THE NORMAL HEART

Biochemistry and
physiology of cardiac muscle
J Layland
A M Shah

The synchronous contraction of cardiac myocytes during ventricular systole generates the power required to pump blood out of the
heart. Conversely, myocyte relaxation and the passive properties
of the ventricles during diastole (dependent largely on the properties of the extracellular matrix) determine the filling of the heart
between beats. Several interacting regulatory processes operate to
ensure that cardiac performance is finely tuned to match circulatory requirements. This contribution provides an overview of the
mechanisms that regulate cardiac contractility, dysfunction of
which is implicated in disease states such as heart failure.

Structure of cardiac muscle

The sarcolemmal membrane of cardiac myocytes has invaginations
that form an extensive T-tubule network, regions of which lie in
close apposition with the sarcoplasmic reticulum. The sarcoplasmic
reticulum is the major intracellular store of calcium, the central
regulator of cardiac contractility. The fundamental contractile
unit, the sarcomere, is formed from contractile myofibrils, which
comprise interdigitating thin filaments (actin and associated

Whats new ?
Alterations in the properties of the SR calcium-release
channels in heart failure may render them functionally
leaky and may contribute to reduced calcium load and
decreased contractility
Reactive oxygen species may directly modulate
EC coupling and contribute to contractile defects in
hypertrophy and heart failure. The clinical benefits of
antioxidant therapies are currently under investigation
Modulation of myofilament properties can significantly
contribute to altered contractility in human heart failure

J Layland PhD is a Post-doctoral Research Fellow at Kings College London,

UK. Her research interest is the intracellular mechanisms responsible for
contractile effects of interventions on cardiac muscle. Conflicts of interest:
none.
A M Shah FRCP FMEdSci is BHF Professor of Cardiology and Consultant
Cardiologist at Kings College Hospital, London, UK. His research interest
is endothelial regulation of cardiovascular function. Conflicts of interest:
none.

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THE NORMAL HEART

regulatory proteins, tropomyosin and troponin-C, I and T) and

thick filaments (myosin). Interspersed between the myofibrils are
numerous mitochondria, which generate the energy (ATP) to fuel
contraction. Individual myocytes are electrically coupled through
specialized areas of the cell membrane, and the overall organization of myocytes and extracellular matrix (largely comprising a
meshwork of collagen) within the cardiac chambers is also critical
for overall pump function.

traction coupling, the cell calcium transient represents the spatial

and temporal summation of individual calcium sparks.2
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.
Relaxation is governed by lowering of the cytoplasmic calcium
concentration, consequent dissociation of calcium from troponinC, and switching off of the actomyosin interaction. This involves
active transport of calcium back into the sarcoplasmic reticulum
(via sarcoplasmic reticulum Ca2+-ATPase) and extrusion across the
sarcolemma, by both the Na+Ca2+ exchanger and the sarcolemmal
ATPase. Mitochondria can also accumulate calcium, particularly
when cytosolic levels become excessively high (e.g. during severe
ischaemia).
The events that comprise excitationcontraction coupling
influence the size and kinetics of the calcium transient. An abnor-

Excitationcontraction coupling
Electrical excitation of the myocyte initiates a dramatic transient
rise in intracellular calcium concentration (the so-called calcium
transient). The events that couple sarcolemmal depolarization to
elevation of calcium and initiation of contraction are known as excitationcontraction 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.1 This calcium influx or calcium current (ICa)
initiates further calcium release from the sarcoplasmic reticulum
(calcium-induced calcium release). 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 excitationcon-

Excitationcontraction coupling in cardiac myocytes

Na+Ca2+ exchanger
Ca2+

3Na+
Sarcolemma

The wave of depolarization

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

L-type
Ca2+ channel
Ca2+

Ca2+

T-tubule

Sarcoplasmic
reticulum
Ca2+

Ca2+

Sarcoplasmic
reticulum
Ca2+-ATPase

Myosin
filaments

Sarcolemmal
Ca2+-ATPase

Mitochondrion

Ca2+
Sarcoplasmic
reticulum
Ca2+-release
channel

(Ca2+)
Z line

Actin
filaments
One sarcomere

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mally low calcium transient may lead to depressed contractility.

Reduction in sarcoplasmic reticulum Ca2+-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
changes in cell structure (e.g. altered gene expression) as a result of
activation of downstream calcium-dependent signalling pathways.3
Up-regulation of Na+Ca2+ exchanger activity may, to some extent,
compensate for reduced sarcoplasmic reticulum Ca2+-ATPase
activity. Independent of excitationcontraction coupling, changes
in myofilament properties (e.g. their responsiveness to calcium)
are also implicated in heart failure, ischaemiareperfusion injury
and hypertrophic cardiomyopathy.4

Contractile reserve
Considerable contractile reserve (Figure 2) is normally available
to meet variations in circulatory demand. Recruitment of this contractile reserve involves changes in the cytosolic calcium transient
and/or myofilament responsiveness to calcium, and is mainly
regulated by the following pathways.
FrankStarling relationship an increase in myocyte length
(brought about by increased ventricular diastolic volume) increases
contractile force. The major underlying mechanism is increased
myofilament responsiveness to calcium, but length-dependent
release of autocrine/paracrine factors (see below) may also be
involved. At a cellular level, the FrankStarling response is thought
to be maintained in human heart failure, though myocyte stretch

