THE NORMAL HEART

Physiology of the normalheartDavid EL Wilcken

Abstract

Impulse-generating and impulse-conducting systems of the heart

Superior vena cava

Left bundle branch

Aorta

The mechanical events of the cardiac cycle provide the circulation with

normal cardiac output and blood pressure. This requires an appropriate

venous return, regulation of outflow resistance, a normal myocardial

contractile state, and heart rate control, together with an adequate supply

of oxygenated blood via the coronary circulation. Other neural influences

contribute to cardiac regulation, including natriuretic peptides, and the

renineangiotensin system. The atria and ventricles are richly supplied

with adrenergic nerves that may augment cardiac function, particularly

with increased cardiac output during exercise. Inhibitory vagal fibres

are largely confined to the sinus and atrioventricular nodes. Exercise

causes increased sympathetic outflow, with a decrease in peripheral

vascular resistance, and increased cardiac output, heart rate, systolic

blood pressure and venous return. Regular rhythmic exercise has a

training effect, which enhances cardiac performance. This is important

for the maintenance of many aspects of cardiovascular health.

Keywords Asymmetric dimethylarginine; cardiac cycle; cardiac output;

FrankeStarling; inotropic effect; nitric oxide synthase; outflow resistance;

renineangiotensin; venous return

The normally functioning heart provides sufficient oxygenated

blood containing nutrients, metabolites and hormones to meet

moment-by-moment metabolic needs and preserve a constant

internal milieu. Its two essential characteristics are contractility

and rhythmicity. In the regulation of these, the nervous system

and neurohumoral effects modulate relationships between

venous return, outflow resistance, frequency of contraction and

inotropic state. There are also intrinsic cardiac autoregulatory

mechanisms.

The cardiac cycle

Anterior

Electrical events

Sinoatrial node

Atrioventricular node

Bundle of His

Right bundle branch

Posterior fascicle

fascicle

Figure 1 shows the impulse-generating and impulse-conducting

system of the normal heart. The cardiac cycle begins with de-

polarization of the sinoatrial node in the upper right atrium and

spread of the action potential through the atria, resulting in atrial

systole. Conduction of the electrical impulse from atrium to

ventricle is permitted only through the specialized cells of the AV

node. This slow conductance delays activation of the bundle of

His, allowing completion of ventricular filling, and passes on via

the right and left bundle branches, producing an orderly

sequence of ventricular contraction. The ECG records the sum-

mation of the spread of these electrical potentials.

David EL Wilcken MD FRCP FRACP is Emeritus Professor of Medicine at the

University of New South Wales and the Prince of Wales Hospital, Sydney,

Australia. He qualified from the University of Sydney, and has worked in

London, UK and San Francisco, USA. Competing interests: none.

MEDICINE 42:8 409

The specialized cells of the sinoatrial node, the AV node and

Purkinje tissue have an inherent rhythmicity and depolarize

spontaneously. The sinoatrial node, with the fastest inherent

depolarization rate, normally determines heart rate. Without

this, the AV node, bundle of His or Purkinje system assumes this

role, but the resulting heart rate is considerably slower.

Mechanical events

After the Pwave of the ECG (and coinciding with atrial systole), ‘a’

waves appear in pressure tracings. Atrial contraction increases

ventricular filling by about 10%. The onset of ventricular

contraction coincides with the R wave, and the rapid increase in

intraventricular pressure closes the mitral and tricuspid valves,

producing the first heart sound. When ventricular pressures

exceed those in the pulmonary artery and aorta, the outflowvalves

open and ventricular ejection follows. As ventricular contraction

declines, the aortic and pulmonary valves close, coinciding with

the end of the Twave of the ECGand the dicrotic notch seen in both

pressure tracings. Aortic closure slightly precedes pulmonary

closure, resulting in the two components of the second heart

sound. A third heart sound, coinciding with early rapid diastolic

filling, is usually audible in children and young adults.

Normal volumes, pressures and flows

The blood volume in adults is about 5 l (haematocrit 45%), of

which 1.5 l is in the heart and lungs (the central blood volume),

0.9 l in the pulmonary arteries, capillaries and veins, and 75 ml in

Purkinje cells

Source: Junqueira L C, Carneiro J, Kelley R O. Basic Histology. 9th ed. Stamford: Appleton and Lange, 1998.

