Cover: The Cardiovascular System at a Glance, Fifth by Philip I. Aaronson, Jeremy P.T. Ward and Michelle J. Connolly

The Cardiovascular System
at a Glance

Fifth Edition

Philip I. Aaronson

BA, PhD
Reader in Pharmacology and Therapeutics
School of Immunology and Microbial Sciences
Faculty of Life Sciences and Medicine
King’s College London
London, UK

Jeremy P.T. Ward

BSc, PhD, FPhysiol
Emeritus Professor of Physiology
King’s College London
London, UK

Michelle J. Connolly

BSc, MBBS, PhD, MRCP
ST6 Interventional Cardiology Fellow
St George’s Hospital
London, UK





No alt text required.

Preface

This book is designed to present a concise description of the cardiovascular system which integrates normal structure and function with pathophysiology, pharmacology and therapeutics. We therefore cover in an accessible yet comprehensive manner all of the topics that preclinical medical students and biomedical science students are likely to encounter when they are learning about the cardiovascular system. However, our aims in writing and revising this book have always been more ambitious – we have also sought to provide to our readers a straightforward description of fascinating and important topics that are often neglected or covered only superficially by other textbooks and most university and medical courses. We hope that this book will not only inform you about the cardiovascular system, but enthuse you to look more deeply into at least some of its many remarkable aspects.

In addition to making substantial revisions designed to update the topics, address reviewers’ criticisms and simplify some of the diagrams, we have added three chapters to expand our coverage of cardiac arrhythmias and congenital heart disease, myopathies and channelopathies, and have also included a new chapter on stroke.

Philip I. Aaronson
Jeremy P.T. Ward
Michelle J. Connolly

Recommended reading

  1. Bonow, R.O., Mann, D.L., Zipes, D.P. & Libby, P. (Eds) (2018) Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine, 11th edition. Elsevier Health Sciences.
  2. Davey, P. (2008) ECG at a Glance, Wiley.
  3. Herring, N. & Paterson, D.J. (2018) Levick’s Introduction to Cardiovascular Physiology, 6th edition. CRC Press.
  4. Klabunde, R.E. (2012) Cardiovascular Physiology Concepts, 2nd edition, Wolters Kluwer.
  5. Lilly, L.S. (Ed). (2015) Pathophysiology of Heart Disease: A Collaborative Project of Medical Students and Faculty, 6th edition. Wolters Kluwer.

Sources of illustrations

Figure 2.4 Adapted from Fawcett, D.W. & McNutt, N.S. (1969). The ultrastructure of the cat myocardium. Journal of Cell Biology, 42: 1–45, Rockefeller University Press.

Figure 3.3 Adapted from Gosling, J.A. et al. (1996). Human Anatomy—color atlas and text, 3rd edition. Mosby Wolfe.

Figure 4.2 Berne, R.M. (1980). Handbook of Physiology. Oxford University Press.

Figure 18.2 Adapted from Berne, R.M. & Levy, M.N. (1997). Cardiovascular Physiology, 7th edition. Mosby.

Figure 19.1 Nichols, W.W. & O’Rourke, M.F. (2005). McDonald’s Blood Flowin Arteries: Theoretical, Experimental and Clinical Principles, 5th edition, Hodder Arnold.

Figure 30.2 Adapted from Berne, R.M. & Levy, M.N. (2001). Cardiovascular Physiology, 8th edition. Mosby; Mitchell, J.H. & Blomqvist, G. (1971). Maximal oxygen uptake. New England Journal of Medicine, 284: 1018.

Figure 33.2 Patel, P.R. (2005). Lecture Notes: Radiology, 2nd edition. Blackwell Publishing.

Figure 33.5 Courtesy of Professor Kawal Rhode and Dr Rashed Karim, Department of Imaging Sciences & Biomedical Engineering, King’s College London, UK.

Figures 50.1–50.3 Davey, P. (2008). ECG at a Glance. Wiley Blackwell.

Figures 50.4.1 and 50.4.2 Davey, P. (2008). ECG at a Glance. Wiley Blackwell.

Figures 51.1–51.5 Davey, P. (2008). ECG at a Glance. Wiley Blackwell.

Figures 53.1–53.3 Davey, P. (2008). ECG at a Glance. Wiley Blackwell.

