# 03 - 244 Basic Biology of the Cardiovascular System

### 244 Basic Biology of the Cardiovascular System

By contrast, two-dimensional and Doppler echocardiography (Chap. 248) 
are indicated in patients with loud systolic murmurs (grades ≥III/
VI), especially those that are holosystolic or late systolic, and in most 
patients with diastolic or continuous murmurs.
■
■PITFALLS IN CARDIOVASCULAR MEDICINE
Increasing subspecialization in internal medicine and the perfection 
of advanced diagnostic techniques in cardiology can lead to several 
undesirable consequences. Examples include the following:
1.	 Failure by the noncardiologist to recognize important cardiac mani­
festations of systemic illnesses. For example, the presence of mitral 
stenosis, patent foramen ovale, and/or transient atrial arrhythmia 
should be considered in a patient with stroke, or the presence of 
pulmonary hypertension and cor pulmonale should be considered 
in a patient with scleroderma or Raynaud’s syndrome. A cardiovas­
cular examination should be carried out to identify and estimate the 
severity of the cardiovascular involvement that accompanies many 
noncardiac disorders.
2.	 Failure by the cardiologist to recognize underlying systemic disor­
ders in patients with heart disease. For example, hyperthyroidism 
should be considered in an elderly patient with atrial fibrillation and 
unexplained heart failure, and Lyme disease should be considered 
in a patient with unexplained (fluctuating) atrioventricular block. A 
cardiovascular abnormality may provide the clue critical to the rec­
ognition of some systemic disorders. For example, an unexplained 
pericardial effusion may provide an early clue to the diagnosis of 
tuberculosis or a neoplasm.
3.	 Overreliance on and overutilization of laboratory tests, particularly 
invasive techniques, for the evaluation of the cardiovascular sys­
tem. Cardiac catheterization and coronary arteriography (Chap. 249) 
provide precise diagnostic information that may be crucial in 
developing a therapeutic plan in patients with known or suspected 
CAD. Although a great deal of attention has been directed to these 
examinations, it is important to recognize that they serve to supple­
ment, not supplant, a careful examination carried out with clinical 
and noninvasive techniques. A coronary arteriogram should not be 
performed in lieu of a careful history in patients with chest pain sus­
pected of having ischemic heart disease. Although coronary arteri­
ography may establish whether the coronary arteries are obstructed 
and to what extent, the results of the procedure by themselves often 
do not provide a definitive answer to the question of whether a 
patient’s symptom of chest discomfort is attributable to coronary 
atherosclerosis and whether or not revascularization is indicated.
Despite the value of invasive tests in certain circumstances, they 
entail some small risk to the patient, involve discomfort and substantial 
cost, and place a strain on medical facilities. Therefore, they should be 
carried out only if the results can be expected to modify the patient’s 
management.
■
■DISEASE PREVENTION AND MANAGEMENT
The prevention of heart disease, especially of CAD, is one of the most 
important tasks of primary health care givers as well as cardiologists. 
Prevention begins with risk assessment, followed by attention to life­
style, such as achieving optimal weight, physical activity, and smoking 
cessation, and then aggressive treatment of all abnormal risk factors, 
such as hypertension, hyperlipidemia, and diabetes mellitus (Chap. 415).
After a complete diagnosis has been established in patients with 
known heart disease, a number of management options are usually 
available. Several examples may be used to demonstrate some of the 
principles of cardiovascular therapeutics:
1.	 In the absence of evidence of heart disease, the patient should be 
clearly informed of this assessment and not be asked to return at 
intervals for repeated examinations. If there is no evidence of dis­
ease, such continued attention may lead to the patient’s developing 
inappropriate concern about the possibility of heart disease.
2.	 If there is no evidence of cardiovascular disease but the patient 
has one or more risk factors for the development of ischemic heart 

disease (Chap. 284), a plan for their reduction should be developed 
and the patient should be retested at intervals to assess compliance 
and efficacy in risk reduction.
3.	 Asymptomatic or mildly symptomatic patients with valvular heart 

disease that is anatomically severe should be evaluated periodically, 
every 6–12 months, by clinical and noninvasive examinations. Early 
signs of deterioration of ventricular function may signify the need 
for surgical treatment before the development of disabling symp­
toms, irreversible myocardial damage, and excessive surgical risk 
(Chap. 272).
4.	 In patients with CAD (Chap. 284), available practice guidelines 
CHAPTER 244
Basic Biology of the Cardiovascular System
should be considered in the decision on the form of treatment 
(medical, percutaneous coronary intervention, or surgical revas­
cularization). Mechanical revascularization may be employed too 
frequently in the United States and too infrequently in Eastern 
Europe and developing nations. The mere presence of angina 
pectoris and/or the demonstration of critical coronary arterial nar­
rowing at angiography should not reflexively evoke a decision to 
treat the patient by revascularization. Instead, these interventions 
should be limited to patients with CAD in whom revasculariza­
tion has been shown to improve the natural history (e.g., acute 
coronary syndrome or multivessel CAD with left ventricular 
dysfunction).
■
■FURTHER READING
Tsao CW et al: Heart disease and stroke statistics—2023 update: A 
report from the American Heart Association. Circulation 147:e93, 
2023.
Joseph Loscalzo, John F. Keaney, Jr., 

