1
Several interacting regulatory processes operate to ensure that
cardiac performance is finely tuned to match changing circulatory
requirements. In this article, we provide an overview of the mech-
anisms that regulate cardiac contractility, dysfunction of which is
implicated in disease states such as heart failure.
Structure of the myocardium
The heart is composed of cardiomyocytes, fibroblasts, endocardial
and endothelial cells, coronary vessels, and the extracellular matrix.
Alex Sirker MB BChir MRCP is a Specialist Registrar and Clinical Research
Fellow at King’s College London, UK. His research interest is the
mechanisms and modulation of cardiac remodelling after myocardial
infarction. Competing interests: none.
Ajay M Shah FRCP FMedSci is BHF Professor of Cardiology and Director of
the King’s College London BHF Centre of Excellence, London, UK. His
research interest is the pathophysiology of cardiac remodelling.
Competing interests: none.
MEDICINE 38:7
What’s new?
C Cross-talk between different cell types within the heart
(cardiomyocytes, endothelial cells, fibroblasts) is important both
for normal physiological function and in the diseased heart.
C Calcium regulates numerous intracellular processes within
myocytes, including excitationecontraction coupling,
excitationetranscription coupling and mitochondrial function.
This is achieved through spatial and temporal compartmentation
of the calcium signal in cellular microdomains.
C Autocrine/paracrine factors and downstream signalling pathways
(e.g. those regulated by eNOS and nNOS) are important
modulators of cardiac function both in health and disease.
Cardiomyocytes account for most of the cardiac mass and
volume but only approximately 30% of cardiac cell numbers.
They are connected to each other via specialized gap junctions,
which provide electrical coupling and allow an action potential to
spread between adjacent cardiomyocytes by the intercellular
movement of ions. This is vital for synchronized contraction of
myocytes. Gap junction channels are formed from a family of
proteins known as the connexins.
The sarcolemmal membrane of cardiomyocytes has invagina-
tions that form an extensive T-tubule network, regions of which lie
in close apposition with the sarcoplasmic reticulum. The sarco-
plasmic reticulum is the major intracellular store of calcium and
a central regulator of cardiac contractility. The fundamental
contractile unit, the sarcomere, is formed from contractile myofi-
brils, which comprise interdigitating thin filaments (actin and
associated regulatory proteins, tropomyosin and troponin-C, I and
T) and thick filaments (myosin). The sarcomere also contains
numerous non-contractile proteins (e.g. titin, myomesin, tele-
thonin) that have important structural and signalling functions.
Interspersed between the myofibrils are numerous mitochondria,
which generate the energy (in the form of ATP) to fuel contraction.
Fibroblasts are the most numerous cells in the heart. They are
responsible for the continual production and turnover of the
extracellular matrix of the heart. In response to injury, such as
myocardial infarction, fibroblast numbers are increased and
undergo a phenotypic change, to so-called myofibroblasts, which
play a crucial role in organ repair and healing by fibrosis.2 In
experimental models of cardiac injury, some of these myofibro-
blasts also appear to be recruited from circulating bone marrow
derived cells or from local endothelial cells which have undergone
a phenotypic change called endothelialemesenchymal transition.3
The extracellular matrix (ECM) is a complex array of molecules
that provides structural support for the cellular components of the
heart. The ECM also allows appropriate transmission of the
mechanical forces generated by cardiomyocytes. The major
components of the ECM are Types I and III collagen. The ECM also
contains various protease enzymes, which allow degradation of
matrix components. Important among these are the matrix metal-
loproteinases (MMPs), of which there are over 20 known subtypes.
The main coronary arteries, which provide the heart with its
blood supply, sit on the epicardial surface of the heart. They divide
into smaller blood vessels that penetrate the myocardium. At
340 Ó 2010 Elsevier Ltd. All rights reserved.
 THE NORMAL HEART