Figures 59.1–59.3 Barker, R.A., Cicchetti, F. and Robinson, E.S. (2017). Neuroanatomy and Neuroscience at a Glance, 5th edition. Wiley‐Blackwell.

Acknowledgements

We are very grateful to Dr Marian Huett, Teaching Fellow in the Department of Physiology at King’s College for her assistance with the figure and text of Chapter 59, and also to Dr Rashid Karim and Prof Kawal Rhode in the Department of Imaging Sciences & Biomedical Engineering at King’s for providing us with the cardiac magnetic resonance image for Figure 33.5.

We would also like to thank our Project Editor Anupama Sreekanth for her assistance in keeping track of our progress and her patience in putting up with our difficulties in meeting our deadlines, and for making sure that this book and its companion website look every bit as good as we were hoping they would. Finally, as always, we thank our readers, particularly our students at King’s College London, whose support over the years has encouraged us to keep trying to make this book better.

List of abbreviations

5‐HT
5‐hydroxytryptamine (serotonin)
AAA
abdominal aortic aneurysm
ABP
arterial blood pressure
AC
adenylate cyclase
ACE
angiotensin‐converting enzyme
ACEI
angiotensin‐converting enzyme inhibitor/s
ACS
acute coronary syndromes
ADH
antidiuretic hormone
ADMA
asymmetrical dimethyl arginine
ADP
adenosine diphosphate
AF
atrial fibrillation
AMP
adenosine monophosphate
ANP
atrial natriuretic peptide
ANS
autonomic nervous system
AP
action potential
APAH
pulmonary hypertension associated with other conditions
APC
active protein C
APD
action potential duration
aPTT
activated partial thromboplastin time
AR
aortic regurgitation
ARB
angiotensin 2 receptor blocker
ARDS
acute respiratory distress syndrome
AS
aortic stenosis
ASD
atrial septal defect
ATP
adenosine triphosphate
AV
atrioventricular
AVA
arteriovenous anastomosis
AVN
atrioventricular node
AVNRT
atrioventricular nodal re‐entrant tachycardia
AVRT
atrioventricular re‐entrant tachycardia
AVSD
Atrioventricular septal defects
BBB
blood–brain barrier
BP
blood pressure
CABG
coronary artery bypass grafting
CAD
coronary artery disease
CaM
calmodulin
cAMP
cyclic adenosine monophosphate
CCB
calcium‐channel blocker
CE
cholesteryl ester
CETP
cholesteryl ester transfer protein
CFU‐E
colony‐forming unit erythroid cell
cGMP
cyclic guanosine monophosphate
CHB
omplete heart block
CHD
congenital heart disease
CHD
coronary heart disease
CHF
chronic heart failure
CICR
calcium‐induced calcium release
CK‐MB
creatine kinase MB
CMR
cardiac magnetic resonance imaging
CNS
central nervous system
CO
cardiac output
COPD
chronic obstructive pulmonary disease
COX
cyclooxygenase
CPVT
catecholaminergic polymorphic ventricular tachycardia
CRP
C‐reactive protein
CSF
cerebrospinal fluid
CT
computed tomography
CTPA
computed tomography pulmonary angiogram
CVD
cardiovascular disease
CVP
central venous pressure
CXR
chest X‐ray
DAD
delayed afterdepolarization
DAG
diacylglycerol
DAPT
dual antiplatelet therapy
DBP
diastolic blood pressure
DC
direct current
DCM
dilated cardiomyopathy
DCCV
direct current cardioversion
DHP
dihydropyridine
DIC
disseminated intravascular coagulation
DM2
type 2 diabetes mellitus
DSE
dobutamine stress echocardiography
DVT
deep venous/vein thrombosis
EAD
early afterdepolarization
ECF
extracellular fluid
ECG
electrocardiogram/electrocardiograph (EKG)
ECM
extracellular matrix
EDHF
endothelium‐derived hyperpolarizing factor
EDP
end‐diastolic pressure
EDRF
endothelium‐derived relaxing factor
EDTA
ethylenediaminetetraacetic acid
EDV
end‐diastolic volume
EET
epoxyeicosatrienoic acid
EnaC
epithelial sodium channel
eNOS
endothelial NOS
ERP
effective refractory period
ESR
erythrocyte sedimentation rate
FDP
fibrin degradation product
GP
glycoprotein
GPI
glycoprotein inhibitor
GTN
glyceryl trinitrate
Hb
haemoglobin