Calum A. MacRae

Basic Biology of the 
Cardiovascular System
DEVELOPMENTAL BIOLOGY OF THE 
CARDIOVASCULAR SYSTEM
The heart forms early during embryogenesis (Fig. 244-1), circulating 
blood, nutrients, molecular signals, and oxygen to the other developing 
organs while continuing to grow and undergo complex morphoge­
netic changes. Early cardiac progenitors arise within crescent-shaped 
fields of lateral splanchnic mesoderm under the influence of mul­
tiple cues and migrate to the midline to form the linear heart tube: a 
single layer of endocardium and a single layer of spontaneously beating 
cardiomyocytes.
The simple linear heart tube undergoes chamber specification and 
asymmetric looping, coordinated with longitudinal and concentric 
growth of different regions of the heart tube, to produce the presump­
tive atria and ventricles. Cells continue to migrate into the heart at both 
ends from additional heart fields in pharyngeal mesoderm as looping 
and growth occur. These cells exhibit distinctive gene expression (e.g., 
Islet-1) and distinctive physiology (e.g., calcium handling), contribut­
ing to discrete areas of the adult heart, including the right atrium and 
the right ventricle. These different embryonic origins of cells within 
the right and left ventricles correlate with distinctive single-cell RNA 
sequencing profiles decades later and help explain why some forms 
of congenital and adult cardiac diseases affect different regions of the 
heart.
After looping and chamber formation, a series of morphogenetic 
events divide the left side from the right side of the heart, separate the

Neural folds
Early heart-forming
regions
Pericardial
coelom
Foregut
Forming heart
PART 6
Disorders of the Cardiovascular System
A
B
First heart field
Second heart field
LV
RV
C
D
E
F
FIGURE 244-1  A. Schematic depiction of a transverse section through an early embryo depicts the bilateral regions 
where early heart tubes form. B. The bilateral heart tubes subsequently migrate to the midline and fuse to form the linear 
heart tube. C. At the early cardiac crescent stage of embryonic development, cardiac precursors include a primary 
heart field fated to form the linear heart tube and a second heart field fated to add myocardium to the inflow and outflow 
poles of the heart. D. Second heart field cells populate the pharyngeal region before subsequently migrating to the 
maturing heart. E. Large portions of the right ventricle and outflow tract and some cells within the atria derive from the 
second heart field. F. The aortic arch arteries form as symmetric sets of vessels that then remodel under the influence 
of the neural crest to form the asymmetric mature vasculature. LA, left atrium; LV, left ventricle; RA, right atrium; RV, 
right ventricle.
atria from the ventricles, and fashion the aorta and pulmonary artery 
from the truncus arteriosus. Cardiac valves form between the atria 
and the ventricles and between the ventricles and the outflow vessels. 
Early in development, myocardial cells secrete an extracellular matrix 
rich in hyaluronic acid, or “cardiac jelly,” which accumulates within the 
endocardial cushions, precursors of the valves. Signals from overlying 
myocardial cells trigger migration, invasion, and phenotypic changes 
in underlying endocardial cells, an epithelial-mesenchymal transfor­
mation, that then invade and populate the endocardial cushion matrix. 
Mesenchymal cells then proliferate and form the mature valve leaflets.
The great vessels form as a series of symmetric bilateral aortic arch 
arteries that remodel asymmetrically to define the mature central 
vasculature. Migrating neural crest cells from the dorsal neural tube 
orchestrate this process and are necessary for aortic arch remodeling 
and septation of the truncus arteriosus. Smooth-muscle cells within the 
tunica media of the aortic arch, the ductus arteriosus, and the carotid 
arteries all derive from neural crest. By contrast, smooth muscle within 
the descending aorta arises from lateral plate mesoderm, and smooth 
muscle of the proximal outflow tract arises from the second heart field. 
Neural crest cells are sensitive to both vitamin A and folic acid, and 
congenital heart diseases involving abnormal remodeling of the aortic 
arch arteries are observed with maternal deficiencies of these vitamins. 
Shared embryonic origins of different cardiovascular cell types lead to 

