THE NORMAL HEART
Physiology of the normal
heart
Andrew Constantine
Konstantinos Dimopoulos
Abstract
The physiology of the heart has been a fascination of thinkers since
ancient times. The function of the heart as a pump was proposed by
the ancient Greek anatomist Erasistratus, but our modern understand-
ing of the flow of blood through the heart started with the work of Wil-
liam Harvey in the 17th century. The 20th century heralded further
breakthroughs, including the electrical conduction system of the
heart, as well as its specialized cellular ultrastructure. A working under-
standing of cardiac physiology, including the integration and fine-
tuning of its electrical and mechanical aspects, is essential for all phy-
sicians and a prerequisite to understanding physiological adaptation in
health and disease.
Keywords Action potential; cardiac myocyte; cardiac output; cardiac
physiology; stroke volume
Introduction
The heart is the central organ of the cardiovascular system,
consisting of two synchronous muscular pumps (right and left
ventricles), filled from two contractile reservoirs (right and left
atria) and supporting the in series pulmonary and systemic cir-
culations. The heart functions to support gas exchange and the
transport of nutrients, metabolites and heat around the body. It
contracts 3 billion times over the human lifespan, pumping 200
million litres of blood.
Heart muscle structure
Cardiac myocytes are specialized muscle cells that perform me-
chanical contractile work when stimulated by the pacemaker
econduction system. Each myocyte has a central nucleus and
is packed with long contractile bundles e myofibrils e which are
themselves composed of multiple contractile units called sarco-
meres. Sarcomeres consist of thick (myosin) and thin (actin)
filaments, along with the regulatory proteins troponin and
tropomyosin. Myocytes are joined, end to end, by an intercalated
disc that consists of gap junctions that facilitate electrical con-
duction, and desmosomes, which provide tensile strength.
Andrew Constantine MB BS MA MRCP(UK) is a PhD Research Fellow at
the National Heart and Lung Institute and a Cardiology Trainee in
London, UK, with a subspeciality interest in adult congenital heart
disease and pulmonary hypertension. Competing interests: none
declared.
Konstantinos Dimopoulos MD PhD MSc FESC is a Consultant
Cardiologist at the Royal Brompton Hospital, London, UK and
Professor of Practice in Adult Congenital Heart Disease and
Pulmonary Hypertension, Imperial College London, UK. Competing
interests: none declared.
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Key points
C Cardiac myocytes are specialized muscle cells consisting of
several contractile units called sarcomeres, which are formed
from thin actin and thick myosin filaments along with regula-
tory proteins such as troponin
C The ventricular cycle comprises a relatively long ventricular
filling phase and a shorter ventricular ejection phase, sepa-
rated by periods of isovolumetric contraction and relaxation
C The cardiac stroke volume changes in response to a change in
ventricular preload, contractility and afterload
Electrical excitation is transmitted to the myocyte interior
through a specialized surface membrane structure (e.g. in-
vaginations called transverse or T-tubules), calcium ion influx
and sarcoplasmic calcium-induced calcium release.1 The result-
ing adenosine triphosphate-dependent sarcomere shortening is
mainly aerobic and causes contraction by thick and thin fila-
ments moving relative to each other at linkage points called
cross-bridges. Cardiac contractility is regulated by changes in
intracellular calcium ion concentration.
The physiology of cardiac conduction: electrophysiology
The contraction of cardiac myocytes is initiated by a process of
electrical stimulation called an action potential. The process of
electrical stimulation and recovery in cardiac muscle depends on
a series of sodium, potassium and calcium ion fluxes through
channels in the membrane of myocytes, consisting of five phases
(phases 0e4): depolarization, early repolarization, plateau,
repolarization and resting potential (Figure 1).2
Most cardiac myocytes have stable resting membrane potentials
with a long action potential compared with other myocytes, char-
acterized by a plateau phase. Specific groups of cardiac myocytes,
however, have smaller, unstable resting potentials resulting in
spontaneous depolarization, called automaticity. These clusters of
myocytes form the heart’s intrinsic pacemaker. The group of myo-
cytes with the highest intrinsic depolarization rate (60e100 beats
per minute) is located in the sinoatrial node, in the superior portion
of the right atrium close to its junction with the superior vena cava.
Electrical impulses arising in the sinoatrial node are trans-
mitted to the rest of the heart via specialized conduction tissue,
leading to finely timed, coordinated contraction of the atria and
ventricles. The electrical impulse travels across the right atrium
to the atrioventricular node and, after a short latency period,
along the bundle of His, bundle branches and Purkinje fibres, to
the remaining ventricular myocardium.
The cardiac cycle
The process of atrial and ventricular contraction and relaxation is
called the cardiac cycle (Figure 2). The ventricular cycle has four
phases based on the positions of the inlet (tricuspid, mitral) and
outlet (pulmonary, aortic) valves.3 Different events during the
cardiac cycle also explain the displacements of the atrial pressure
curve. The uninterrupted column of blood between the right
1 Ó 2022 Published by Elsevier Ltd.
 THE NORMAL HEART

