2

Basic cardiac physiology

Michael Cheung
Murdoch Childrens Research Institute and The Royal Childrens Hospital, Melbourne, VIC, Australia

The ability of the heart to alter contractile patterns and

generate adequate cardiac output in response to demand
is remarkable in terms of chronicity, rate of response, and
also magnitude of change. Some of the governing factors
in this process will be discussed in this chapter, and a brief
account of the fetal circulation and postnatal changes will
be presented.

Initiation of contraction
Much of our knowledge regarding cardiac muscle contraction is derived from the study of skeletal muscle.
Although there are some important differences between
cardiac and skeletal muscle, the general scheme of
excitationcontraction coupling is similar.
Cardiac muscle consists of thick (myosin) and thin
(actin) laments, contractile components linked to these,
and a major protein titin, which is important in the
passive spring-like properties of the myocardium.
Associated with these laments are the contractile components, which consist of troponin subunits (I, C, and T)
and tropomyosin. The troponin subunits function to
bind calcium (TnC) and tropomyosin (TnT), and also
inhibit this interaction (TnI). Essentially then, the cardiac
action potential inuences ion channels, resulting in a
transient calcium ion inux. This entry of calcium into
the cell causes release of a larger amount of calcium from
the sarcoplasmic reticulum, so-called calcium-induced
calcium release. In the absence of calcium the interaction
between myosin and actin is blocked by the binding of
TnI to actin. With the binding of calcium by TnC however,
a change in conguration of tropomyosin permits interaction between myosin and actin and subsequent force
generation. This process requires energy and appears to
be driven by the activity of myosin ATPase. Once attached

to actin, the power stroke of myosin head rotation causes

myolament shortening. The reuptake and release of
calcium from TnC permits relaxation to occur.
There are multiple levels where this process can be
affected. For example, alterations in the myosin heavy
chain isoforms and ATPase activity have been shown in
disease states such as hypothyroidism and diabetes.
Furthermore, genetic mutations resulting in abnormal
troponin development account for particular types of
cardiomyopathy.

Properties of myocardium
Forcevelocity relationship
Contractile performance of muscle, dened as its ability
to do work, can be expressed in different ways. One of the
fundamental properties of the myocardium is its force
velocity relationship. This relationship describes the
ability of myolaments to shorten more rapidly and to a
greater degree when faced with a light load as compared
to a heavy load. Conversely, in the face of a heavy load, a
muscle shortens more slowly and also to a lesser degree.
Using in vitro methods of measurement, such as the isovelocity release technique, plots of the load dependence of
these shortening velocities yield hyperbolic forcevelocity
curves (Figure 2.1). It can be seen that maximal velocity
of shortening (Vmax) occurs at zero load. Vmax is considered
to reect the intrinsic velocity of myosin cross-bridge
turnover, which can be measured in vitro as myosin
ATPase activity. The x-intercept of this curve, where generated force is maximal, is designated P0. It is important
to note therefore, that for the same contractile state, the
changes in performance in the face of changing load are a
reection of the way in which work is performed in the
face of a changing hemodynamic environment.

Pediatric Heart Disease: A Practical Guide, First Edition. Piers E. F. Daubeney, Michael L. Rigby, Koichiro Niwa, and Michael A. Gatzoulis.
2012 Blackwell Publishing Ltd. Published 2012 by Blackwell Publishing Ltd.

Basic cardiac physiology 7

Velocity
Peak isometric twitch tension (mN/mm2)

40

Vmax

NF

30

20
DCM
10
MR

0
Force
Figure 2.1 Forcevelocity relationship.

Lengthtension relationship
This is another fundamental property of muscle which
relates the maximum developed force to sarcomere
length. It is thought that the generated force is dependent
upon the degree of overlap of thick and thin myolaments. As muscle length is gradually increased, developed
force on contraction increases up to an optimal length.
In skeletal muscle, it is possible to continue beyond this
length to such a degree that the developed force decreases,
to a point where there is no overlap of myolaments and
therefore force cannot be generated. Cardiac muscle
differs signicantly however, in that under physiologic
conditions it does not appear possible to elicit this
descending limb of the relationship. The heart therefore
functions on the ascending limb of the lengthtension
curve. This relationship is thought to partly account for
the FrankStarling relationship (see below).

Forcefrequency relationship
First described by Bowditch in 1871, the intrinsic property of the myocardium to alter contractile force with
change in rate of stimulation is known as the force
frequency relationship (FFR) or treppe effect. The
majority of data support rate-related uctuations in
calcium cycling as the underlying mechanism for this
phenomenon.
In vitro studies have shown that the response of normal
myocardium to an increasing stimulation rate is to

180
60
120
Stimulation frequency (per min)

240

Figure 2.2 Plot of peak force versus rate of stimulation for

normal non-failing myocardium (NF), and myocardium from
patients with dilated cardiomyopathy (DCM) and chronic
mitral regurgitation (MR). (Reproduced from Alpert NR,
Leavitt BJ, Ittleman FP, et al. A mechanistic analysis of the
force-frequency relation in non-failing and progressively
failing human myocardium. Basic Res Cardiol 1998;93:2332,
with kind permission of Springer Science + Business Media.)

increase the force of contractility (Figure 2.2), up to an

optimal rate where generated force is maximal, after
which there is a decline in force. The effect of increasing
stimulation rate is thought to be an increase in activity
of sarcoplasmic reticulum calcium ATPase. The ratedependent intracellular ux of calcium can be demonstrated through the use of calcium dyes such as
aequorin.
Using the same approach, dramatically differing
responses may be observed in samples of diseased myocardium. In patients with dilated cardiomyopathy, for
example, the FFR may become negative. Consequently, at
relatively low heart rates the generated force decreases
with increasing rate of stimulation.