capillary level, there is a close apposition between endothelial cells
and cardiomyocytes. These endothelial cells not only provide the
lining of blood vessels but also modulate cardiac function through
the release of diffusible factors (as described later).
Excitationecontraction coupling and contractile function
Electrical excitation of the cardiomyocyte initiates a dramatic
transient rise in intracellular calcium concentration (the so-called
calcium transient). The events that couple sarcolemmal depolar-
ization to elevation of calcium and initiation of contraction are
known as excitationecontraction coupling (Figure 1). During each
heartbeat, the depolarization wave spreads across the sarcolemma
and T-tubule system, and initiates calcium influx through voltage-
gated L-type calcium channels.4 This calcium influx or calcium
current (ICa) initiates further calcium release from the sarcoplasmic
reticulum (calcium-induced calcium release) via the Ryanodine
receptor. The elementary unit of sarcoplasmic reticulum calcium
release, the calcium spark, represents calcium released locally from
the opening of a few calcium-release channels. According to the
local control theory of excitationecontraction coupling, the cell
calcium transient induced by an action potential represents the
spatial and temporal summation of individual calcium sparks.5
The contractile machinery is switched on by binding of calcium
to troponin-C on the thin filament, which enables projections (S1
heads) on the myosin molecules to interact with actin filaments,
forming cross-bridges. This energy-requiring process involves
ATP hydrolysis by myosin ATPase. Repetitive cross-bridge cycles
of attachment and detachment continue as long as the cytosolic
calcium concentration is high. The power stroke generated by the
cross-bridge cycle is responsible for force generation or muscle
shortening. Cross-bridge interactions show cooperativity; that is,
force-generating cross-bridges promote further binding of more
cross-bridges, which effectively amplifies the calcium signal.
Muscle relaxation is governed by lowering of the cytoplasmic
calcium concentration, consequent dissociation of calcium from
troponin-C, and switching off of the actinemyosin interaction. This
involves active transport of calcium back into the sarcoplasmic
reticulum (via sarcoplasmic reticulum Ca2þ-ATPase) and extru-
sion across the sarcolemma, by both the NaþeCa2þ exchanger and
(less importantly) the sarcolemmal Ca2þ-ATPase. Mitochondria
can also accumulate calcium, particularly when cytosolic
concentrations become excessively high (e.g. during severe
ischaemia). In addition to the reduction in cytosolic Ca2þ, recoil of
elastic elements within the myocyte (notably within titin molecules
in the sarcomere) may also be involved in the process of relaxation.
The events that comprise excitationecontraction coupling
influence the size and kinetics of the calcium transient.6 An
abnormally low calcium transient may lead to depressed contrac-
tility. Reduction in sarcoplasmic reticulum Ca2þ-ATPase activity
and abnormalities of sarcoplasmic reticular calcium release occur
in heart failure and are generally accompanied by diastolic calcium
overload; this may contribute to delayed relaxation and diastolic
dysfunction, triggering of ventricular arrhythmias, and chronic

Excitation–contraction coupling in cardiac myocytes

Na+–Ca2+ exchanger
L-type
3Na+ Ca2+ Ca2+ channel
Sarcolemma Ca2+
Ca2+ Sarcolemmal
Ca2+-ATPase

The wave of depolarization

spreading along the sarcolemma T-tubule
Sarcoplasmic
Mitochondrion
and T-tubule system initiates reticulum
calcium entry via L-type calcium
channels (the calcium current), Ca2+ Ca2+
which stimulates further calcium
release from the sarcoplasmic Sarcoplasmic Sarcoplasmic
reticulum. The resulting rise in reticulum reticulum
intracellular calcium Ca2+ Ca2+-ATPase Ca2+-release (Ca2+)
concentration activates the channel
Z line
contractile machinery (actin and
myosin filaments). Following
contraction, the cytoplasmic
calcium concentration is
reduced again by transport back Myosin Actin
into the sarcoplasmic reticulum filaments filaments
(Ca2+-ATPase) and across the
sarcolemma (Na+–Ca2+ exchange
and sarcolemmal Ca2+-ATPase), One sarcomere
thus allowing relaxation.

Figure 1

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 THE NORMAL HEART

changes in cell structure (e.g. altered gene expression) as a result of
activation of downstream calcium-dependent signalling path-
ways.7 Up-regulation of NaþeCa2þ exchanger activity may, to
some extent, compensate for reduced sarcoplasmic reticulum
Ca2þ-ATPase activity. Independent of excitationecontraction
coupling, changes in myofilament properties (e.g. their respon-
siveness to calcium) are also implicated in heart failure, ischae-
miaereperfusion injury and hypertrophic cardiomyopathy.8
Calcium concentrations within the cardiomyocyte also influ-
ence other cellular processes. They have been found to be
involved in the control of gene transcription (so-called excita-
tionetranscription coupling) and may in part mediate processes
such as cardiac hypertrophy. The binding of calcium to
calmodulin leads to activation of certain protein kinases (e.g.
calmodulin kinase) or phosphatases (e.g. calcineurin), which
then modulate signal transduction pathways and/or transcription
factors to alter the expression of specific genes.9
Calcium is involved in matching mitochondrial energy produc-
tion (by oxidative phosphorylation) to cardiac work.10 Various sites
within mitochondria, including key dehydrogenases (such as
pyruvate kinase) and also the F1F0 ATPase, are susceptible to
changes in activity determined by local calcium concentration.
The multiple described actions of calcium within the car-
diomyocyte are feasible because of distinct local calcium
concentrations within the cell, in so-called microdomains. For
example, excitationecontraction coupling (involving sarco-
lemmal ICa and SR Ryanodine receptors in close proximity) is
likely to involve a local free calcium transient signal which is
spatially distinct from that seen in perinuclear pathways identi-
fied in excitationetranscription coupling.