Figure 1 The action potential of a ventricular myocyte, displaying the different phases and main ionic currents responsible for each phase. In ven-
tricular myocytes, an external excitation causes the membrane potential to surpass the threshold potential, initiating depolarization (phase 0)
mediated by a rapid influx of sodium ions (INa) through voltage-gated, fast Naþ channels. Immediate, but incomplete, early repolarization (phase 1) is
mediated by a transient outward current (Ito) caused by an efflux of potassium ions (Kþ) through voltage-gated Kþ channels followed by a long plateau
phase. The plateau phase (phase 2) maintains the membrane potential at around 0 mV for 200e400 ms by an influx of calcium ions (Ca2þ) through
long-lasting or L-type Ca2þ channels (ICa-L) almost electrically balanced with the small outward Kþ current. This outward Kþ current, present
throughout, is reduced during the plateau phase as membrane Kþ conductance decreases on depolarization in a process of inward rectification.
Repolarization (phase 3) occurs L-type Ca2þ channels close while delayed rectifier or slow Kþ channels open (Ik), returning the membrane potential to
around e90 mV. The equilibrium of the resting phase (phase 4) is generated by outward diffusion of Kþ (Ik1) through open Kþ-selective channels
maintaining a slight excess of intracellular negative charge. The inward background current (Ib) is mediated mainly by passive Naþ influx, which at-
tenuates the resting membrane potential. Naþ and Ca2þ channels are closed during the resting phase, which is stable in ventricular myocytes.

atrium and jugular veins means that these waves are also visible
as the jugular venous pulse.
Ventricular filling
Ventricular filling is the longest portion of the cardiac cycle at rest,
characterized by diastole in the presence of open inlet valves.
There is an initial phase of rapid filling, accompanied by an
initially falling ventricular pressure despite a rising ventricular
blood volume, caused by the elastic recoil of the ventricle, which
sucks blood from the atria in early diastole. In the second phase
of diastole, filling slows as the ventricle fills past its relaxed
volume in a process called diastasis; filling at this stage depends
on the venous pressure. In late diastole, atrial contraction con-
tributes around 15% to ventricular filling, this contribution
increasing with age and during exercise. The final ventricular
blood volume at the end of diastole is termed the end-diastolic
volume. The opening of the inlet valves is followed by rapid
passage of atrial blood to the ventricles, causing the central
venous ‘Y descent’, followed by the ‘a wave’ of atrial contraction.
Isovolumetric contraction
Ventricular systole consists of an initial, short isovolumetric
phase followed by an ejection phase. Isovolumetric contraction,
i.e. contraction of a closed ventricular chamber without a change
in volume, occurs from the point of closure of the inlet valves, as
ventricular pressure surpasses atrial pressure (first heart sound,
S1), to the time of outlet valve opening. The bulging of the inlet
valves into the atria slightly increases the atrial pressure,
resulting in the central venous ‘c wave’, which is followed
quickly by atrial diastole visualized as the ‘X descent’.
Ejection
As the ventricular pressure continues to rise, the outlet valves open,
resulting in an ejection phase. Initial ejection is rapid, with three-
quarters of the stroke volume being ejected in the first half of this
phase. Overall, around two-thirds of end-diastolic blood volume is
ejected from a resting human heart, amounting to a stroke volume of
70e80 ml and a residual end-systolic volume of approximately
50 ml. The proportion of blood ejected is the ejection fraction, which
is 55e65% at rest in the healthy heart. As the inlet valves are closed,
but the atria continue to receive blood from the systemic or pul-
monary veins, the venous ‘v wave’ is produced.
Isovolumetric relaxation
Ventricular repolarization is accompanied by reduced ventricular
tension and relaxation. As the ventricular pressure drops below the
diastolic aortic and pulmonary pressures, this causes closure of the
outlet valves (second heart sound, S2). Immediately after this, the
ventricular pressure, although falling, is still above that of the atria;
hence the inlet valves remain closed, and the ventricular volume
remains unchanged during this phase. Once the inlet valves open,
ventricular filling commences with the next cardiac cycle.

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 THE NORMAL HEART

Figure 2 Wigger’s diagram displaying changes in pressure, volume and flow in the aorta, left ventricle and left atrium during the cardiac cycle.
Right-sided chambers have similar patterns, albeit with lower pressures. The jugular venous pulse and right atrial pressure have similar A, C and V
waves and X and Y descents to the left atrial pressure. Corresponding phonographic and electrocardiographic patterns are shown. The first and
physiologically split second heart sounds (split into an aortic (A) and pulmonary (P) component) along with additional, third and fourth heart
sounds. CVP, central venous pressure; EDV, end-diastolic volume; ESV, end-systolic volume; SV, stroke volume. Figure reproduced with
permission from reference 5.

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 THE NORMAL HEART

Derived haemodynamic measurements frequently used in clinical practice.