Figure 1

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Normal resting values for pressures in the heart and great vessels

Site Systolic pressure (mmHg) Diastolic pressure (mmHg) Mean pressure (mmHg)C Right atrium a � 7 x � 3 �5

v � 5 y � 3

C Right ventricle �25 End-pressure before a � 3 Not applicable

End-pressure on a � 7

C Pulmonary artery �25 �15 �18

C Left atrium (direct or indirect

pulmonary capillary wedge)

a � 12 x � 7 �10

v � 10 y � 7

C Left ventricle 120 End-pressure � 7 Not applicable

End-pressure on a � 12

Table 1

Left ventricular end-diastolic fibre length and left ventricular stroke work

Positiveinotropic effect

Stro

ke w

ork

(for

ce o

f co

ntra

ctio

n)

Negativeinotropic effect

THE NORMAL HEART

the pulmonary capillaries. About 0.6 l of blood is in the heart; the

left ventricular (LV) end-diastolic volume (EDV) constitutes about

140 ml, the stroke volume (SV) about 90 ml and the ejection

fraction (SV/EDV) about 70% for each ventricle. The normal

resting values for pressures in the heart and great vessels

(measured with reference to the zero pressure, arbitrarily set at 5

cm below the sternal angle with the patient recumbent) are shown

in Table 1. Cardiac output (stroke volume � heart rate) is related

to body size and is expressed in l/min/m2 body surface area (the

‘cardiac index’). The mean cardiac index under relaxed resting

conditions is 3.5 l/min/m2 (values below 2 and above 5 are

abnormal). In normal subjects, the arteriovenous difference for

oxygen at rest is maintained within narrow limits (35e45 ml/l,

values of 55 ml/l or more are always abnormal). Estimated

pulmonary or systemic vascular resistance is the difference

between the mean inflow and outflow pressures in mmHg,

divided by flow in l/min. In normal subjects, this flow is the

cardiac output. Stroke work is usually estimated as the product of

stroke volume and mean ejection pressure. Normal LV work at

rest is about 6 kg/m2/min.

Regulation of cardiac function

Four essential factors determine the performance of the heart:

� venous return (preload)

� outflow resistance (afterload)

� inotropic state (or contractility) and

� heart rate.

Mechanisms altering these factors modulate cardiac

performance.

Venous return, preload and the FrankeStarling relationship

The relationship between left ventricular end-diastolic fibre length and left ventricular stroke work exhibits displacement upwards and to the left with increased contractility, and downwards and to the right with decreased contractility. Similar but not identical curves are obtained by plotting left ventricular stroke work as a measure of the force of contraction against ventricular end-diastolic pressure or volume. Similar function curves are obtained from both ventricles and both atria.

End-diastolic fibre length

Figure 2

The relationship between end-diastolic fibre length and force of

contraction was described independently by FrankeStarling

(Figure 2). When the ventricle contracts against a constant

pressure, the degree of stretch of the muscle fibres in diastole

(resulting from variations in venous return) determines

contraction strength and work output. Within limits, force of

contraction and stroke work are positively related to end-

diastolic fibre length. For clinical purposes, venous return can

be equated with preload e as this changes from beat to beat it

adjusts the strength of the subsequent contraction by varying the

force stretching the relaxed cardiac muscle and altering end-

diastolic fibre length.

MEDICINE 42:8 410

The contractile response of the heart at any particular time

depends on:

� the intrinsic state of the muscle

� the prevailing neurohumoral state (increased sympathetic

outflow produces a more forceful contraction at any end-

diastolic fibre length and shifts the FrankeStarling curve

upwards and to the left) and

� extrinsic inotropic influences (drugs with a positive

inotropic effect shift the FrankeStarling curve upwards

� 2014 Elsevier Ltd. All rights reserved.

THE NORMAL HEART

and to the left, whereas myocardial depressants shift the

curve downwards and to the right).

Outflow resistance (afterload)

The pressures needed to open the pulmonary and aortic valves

are determined largely by pulmonary and systemic vascular

resistance, respectively. These resistances (together with an in-

ertial component) constitute the impedance to ventricular

outflow e the afterload against which the ventricle contracts.

Ventricular volume has a major effect on afterload. Because

pressure represents force per unit area, the force acting radially

on the inner surface of the whole ventricle at any time during

systole is the product of intraventricular pressure and ventricular

surface area at that time. An increase in LV diameter from 5 cm

(normal) to, for example, 10 cm would result in an approximate

fourfold increase in the force opposing ejection for the same

intracavity systolic pressure. To overcome that force, the

ventricle must develop greatly increased wall tension. Wall ten-

sion developed during systole is the major determinant of

myocardial oxygen consumption, so contraction is much less

efficient in the larger heart for the same stroke volume and

ejection pressure (stroke work).