HCM
hypertrophic cardiomyopathy
HDL
high‐density lipoprotein
HEET
hydroxyeicosatetraenoic acid
HMG‐CoA
hydroxy‐methylglutanyl coenzyme A
hPAH
heritable pulmonary arterial hypertension
HPV
hypoxic pulmonary vasoconstriction
HR
heart rate
IABP
intra‐aortic balloon pump
ICD
implantable cardioverter defibrillator
IDL
intermediate‐density lipoprotein
Ig
immunoglobulin
IML
intermediolateral
iNOS
inducible NOS
INR
international normalized ratio
IP3
inisotol 1,4,5‐triphosphate
iPAH
idiopathic pulmonary arterial hypertension
ISH
isolated systolic hypertension
IVUS
intravascular ultrasound
JVP
jugular venous pressure
LA
left atrium
LBBB
left bundle branch block
LDL
low‐density lipoprotein
LITA
left internal thoracic artery
LMWH
low molecular weight heparin
L‐NAME
L‐nitro arginine methyl ester
LPL
lipoprotein lipase
LQT
long QT
LV
left ventricle/left ventricular
LVAD
left ventricular assist device
LVH
left ventricular hypertrophy
MABP
mean arterial blood pressure
MCH
mean cell haemoglobin
MCHC
mean cell haemoglobin concentration
MCV
mean cell volume
MI
myocardial infarction
MLCK
myosin light‐chain kinase
mPAP
mean pressure in the pulmonary artery
MR
mitral regurgitation
MRI
magnetic resonance imaging
MS
mitral stenosis
MW
molecular weight
NCX
Na+–Ca2+ exchanger
NK
natural killer
NO
nitric oxide
NOS
nitric oxide synthase
nNOS
neuronal nitric oxide synthase
NSAID
non‐steroidal anti‐inflammatory drug
NSCC
non‐selective cation channel
NSTEMI
non‐ST segment elevation myocardial infarction
NTS
nucleus tractus solitarius
NYHA
New York Heart Association
OCT
optical coherence tomography
PA
postero‐anterior
PA
pulmonary artery
PAH
pulmonary arterial hypertension
PAI‐1
plasminogen activator inhibitor‐1
PCI
percutaneous coronary intervention
PCV
packed cell volume
PD
potential difference
PDA
patent ductus arteriosus
PDE
phosphodiesterase
PE
pulmonary embolism
PGE2
prostaglandin E2
PGI2
prostacyclin
PH
pulmonary hypertension
PI3K
phosphatidylinositol 3‐kinase
PKA
protein kinase A
PKC
protein kinase C
PKG
cyclic GMP‐dependent protein kinase
PLD
phospholipid
PMCA
plasma membrane Ca2+‐ATPase
PMN
polymorphonuclear leucocyte
PND
paroxysmal nocturnal dyspnoea
PPAR
proliferator‐activated receptor
PRU
peripheral resistance unit
PT
prothrombin time
PTCA
percutaneous transcoronary angioplasty
PVC
premature ventricular contraction
PVR
pulmonary vascular resistance
RAA
renin–angiotensin–aldosterone
RBBB
right bundle branch block
RCA
radiofrequency catheter ablation
RCC
red cell count
RGC
receptor‐gated channel
RMP
resting membrane potential
RV
right ventricle/right ventricular
RVLM
rostral ventrolateral medulla
RVOT
right ventricular outflow tract tachycardia
RyR
ryanodine receptor
SAN
sinoatrial node
SBP
systolic blood pressure
SERCA
smooth endoplasmic reticulum Ca2+‐ATPase
SK
streptokinase
SMTC
S‐methyl‐L‐thiocitrulline
SOC
store‐operated Ca2+ channel
SPECT
single photon emission computed tomography
SR
sarcoplasmic reticulum
STEMI
ST elevation myocardial infarction
SV
stroke volume
SVR
systemic vascular resistance
SVT
supraventricular tachycardia
TAFI
thrombin activated fibrinolysis inhibitor
TAVI
transcatheter aortic valve implantation
TB
tuberculosis
TEE
transthoracic echocardiogram
TF
tissue factor thromboplastin
TFPI
tissue factor pathway inhibitor
TGF
transforming growth factor
TIA
transient ischaemic attack
TOE
transoesophageal echocardiography/echocardiogram
tPA
tissue plasminogen activator
TPR
total peripheral resistance
TRP
transient receptor potential
TXA2
thromboxane A2
UA
unstable angina
uPA
urokinase
VF
ventricular fibrillation
VGC
voltage‐gated channel
VLDL
very low density lipoprotein
VSD
ventricular septal defect
VSM
vascular smooth muscle
VT
ventricular tachycardia
VTE
venous thromboembolism
vWF
von Willebrand factor
WBCC
white blood cell count
WPW
Wolff–Parkinson–White