Measurement Definition

Stroke volume (SV) The volume of blood ejected from the ventricle with each heartbeat
SV ¼ EDV  ESV
In a resting adult man, this is around 90 ml
Ejection fraction (EF) The proportion of blood ejected during each cardiac cycle
EDV  ESV SV
EF ¼  100 ¼  100
EDV EDV
The normal range at rest is 55e70%
Cardiac output (CO) The volume of blood pumped from the left ventricle in 1 minute
CO ¼ SV  heart rate ðHRÞ
CO
Cardiac index ðCIÞ ¼
Body surface area ðBSAÞ
The CO in a healthy adult is around 4e7 litres/minute at rest but can increase to >15 litres/minute
during exercise. The normal resting CI, which relates CO to BSA, is around 3 litres/minute/m2

EDV, end-diastolic volume; ESV, end-systolic volume.

Table 1

Cardiac haemodynamics
Cardiac performance is assessed by various haemodynamic
measurements (selected measurements are shown in Table 1).
The stroke volume is modified by three main physiological
drivers. First, the ventricular preload or filling pressure raises the
end-diastolic pressure, increasing the myocardial wall tension,
myocyte stretch and myocytes’ contractile force e the Frank
eStarling law.4 Second, contractility for a given preload is
under the control of circulating hormones (e.g. adrenaline
(epinephrine), which increases contractility) and autonomic
nerves (via direct sympathetic/parasympathetic innervation).
Third, an increased arterial pressure opposing ventricular ejec-
tion, i.e. an increase in afterload, reduces the effective stroke
volume, as more energy is expended in the isovolumetric
contraction phase to raise the ventricular pressure above the
arterial pressure to initiate ejection. This can be caused by sys-
temic (or pulmonary) hypertension or valvular stenosis. A
KEY REFERENCES
1 Bers DM. Calcium cycling and signaling in cardiac myocytes. Ann
Rev Physiol 2008; 70: 23e49.
2 Noble D. The surprising heart: a review of recent progress in car-
diac electrophysiology. J Physiol 1984; 353: 1e50.
3 Noble MIM. The contribution of blood momentum to left ventricular
ejection in the dog. Circ Res 1968; 23: 663e70.
4 Sequeira V, van der Velden J. The FrankeStarling law: a jigsaw of
titin proportions. Biophys Rev 2017; 9: 259e67.
5 Herring N, Paterson DJ. Levick’s introduction to cardiovascular
physiology. CRC Press, 2018.

TEST YOURSELF
To test your knowledge based on the article you have just read, please complete the questions below. The answers can be found at the
end of the issue or online here.

Question 1 ‘v wave’. Auscultation revealed a mid-systolic murmur, accentuated

Unlike skeletal muscle, cardiac muscle contraction fibres have a on inspiration, and a prominent pulmonary second heart sound.
long refractory period. What ionic current is mainly associated
What physiological cardiac event corresponds to the central
with this period?
venous ‘v wave’?
A. Efflux of Naþ
A. Atrial diastole
B. Influx of Ca2þ
B. Atrial contraction
C. Efflux of Ca2þ
C. Passive atrial filling during ventricular ejection
D. Influx of Kþ
D. Opening of the atrioventricular or inlet valves
E. Efflux of Kþ
E. Isovolumetric ventricular contraction causing bulging of
the inlet valves into the atria
Question 2
A 73-year-old woman presented for review. She had a history of Question 3
chronic thromboembolic pulmonary hypertension. On examination, A 60-year-old man presented with a 3-month history of progressive
her heart rate was 70 beats per minute, and blood pressure 125/ exertional dyspnoea and orthopnoea. He had a history of a
83 mmHg. The jugular venous pressure was raised with a prominent myocardial infarction and hypercholesterolaemia. On examination,

MEDICINE xxx:xxx 4 Ó 2022 Published by Elsevier Ltd.

 THE NORMAL HEART

his heart rate was 90 beats per minute, blood pressure 150/ What physiological change would be most helpful to improve
86 mmHg, and jugular venous pressure raised at 5 cm. There this patient’s condition?
were coarse bibasal crackles and pitting oedema to the knees. A. Increasing heart rate
Investigations B. Increasing preload
 ECG, no evidence of myocardial ischaemia C. Decreasing afterload
 Serum troponin I <0.1 micrograms/litre (<0.1) D. Peripheral vasoconstriction
 Bedside echocardiography, a left ventricular ejection frac- E. Increasing ventricular myocardial stretch
tion of 25%.

MEDICINE xxx:xxx 5 Ó 2022 Published by Elsevier Ltd.

Please cite this article as: Constantine A, Dimopoulos K, Physiology of the normal heart, Medicine, https://doi.org/10.1016/j.mpmed.2022.03.010
Descargado para Ronald Eduardo Lozano Acosta (loacro@yahoo.com) en Cayetano Heredia Pervuvian University de ClinicalKey.es por Elsevier en mayo 30,
2022. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2022. Elsevier Inc. Todos los derechos reservados.