The heart as a pump

The main function of the heart is to act as a pump and
supply the body with blood, and in order to understand
this, it is worthwhile considering the different phases of
the cardiac cycle as described in the Wiggers diagram

8 General cardiology

Stroke
volume

E F
G

Afterload

Control

Aortic pressure
J K

Afterload
Ventricular
pressure
Atrial
B pressure
C
A

Failing
heart
H
I

Figure 2.3 Wiggers diagram (see text for details).

Preload
Figure 2.4 Ventricular function curve (see text for details).

(Figure 2.3). Wiggers divided the cardiac cycle for the left
ventricle into separate phases. Systole begins with isovolumic contraction (AC), followed by maximum ejection
(CD), and ending with a period of reduced ejection
(DF). In the rst period of diastole, known as protodiastole (FG), the rst effect of relaxation is a drop in
ventricular pressure leading to closure of the aortic valve.
Ventricular pressure continues to fall as myocardial relaxation proceeds throughout this period of isovolumic
relaxation (GH). Once the ventricular pressure is lower
than that of the atrium, the mitral valve opens and the
period of early rapid lling begins (HI). Ventricular
pressure continues to fall during this phase, albeit at a
slower rate. In the normal heart the majority of ventricular lling (approximately 70%) occurs during this period.
A period of diastasis (IJ) may be observed when transmitral ow ceases, or occurs at a slow rate as pressure in
the atrium and ventricle approximate prior to atrial contraction (JK). It is important to consider blood ow in
the heart as being driven by pressure gradients and that
these changes in relative pressure in the connecting
chambers and vessels explain the ow proles demonstrated, for example, by echocardiography.

some of these factors can be described by examining the

ventricular function curve (Figure 2.4). For the individual heart a whole family of curves is generated in response
to the changing environment and demands of the patient.
As can be seen in the control curve, the varying preload
alters stoke volume or the amount of blood ejected per
beat (FrankStarling relationship). The most appropriate
manner to assess preload (usually expressed as either
end-diastolic pressure or end-diastolic volume) is debatable; however, essentially this is a reection of the length
tension relationship mechanism (see above), which
accounts partly for the FrankStarling relationship. Note
that the ventricular function curves do not have a downward or descending limb; indeed several studies have
demonstrated no reduction in stroke volume despite
elevation of preload to non-physiologic levels. In the
control curve, the effect of increasing preload is to
increase stoke volume. The effect of varying afterload is
demonstrated by the other curves. Afterload reduction
increases the amount of blood ejected and conversely an
increase in afterload reduces stroke volume. Improved
contractility causes a leftward shift to a different ventricular function curve.

Ventricular function curves

Optimizing pump function

Understanding the properties of isolated myocardium

presented above is useful; however, control of pump
function in vivo is a more complicated issue since there
are additional reexes involved. The major factors that
inuence ventricular pump function in vivo are preload,
afterload, contractility, and heart rate. The relationship of

In the heart that is failing due to impaired contractility,

it can be seen from the ventricular function curves that
improvements in stroke volume could be brought about
through either afterload reduction or by giving a positive
inotrope to improve contractility, both of which should
induce a leftward shift to a different curve. Further

Basic cardiac physiology 9

increases in preload will produce less improvement in

stroke volume since the curve is relatively atter in these
patients with failing myocardium. Indeed, in these
patients, although preload reduction in the form of diuretics may provide symptomatic improvement, stroke
volume may not increase.

Diastolic function
It is of course obvious that if the heart does not ll properly, then output will be reduced. Referring to the Wiggers
diagram (see Figure 2.3), there seem to be discrete phases
of diastole which could potentially be assessed. The whole
period of diastole is complex, however, with overlap of
multiple processes affecting this part of the cardiac cycle.
Following systolic contraction the ventricle has been
deformed by shortening of myocardial bers. The ventricle has passive elastic properties and as a consequence of
this deformation there is stored potential energy which is
released upon onset of relaxation. The process of relaxation is active and energy consuming. The fall in pressure
during isovolumic relaxation therefore is inuenced by a
combination of active relaxation and also the release of
the stored potential energy due to deformation of elastic
material. Pressure cross-over with atrial pressure exceeding that of the ventricle opens the mitral valve and the
generated pressure gradient across the valve induces ow
into the ventricle during the so-called early rapid phase
of ventricular lling. With equalization of ventricular and
atrial pressures, a period of diastasis ensues during which
time there may be no or only a small amount of low
velocity ow. With atrial contraction an increase in the
pressure gradient between the atrium and ventricle is
developed, which drives blood into the ventricle. It can
be seen therefore that during diastole there are two main
phases of blood ow into the ventricle. These periods of
blood ow during diastole can be routinely examined
non-invasively using techniques such as echocardiography. Changes in diastolic lling may be due to abnormalities of relaxation, ventricular compliance, and timing, e.g.
duration of diastole relative to the total duration of the
cardiac cycle, atrioventricular delay, and rhythm. The
common nal mechanism, however, is the effect of these
processes on the relative pressures within the atrium and
ventricle and thus the impetus to blood ow.