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Introduction

1
Overview of the cardiovascular system

Schematic illustration of the cardiovascular system with the details marked.

Figure 1.1 Schematic of the cardiovascular system

The cardiovascular system is composed of the heart, blood vessels and blood. In simple terms, its main functions are:

  1. distribution of O2 and nutrients (e.g. glucose, amino acids) to all body tissues
  2. transportation of CO2 and metabolic waste products (e.g. urea) from the tissues to the lungs and excretory organs
  3. distribution of water, electrolytes and hormones throughout the body
  4. contributing to the infrastructure of the immune system
  5. thermoregulation.

Blood is composed of plasma, an aqueous solution containing electrolytes, proteins and other molecules, in which cells are suspended. The cells comprise 40–45% of blood volume and are mainly erythrocytes, but also white blood cells and platelets. Blood volume is about 5.5 L in an ‘average’ 70‐kg man.

Figure 1.1 illustrates the ‘plumbing’ of the cardiovascular system.

Blood is driven through the cardiovascular system by the heart, a muscular pump divided into left and right sides. Each side contains two chambers, an atrium and a ventricle, composed mainly of cardiac muscle cells. The thin‐walled atria serve to fill or ‘prime’ the thick‐walled ventricles, which when full constrict forcefully, creating a pressure head that drives the blood out into the body. Blood enters and leaves each chamber of the heart through separate one‐way valves, which open and close reciprocally (i.e. one closes before the other opens) to ensure that flow is unidirectional.

Consider the flow of blood, starting with its exit from the left ventricle.

When the ventricles contract, the left ventricular internal pressure rises from 0 to 120 mmHg (atmospheric pressure = 0). As the pressure rises, the aortic valve opens and blood is expelled into the aorta, the first and largest artery of the systemic circulation. This period of ventricular contraction is termed systole. The maximal pressure during systole is called the systolic pressure, and it serves both to drive blood through the aorta and to distend the aorta, which is quite elastic. The aortic valve then closes, and the left ventricle relaxes so that it can be refilled with blood from the left atrium via the mitral valve. The period of relaxation is called diastole. During diastole aortic blood flow and pressure diminish but do not fall to zero, because elastic recoil of the aorta continues to exert a diastolic pressure on the blood, which gradually falls to a minimum level of about 80 mmHg. The difference between systolic and diastolic pressures is termed the pulse pressure. Mean arterial blood pressure (MABP) is pressure averaged over the entire cardiac cycle. Because the heart spends approximately 60% of the cardiac cycle in diastole, the MABP is approximately equal to the diastolic pressure + one‐third of the pulse pressure, rather than to the arithmetic average of the systolic and diastolic pressures.

The blood flows from the aorta into the major arteries, each of which supplies blood to an organ or body region. These arteries divide and subdivide into smaller muscular arteries, which eventually give rise to the arterioles – arteries with diameters of <100 μm. Blood enters the arterioles at a mean pressure of about 60–70 mmHg.

The walls of the arteries and arterioles have circumferentially arranged layers of smooth muscle cells. The lumen of the entire vascular system is lined by a monolayer of endothelial cells. These cells secrete vasoactive substances and serve as a barrier, restricting and controlling the movement of fluid, molecules and cells into and out of the vasculature.