EDV is influenced by preload, afterload, circulating blood

volume, the inotropic state of the ventricle, heart rate and

neurohumoral influences. For example, it is smaller in the erect

position than in the horizontal position because of reduced

venous return. It is difficult to measure changes in cardiac

contractility accurately in vivo, despite the number of different

approaches explored. However, peak rate of change of intra-

ventricular pressure (peak dp/dt) is easy to measure and a useful

index of change in contractility, provided that preload, afterload

and heart rate remain constant. Natriuretic peptides and the

renineangiotensin system are important contributors to the

regulation of ventricular volume and afterload. Atrial natriuretic

peptide and B-type natriuretic peptide are released from secretory

granules in atrial and ventricular muscle, respectively,1 in

response to increasing volume of these chambers. Subsequent

mediation of salt and water excretion by the kidneys contributes

to regulation of preload and afterload.

Activation of the renineangiotensin system increases aldo-

sterone production, promoting reabsorption of sodium by the

kidney and expansion of the circulating blood volume. Release of

angiotensin II, a potent vasoconstrictor, increases blood pressure

and smooth cell proliferation,2 underpinning the clinical rele-

vance of angiotensin-converting enzyme inhibition, angiotensin

receptor antagonism, and aldosterone inhibition in the treatment

of hypertension and cardiac failure.3

Coronary blood flow and myocardial oxygen supply

Coronary blood flow accounts for about 4% of cardiac output.

The heart extracts most (70%) of the oxygen carried in the cor-

onary circulation. The arteriovenous difference for oxygen across

the heart is w110 ml/l, compared with w40 ml/l for the whole

body under resting conditions. Elevated myocardial oxygen re-

quirements are met largely by increases in coronary blood flow

(up to sixfold during strenuous exercise).

Most of this supply is to the left ventricle, two-thirds occurring

during diastole. Myocardial oxygen requirements and coronary

MEDICINE 42:8 411

blood flow are finely adjusted e major determinants are

myocardial metabolism, aortic pressure, myocardial extravas-

cular compression during systole, and the level of neurohumoral

control. Coronary flow is closely related to coronary perfusion

pressure and myocardial oxygen consumption. Sharp increases in

flow occur when coronary venous oxygen content falls below

5 ml/100 ml. There are individual contributions from endothelial-

derived nitric oxide, adenosine, vasodilator prostaglandins, and

myocardial oxygen and carbon dioxide tensions. In addition, there

is diurnal variation in systemic autonomic function; the normal

early morning adrenergic surge results in increased vascular tone

and blood pressure. Adverse cardiac events (e.g., acute myocar-

dial infarction) occur more commonly at this time.

An important additional contribution to vascular regulation

stems from the balance between extracellular L-arginine (the

precursor of nitric oxide) and the endogenous nitric oxide syn-

thase inhibitor, asymmetric dimethylarginine (ADMA), which

influences production of endothelial-derived nitric oxide.4 This

balance may be disrupted in clinical situations (e.g., renal fail-

ure) leading to increased ADMA concentration and reduced

endothelial dilatation.

Neural influences and the heart

The atria and ventricles are richly supplied with adrenergic

nerves. Sympathetic stimulation mediated by release of

noradrenaline increases myocardial contractility and heart rate

and the rate of spread of electrical activation through the AV

node and Purkinje system. The distribution of parasympathetic

fibres is much more limited and largely confined to the sinoatrial

and AV nodes and the atria; only a few fibres reach the ventri-

cles. Under resting conditions, vagal inhibitory effects predomi-

nate and maintain a slow heart rate, there being virtually no

sympathetic outflow. With exercise, there is withdrawal of vagal

activity and an increase in sympathetic outflow. Afferents from

stretch receptors in the carotid sinus and the aortic arch (the

baroreceptors) also impact on cardiac performance. A fall in

blood pressure reduces stretch in the carotid sinus, resulting in

reduced inhibitory afferent traffic and increased sympathetic

outflow. This leads to increased heart rate, a positive inotropic

effect, and venous/arteriolar constriction so that preload and

afterload increase, respectively. Elevation of blood pressure in

the carotid sinus has the reverse effect.

There are also mechanoreceptors in all four chambers of the

heart that give rise to depressor reflexes. Their clinical relevance

is uncertain, but they may contribute to the bradycardia and

hypotension that often occur in acute myocardial infarction, and

to exertional syncope in patients with critical aortic stenosis.

Exercise and the heart: cardiac reserve

The normal response to exercise is an increase in cardiac output;

values of 30 l/min may be achieved in trained athletes. This

response is the limiting factor for aerobic exercise. On exercise,

augmented sympathetic discharge and withdrawal of para-

sympathetic outflow occur. The heart rate and venous return in-

crease immediately and there is vasodilatation in active areas and

vasoconstriction (with increased oxygen extraction) in non-active

areas, associated with a marked reduction in total peripheral

vascular resistance. This reduces afterload and encourages greater

� 2014 Elsevier Ltd. All rights reserved.