Contractile reserve

Nitric oxide
Acetylcholine

Calcium
current
Ca2+

Sarcoplasmic
reticulum Ca2+
release

-stimulation
Heart rate

Activation

Ca2+

Ca2+
transient
Ca2+

Negative
inotropic effect

Angiotensin II
Endothelin-1
Length

Myofilament activation

+
Positive
inotropic effect

Relaxation
Sarcoplasmic
reticulum
Ca2+ uptake

+
-stimulation

-stimulation
Nitric oxide
Angiotensin II
Endothelin-1
Length

Sarcolemmal
Ca2+ extrusion

Decreased
cytoplasmic
Ca2+ concentration

Myofilament
Ca2+ dissociation

Positive
lusitropic effect

Negative
lusitropic effect

These are the major pathways by which muscle length, heart rate, autonomic control (-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 excitationcontraction
coupling. Effects of nitric oxide and acetylcholine on the calcium current are significant only following
prior -adrenergic stimulation.
2

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may be a limiting factor in a heart that is dilated and stiff. Changes

in length or stretch may also alter gene regulation in the heart,
with the potential to alter phenotype.
Heart rate increased heart rate enhances contractile force
primarily by increasing sarcolemmal calcium influx per unit time,
with consequent increased calcium loading of the sarcoplasmic
reticulum. The failing human heart exhibits a greatly blunted
forcefrequency relationship.
Autonomic control sympathetic activation, involving catecholamine release, has both positive inotropic and chronotropic
effects via -adrenoceptors. These actions are antagonized by
parasympathetic release of acetylcholine. The inotropic effect of
-stimulation results from an increase in the intracellular calcium
transient caused by increases in ICa and sarcoplasmic reticulum
calcium release. -stimulation also accelerates relaxation by stimulating sarcoplasmic reticulum calcium uptake, promoting faster
dissociation of calcium from the myofilaments, and accelerating
cross-bridge cycling. Reduced responsiveness to -adrenergic
stimulation is a fundamental feature of human heart failure.
Autocrine/paracrine regulation cardiac myocytes are in
intimate contact with the endothelial cells of the coronary microvasculature, which are ideally positioned to sense and transduce
local signals (e.g. mechanical forces, hypoxia, hormones) in the
perfusing blood. Coordinated release of factors such as nitric oxide,
endothelin-1 and angiotensin II by these endothelial cells allows
local regulation of contractile function. Many of these factors
(notably nitric oxide) are also generated within cardiac myocytes
themselves, and may be involved in autocrine regulation.
Nitric oxide has direct actions on cardiac myocytes, independent of its vasodilator effects.5 These include:
acceleration of myocyte relaxation and reduction in diastolic
tone, resulting from a reduction in myofilament calcium responsiveness
modulation of excitationcontraction coupling
damping down of responses to -adrenergic stimulation.
In health, local release of nitric oxide from adjacent endothelial cells
and within cardiomyocytes serves to fine-tune and optimize cardiac pump function through more efficient excitationcontraction
coupling and improved ventricular filling and coronary perfusion.
Abnormal nitric oxide bioactivity (excessively low or high) contributes to contractile dysfunction in conditions such as cardiac
hypertrophy, heart failure and myocarditis.
Other local factors such as endothelin-1, angiotensin II and
reactive oxygen species also modulate contractile properties, particularly in the diseased heart. Endothelin-1 has potent vasoconstrictor and positive inotropic effects and may also stimulate release
of angiotensin II, which has similar actions. Stretch-induced release
of these peptides is suggested to contribute to length-dependent
increases in contractile force. Increased angiotensin II production
through increased local angiotensin-converting enzyme activity
is a cardinal feature of hypertrophy and heart failure and has several detrimental effects, including slowed ventricular relaxation,
increased fibrosis, and promotion of inappropriate hypertrophy and
ventricular remodelling. Some, if not all, of these effects involve
induced generation of reactive oxygen species such as superoxide
and hydrogen peroxide within the heart.

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REFERENCES
1 Bers D M. Calcium fluxes involved in control of cardiac myocyte
contraction. Circ Res 2000; 87: 27581.
2 Wier W G, Balke C W. Ca2+ release mechanisms, Ca2+ sparks, and local
control of excitationcontraction coupling in normal heart muscle.
Circ Res 1999; 85: 7706.
3 Marks A R. Cardiac intracellular calcium release channels. role in
heart failure. Circ Res 2000; 87: 811.
4 Layland J, Solaro R J, Shah A M. Regulation of cardiac contractile
function by troponin I phosphorylation. Cardiovasc Res 2005; 66:
1221.
5 Shah A M, MacCarthy P A. Paracrine and autocrine effects of nitric
oxide on myocardial function. Pharmacol Ther 2000; 86: 4986.
FURTHER READING
Bers D M. Excitationcontraction coupling and cardiac contractile force.
Dordrecht: Kluwer Academic, 1992.
(An excellent, detailed account of all aspects of excitationcontraction
coupling.)
Opie L H. The heart. Physiology, from cell to circulation. 3rd ed.
Philadelphia: Lippincott-Raven, 1998.
(A comprehensive general reference book on cardiac physiology.)

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