Contractile reserve

– Calcium Activation
Nitric oxide
Acetylcholine current

+ Ca2+
Sarcoplasmic Ca2+ Ca2+
reticulum Ca2+ transient
β-stimulation +
release
↑Heart rate
Ca2+ Negative
– inotropic effect
Angiotensin II +
Myofilament activation +
Endothelin-1
Positive
↑Length
inotropic effect

Relaxation

+ Sarcoplasmic
reticulum
β-stimulation Decreased
+ Ca2+ uptake
cytoplasmic
Ca2+ concentration
Sarcolemmal
β-stimulation Ca2+ extrusion
Positive
Nitric oxide + + lusitropic effect
Myofilament
– Ca2+ dissociation –
Angiotensin II
Negative
Endothelin-1
lusitropic effect
↑Length

These are the major pathways by which muscle length, heart rate, autonomic control (β-adrenergic stimulation) and paracrine factors (nitric
oxide, endothelin-1 and angiotensin II) produce changes in:
• level of activation and contractile strength (inotropic effects, top)
• rate of relaxation (lusitropic effects, bottom).
Blue arrows indicate an increase and red arrows a decrease in the components of excitation–contraction coupling. Effects of nitric oxide and
acetylcholine on the calcium current are significant only following prior β-adrenergic stimulation.

Figure 2

MEDICINE 38:7 342 Ó 2010 Elsevier Ltd. All rights reserved.

 THE NORMAL HEART

Contractile reserve and regulation low or high) contributes to contractile dysfunction in conditions
such as cardiac hypertrophy, heart failure and myocarditis.
Considerable contractile reserve (Figure 2) is normally available
Other local factors such as endothelin-1, angiotensin II and
to meet variations in circulatory demand, e.g. during exercise. At
reactive oxygen species also modulate contractile properties,
a cellular level, the recruitment of this contractile reserve involves
particularly in the diseased heart. Endothelin-1 has potent
changes in the cytosolic calcium transient and/or myofilament
vasoconstrictor and positive inotropic effects and may also
responsiveness to calcium, and is regulated by several important
stimulate release of angiotensin II, which has similar actions.
pathways as outlined below. There is usually significant impair-
It has been suggested that stretch-induced release of these
ment of these pathways in heart failure, which is a major reason
peptides contributes to length-dependent increases in contractile
for the exercise intolerance characteristic of this condition.
force. Increased angiotensin II production through increased
The FrankeStarling response describes an increase in
local angiotensin-converting enzyme activity is a cardinal feature
contractile force that occurs with increasing myocyte length or
of hypertrophy and heart failure. It also has several detrimental
stretch (the latter brought about by increased ventricular dia-
effects, including slowed ventricular relaxation, increased
stolic volume). The main underlying mechanism is an increase in
fibrosis, and promotion of inappropriate hypertrophy and
myofilament responsiveness to calcium, but length-dependent
ventricular remodelling. Some, if not all, of these effects involve
release of autocrine/paracrine factors may also be involved.
induced generation of reactive oxygen species, such as super-
The FrankeStarling response is thought to be preserved at
oxide and hydrogen peroxide, within the heart. Pathways
a cellular level in human heart failure, but in a heart that is
involving the actions of autocrine/paracrine factors in disease
dilated and stiff it may be functionally impaired by the limitation
may be important novel therapeutic targets in heart failure. A
in the ability to stretch myocytes.
An increase in heart rate enhances contractile force primarily
by increasing sarcolemmal calcium influx per unit time, with
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specific actions.12 Abnormal nitric oxide bioactivity (excessively (A comprehensive general reference book on cardiac physiology.)

MEDICINE 38:7 343 Ó 2010 Elsevier Ltd. All rights reserved.