The arterioles lead to the smallest vessels, the capillaries, which form a dense network within all body tissues. The capillary wall is a layer of overlapping endothelial cells, with no smooth muscle cells. The pressure in the capillaries ranges from about 25 mmHg on the arterial side to 15 mmHg at the venous end. The capillaries converge into small venules, which also have thin walls of mainly endothelial cells. The venules merge into larger venules, with an increasing content of smooth muscle cells as they widen. These then converge to become veins, which progressively join to give rise to the superior and inferior venae cavae, through which blood returns to the right side of the heart. Veins have a larger diameter than arteries and thus offer relatively little resistance to flow. The small pressure gradient between venules (15 mmHg) and the venae cavae (0 mmHg) is therefore sufficient to drive blood back to the heart.

Blood from the venae cavae enters the right atrium and then the right ventricle through the tricuspid valve. Contraction of the right ventricle, simultaneous with that of the left ventricle, forces blood through the pulmonary valve into the pulmonary artery, which progressively subdivides to form the arteries, arterioles and capillaries of the pulmonary circulation. The pulmonary circulation is shorter and has a much lower pressure than the systemic circulation, with systolic and diastolic pressures of about 25 and 10 mmHg, respectively. The pulmonary capillary network within the lungs surrounds the alveoli of the lungs, allowing exchange of CO2 for O2. Oxygenated blood enters pulmonary venules and veins and then the left atrium, which pumps it into the left ventricle for the next systemic cycle.

The output of the right ventricle is slightly lower than that of the left ventricle. This is because 1–2% of the systemic blood flow never reaches the right atrium but is shunted to the left side of the heart via the bronchial circulation (Figure 1.1), and a small fraction of coronary blood flow drains into the thebesian veins (see Chapter 2).

Blood vessel functions

Each vessel type has important functions in addition to being a conduit for blood.

The branching system of elastic and muscular arteries progressively reduces the pulsations in blood pressure and flow imposed by the intermittent ventricular contractions.

The smallest arteries and arterioles have a crucial role in regulating the amount of blood flowing to the tissues by dilating or constricting. This function is regulated by the sympathetic nervous system and factors generated locally in tissues. These vessels are referred to as resistance arteries, because their constriction resists the flow of blood.

Capillaries and small venules are the exchange vessels. Through their walls, gases, fluids and molecules are transferred between blood and tissues. White blood cells can also pass through the venule walls to fight infection in the tissues.

Venules can constrict to offer resistance to the blood flow, and the ratio of arteriolar and venular resistance exerts an important influence on the movement of fluid between capillaries and tissues, thereby affecting blood volume.

The veins are thin walled and very distensible, and therefore contain about 70% of all blood in the cardiovascular system. The arteries contain just 17% of total blood volume. Veins and venules thus serve as volume reservoirs, which can shift blood from the peripheral circulation into the heart and arteries by constricting. In doing so, they can help to increase the cardiac output (volume of blood pumped by the heart per unit time), and they are also able to maintain the blood pressure and tissue perfusion in essential organs if haemorrhage (blood loss) occurs.

Anatomy and histology

2
Gross anatomy and histology of the heart

Schematic illustrations of the gross anatomy of the heart, the arrangement of sarcomere lines and bands, arrangement of intercalated disks, the structure of diad, coronary circulation, and the structure of sarcomere with the details.

Gross anatomy of the heart (Figure 2.1)

The heart consists of four chambers. Blood flows into the right atrium via the superior and inferior venae cavae. The left and right atria connect to the ventricles via the mitral (two cusps) and tricuspid (three cusps) atrioventricular (AV) valves, respectively. The AV valves are passive and closed when the ventricular pressure exceeds that in the atrium. They are prevented from being everted into the atria during systole by fine cords (chordae tendineae) attached between the free margins of the cusps and the papillary muscles, which contract during systole. The outflow from the right ventricle passes through the pulmonary semilunar valve to the pulmonary artery, and that from the left ventricle enters the aorta via the aortic semilunar valve. These valves close passively at the end of systole, when ventricular pressure falls below that of the arteries. Both semilunar valves have three cusps.

The cusps or leaflets of the cardiac valves are formed of fibrous connective tissue, covered in a thin layer of cells similar to and contiguous with the endocardium (AV valves and ventricular surface of semilunar valves) and endothelium (vascular side of semilunar valves). When closed, the cusps form a tight seal (come to apposition) at the commissures (line at which the edges of the leaflets meet).