Fetal circulation
The circulation in the fetus is different from that in postnatal life in that the systemic circulation is fed by the left

and right ventricles in parallel. Shunting of blood occurs

at three important levels (ductus venosus, foramen ovale,
and ductus arteriosus) in this circulation. The placenta
serves to oxygenate blood in addition to many other
functions. Of the blood returning from the placenta via
the umbilical vein, some goes to the hepatic veins, and
the rest goes through the ductus venosus to enter the
right atrium. Some of this highly oxygenated blood is
diverted through the foramen ovale to the left atrium
where it mixes with the small amount of pulmonary
venous return. Blood supply to the coronaries and cerebral circulation is largely via the left ventricle and with
relatively highly oxygenated blood (approx 65% saturated). Since the uid-lled lungs are not inated
in utero, vascular resistance in this compartment is relatively high. The blood entering the pulmonary artery via
the right ventricle therefore goes predominantly to the
descending aorta via the ductus arteriosus, with a small
proportion (approx 10%) of blood from the right ventricle being directed to the lungs. The left ventricle largely
supplies the upper body, cerebral circulation, and coronaries, whilst the lower body is supplied by the right
ventricle. The two vascular beds are connected by the
aortic isthmus, the portion of the aorta between the left
subclavian artery and the insertion of the ductus
arteriosus.
The parallel nature of the fetal circulation means that
changes in output can occur in one ventricle to compensate for derangements in the contralateral ventricle.
These changes lead to the disproportionate growth of
ventricles seen in many forms of congenital heart disease.

Fetal ventricular function

The contractile performance of the fetal myocardium has
been shown to be reduced in comparison with adult
myocardium in vitro. At similar muscle lengths, less active
tension is developed by the fetal myocardium. This is
perhaps not surprising considering the immaturity of
structure and function of the fetal myocardium. The
responses of the fetal ventricle to changes in loading conditions are also different. It appears that, although the
stroke volume of the fetal ventricle increases in response
to an increase in preload, the magnitude of response is
limited and furthermore the right ventricle responds less
than the left ventricle. The FrankStarling mechanism is
intact but within the fetus the ventricle is operating at the
top, relatively at part of the function curve. The fetal
ventricular response to an increase in afterload created by
balloon occlusion of the descending aorta in animal
studies is a dramatic fall in right ventricular output. It

10 General cardiology

appears therefore that changes in fetal heart rate are the

major determinant of cardiac output.

age-related changes in ventricular function must be considered during assessment of ventricular performance.

Postnatal circulatory changes

With the rst postnatal breath and ination of the lungs,
pulmonary vascular resistance falls and the amount of
blood ow to the lungs increases. With increasing pulmonary venous return, left atrial pressure rises above that of
the right atrium, leading to closure of the foramen ovale.
Pulmonary vascular resistance continues to fall but may
take several weeks to reach the lowest levels. Increasing
levels of blood oxygenation stimulate the ductus arteriosus to close and this usually occurs in the rst few days
of life. Closure of the shunts present in fetal life creates a
circulation in series, in contrast to the previous situation
of a circulation with the ventricles supporting a parallel
circulation.
In addition to the changes in the circulation, changes
occur in myocardial function in postnatal life, albeit more
slowly. Continued maturation of the myocardium occurs
with alterations in systolic function with increased active
tension development and altered responses to changes in
loading conditions. Ventricular lling patterns change
with a gradual improvement in early relaxation during
childhood prior to a gradual decline in diastolic function
during adulthood, both in terms of active relaxation and
also passive properties of the myocardium. These normal

Summary
Consideration of the factors involved in the control of
ventricular function is important in the assessment and
interpretation of clinical ndings. Furthermore, understanding these factors is useful in instituting appropriate
therapy.

Further reading
Alpert NR, Leavitt BJ, Ittleman FP, Hasenfuss G, Pieske B,
Mulieri LA. A mechanistic analysis of the forcefrequency
relation in non-failing and progressively failing human myocardium. Basic Res Cardiol 1998;93:2332.
Gwathmey JK, Slawsky MT, Hajjar RJ, Briggs GM, Morgan JP.
Role of intracellular calcium handling in forceinterval relationships of human ventricular myocardium. J Clin Invest
1990;85:15991613.
Pieske B, Kretschmann B, Meyer M, et al. Alterations in intracellular calcium handling associated with the inverse force
frequency relation in human dilated cardiomyopathy.
Circulation 1995;92:11691178.