THE NORMAL HEART

systolic emptying of the LV. At about 80% of maximal exercise

capacity, the relationship between work intensity and heart rate

response, cardiac output and oxygen uptake is almost linear. With

further exercise, the heart rate and cardiac output responses are

restricted. Additional increases in oxygen consumption then result

from increased oxygen extraction and widening of the arteriove-

nous oxygen difference.

Despite the reduced peripheral resistance, systolic blood

pressure and pulse pressure both increase because of the elevated

cardiac output. Pulmonary arterial pressures increase only

slightly because of the low resistance of the normal pulmonary

circulation. The speed and force of cardiac contraction are

increased with increased adrenergic outflow; the ejection fraction

and stroke volume are elevated, and the FrankeStarling curve

shifts to the left. Peak dp/dt is increased and there is a rapid rise in

coronary blood flow to meet myocardial oxygen requirements.

With severe exercise, end-diastolic dimensions and end-diastolic

fibre length increase slightly, and the FrankeStarling mecha-

nism then operates to further augment the force of contraction.

Haemodynamic and ventilatory responses take about 2e3

minutes to equilibrate and adjust oxygen supply to the greater

demand of a new steadywork-load (exercise testing protocols also

adjust work increments at 3-min intervals). The heart rate

response to peak exercise peaks at about 200 beats/min in healthy

20-year-olds and about 170 beats/min in those aged 65 years.

When exercise ceases, the cardiopulmonary and metabolic

changes return rapidly to resting levels with an exponential re-

covery during the first few min. Reduced circulatory function

slows the recovery rate.

Training effects

Regular exercise to about 60% of maximal heart rate for 20e30

minutes three times per week is the minimal requirement for

improved effort tolerance through training. The resting heart rate

becomes slower, cardiac output is maintained by increased EDV

and stroke volume, the heart rate response to a standard sub-

maximal work-load is reduced, systemic blood flow is more

effectively distributed away from visceral and skin circulations to

working muscles, and oxygen extraction is improved. Rhythmic

MEDICINE 42:8 412

exercise (e.g., running) and isometric exercise (e.g., weight-

lifting) have different physiological effects. Blood pressure rises

disproportionately during the latter, partly as a result of reflex

mechanisms and partly due to mechanical effects of a muscle

contraction.

Regular exercise may partly prevent endothelial dysfunction

associated with ageing, improve nitric oxide availability and

reduce blood pressure in normotensive and mildly hypertensive

individuals via modulation of catecholamine release. Amongst

other diverse exercise-induced hormonal changes, reduced

glucose-stimulated insulin release is of particular clinical rele-

vance in individuals with type 2 diabetes mellitus. A

REFERENCES

1 Rademaker MT, Richards M. Cardiac natriuretic peptides for cardiac

health. Clin Sci 2005; 108: 23e36.

2 Struthers AD, MacDonald TM. Review of aldosterone and angiotensin

II-induced target organ damage and prevention. Cardiovasc Res 2004;

61: 663e70.

3 Black HR. Evolving role of aldosterone blockers alone and in

combination with angiotensin-converting enzyme inhibitors or

angiotensin II receptor blockers in hypertension management: a review

of mechanistic and clinical data. Am Heart J 2004; 147: 564e72.

4 Wilcken DE, Sim AS, Wang J, Wang XL. Asymmetric dimethylarginine

(ADMA) in vascular, renal and hepatic disease and the regulatory role

of L-arginine on its metabolism. Mol Genet Metab 2007; 91: 309e17.

FURTHER READING

Ganong WF. Review of medical physiology. 21st edn. New York: McGraw

Hill, 2003 (A clear, up-to-date account of cardiovascular physiology.).

Jones NL, Killian KJ. Exercise limitation in health and disease. N Engl J Med

2000; 243: 632e41 (A good review of exercise testing.).

Libby P, Bonow RO, Mann DL, Zipes DP, eds. Braunwald’s heart disease; a

textbook of cardiovascular medicine. 8th edn. Philadelphia: Saunders

Elsevier, 2008 (Detailed discussion of cardiovascular physiology in

health and disease.).

Wilcken DEL. Clinical physiology of the normal heart. In: Warrell DA,

Cox TM, Firth JD, et al., eds. Oxford textbook of medicine. 4th edn, vol.

2. Oxford: Oxford University Press, 2003; 820e8.

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