The atria and ventricles are separated by a band of fibrous connective tissue called the annulus fibrosus, which provides a skeleton for attachment of the muscle and insertion of the valves. It also prevents electrical conduction between the atria and ventricles except at the atrioventricular node (AVN). This is situated near the interatrial septum and the mouth of the coronary sinus and is an important element of the cardiac electrical conduction system (see Chapter 13).

The ventricles fill during diastole; at the initiation of the heartbeat the atria contract and complete ventricular filling. As the ventricles contract the pressure rises sharply, closing the AV valves. When ventricular pressure exceeds the pulmonary artery or aortic pressure, the semilunar valves open and ejection occurs (see Chapter 16). As systole ends and ventricular pressure falls, the semilunar valves are closed by backflow of blood from the arteries.

The force of contraction is generated by the muscle of the heart, the myocardium. The atrial walls are thin. The greater pressure generated by the left ventricle compared with the right is reflected by its greater wall thickness. The inside of the heart is covered in a thin layer of cells called the endocardium, which is similar to the endothelium of blood vessels. The outer surface of the myocardium is covered by the epicardium, a layer of mesothelial cells. The whole heart is enclosed in the pericardium, a thin fibrous sheath or sac, which prevents excessive enlargement. The pericardial space contains interstitial fluid as a lubricant.

Structure of the myocardium

The myocardium consists of cardiac myocytes (muscle cells) that show a striated subcellular structure, although they are less organized than skeletal muscle. The cells are relatively small (100 × 20 μm) and branched, with a single nucleus, and are rich in mitochondria. They are connected together as a network by intercalated discs (Figure 2.2), where the cell membranes are closely opposed. The intercalated discs provide both a structural attachment by ‘glueing’ the cells together at desmosomes, and an electrical connection through gap junctions formed of pores made up of proteins called connexons. As a result, the myocardium acts as a functional syncytium, in other words as a single functional unit, even though the individual cells are still separate. The gap junctions play a vital part in conduction of the electrical impulse through the myocardium (see Chapter 13).

The myocytes contain actin and myosin filaments which form the contractile apparatus and exhibit the classic M and Z lines and A, H and I bands (Figure 2.3). The intercalated discs always coincide with a Z line, as it is here that the actin filaments are anchored to the cytoskeleton. At the Z lines the sarcolemma (cell membrane) forms tubular invaginations into the cells known as the transverse (T) tubular system. The sarcoplasmic reticulum (SR) is less extensive than in skeletal muscle and runs generally in parallel with the length of the cell (Figure 2.4). Close to the T tubules the SR forms terminal cisternae that with the T tubule make up diads (Figure 2.5), an important component of excitation–contraction coupling (see Chapter 12). The typical triad seen in skeletal muscle is less often present. The T tubules and SR never physically join, but are separated by a narrow gap. The myocardium has an extensive system of capillaries.

Coronary circulation (Figure 2.6)

The heart has a rich blood supply, derived from the left and right coronary arteries. These arise separately from the aortic sinus at the base of the aorta, behind the cusps of the aortic valve. They are not blocked by the cusps during systole because of eddy currents, and remain patent throughout the cardiac cycle. The right coronary artery runs forward between the pulmonary trunk and right atrium, to the AV sulcus. As it descends to the lower margin of the heart, it divides to posterior descending and right marginal branches. The left coronary artery runs behind the pulmonary trunk and forward between it and the left atrium. It divides into the circumflex, left marginal and anterior descending branches. There are anastomoses between the left and right marginal branches and the anterior and posterior descending arteries, although these are not sufficient to maintain perfusion if one side of the coronary circulation is occluded.

Most of the blood returns to the right atrium via the coronary sinus, and anterior cardiac veins. The large and small coronary veins run parallel to the left and right coronary arteries, respectively, and empty into the sinus. Numerous other small vessels empty into the cardiac chambers directly, including thebesian veins and arteriosinusoidal vessels.

The coronary circulation is capable of developing a good collateral system in ischaemic heart disease, when a branch or branches are occluded by, for example, atheromatous plaques. Most of the left ventricle is supplied by the left coronary artery, and occlusion can therefore be very dangerous. The AVN and sinus node are supplied by the right coronary artery in the majority of people; disease in this artery can cause a slow heart rate and AV block (see Chapters 13 and 14).