syndromic associations between various 
congenital heart diseases and a range of 
extracardiac abnormalities.
Coronary artery formation requires 
the addition of yet another cell popula­
tion to the embryonic heart. Epicardial 
cells arise in the proepicardial organ, a 
derivative of the septum transversum, 
which also contributes to the fibrous 
portion of the diaphragm and to the 
liver. Proepicardial cells contribute 
smooth muscle to the coronary arteries 
and are required for proper coronary 
patterning. Other cell types within the 
heart (e.g., fibroblasts) also can arise 
from the proepicardium.
The cardiac conduction system, 
which generates and propagates electri­
cal impulses, differentiates from car­
diomyocyte precursors. The conduction 
system is composed of slow-conducting 
(proximal) components, such as the 
sinoatrial (SA) and atrioventricular (AV) 
nodes, as well as fast-conducting (distal) 
components, including the His bundle, 
bundle branches, and Purkinje fibers. 
Precursors within the sinus venosus 
give rise to the SA node, whereas those 
within the AV canal mature into hetero­
geneous cell types that compose the AV 
node. Decremental conduction through 
the AV node delays electrical impulses 
between atria and ventricles, enabling 
sequential antegrade contraction. The 
AV node also reduces the transmission 
of higher impulse rates to the vulner­
able ventricle, whereas the distal con­
duction system rapidly propagates each 
impulse throughout the ventricles. The 
conduction system is composed of com­
plex and heterogeneous cell populations 
with distinct gap junction proteins and 
ion channels that define the particular 
local electrical properties. Developmen­
tal defects in the conduction system 
can lead to clinical electrophysiologic 
disorders, such as congenital heart block or pre-excitation (WolffParkinson-White syndrome) (Chap. 256).
RA
LA
RV
LV
■
■ORIGIN OF VASCULAR CELLS
Smooth-muscle cells are of varied origin. Some upper-body arterial 
smooth-muscle cells derive from the neural crest, whereas lower-body 
arteries develop smooth-muscle cells from neighboring mesodermal 
structures. Embryonic endothelial progenitor cells are derived from 
mesoderm. In adults, resident vascular or bone marrow–derived 
endothelial progenitors may aid repair of damaged or aging arteries. 
Bone marrow clonality, increasingly prevalent in aging, may impart 
significant clonality to endothelial cell populations. Vascular stem cells 
resident in the vessel wall may give rise to some smooth-muscle cells 
in injured or atheromatous arteries.
THE BLOOD VESSEL
■
■VASCULAR ULTRASTRUCTURE
Blood vessels participate in disease biology as well as physiologic 
function in virtually every organ system. The smallest blood vessels—
capillaries—consist of a monolayer of endothelial cells on a basement 
membrane adjacent to a discontinuous layer of smooth-musclelike cells known as pericytes (Fig. 244-2A). Arteries typically have

A. Capillary
B. Vein
C. Small muscular artery
Pericyte
Endothelial cell
D. Large muscular artery
Internal elastic
lamina
External elastic
lamina
Adventitia
FIGURE 244-2  Schematics of the structures of various types of blood vessels. A. Capillaries consist of an endothelial 
tube in contact with a discontinuous population of pericytes. B. Veins typically have thin medias and thicker adventitias. 
C. A small muscular artery features a prominent tunica media. D. Larger muscular arteries have a prominent media 
with smooth-muscle cells embedded in a complex extracellular matrix. E. Larger elastic arteries have cylindrical layers 
of elastic tissue alternating with concentric rings of smooth-muscle cells as well as vasa vasorum to facilitate tissue blood 
supply.
a trilaminar structure (Fig. 244-2B–E). The intima consists of a 
monolayer of endothelial cells continuous with those of the capil­
laries. The middle layer, or tunica media, consists of a syncytium of 
smooth-muscle cells that in veins are much sparser than in arteries 
(Fig. 244-2B). The outer layer, or adventitia, consists of extracellular 
matrix with fibroblasts, mast cells, and nerve terminals. Larger arteries 
require nourishment of the tunica media that is accomplished via their 
own vasculature, the vasa vasorum (Fig. 244-2E).
Arterioles are small muscular arteries (Fig. 244-2C) that regulate 
blood pressure and flow through arterial beds. Medium-size muscular 
arteries also contain prominent smooth-muscle layers (Fig. 244-2D) 
that participate in atherogenesis. Larger elastic arteries have a highly 
structured tunica media with concentric bands of smooth-muscle cells, 
interspersed with strata of elastin-rich extracellular matrix (Fig. 244-2E). 
Larger arteries form an internal elastic lamina between intima and 
media while an external elastic lamina partitions the media from sur­
rounding adventitia.
■
■VASCULAR CELL BIOLOGY
Endothelial Cell 
The endothelium forms the interface between 
tissues and the blood compartment, regulating the passage of mol­
ecules and cells. This function of endothelial cells as a selectively 
permeable barrier fails in vascular diseases, including atherosclerosis, 
hypertension, and renal disease, as well as in pulmonary edema, sepsis, 
and other situations exhibiting “capillary leak.”
The endothelium also participates in the local regulation of vascular 
tone and blood flow. Endogenous endothelium-derived substances, 
such as prostacyclin, endothelium-derived hyperpolarizing factor, 
nitric oxide (NO), and hydrogen peroxide (H2O2), provide tonic stimu­
lation of endothelial homeostatic properties under physiologic condi­
tions in vivo (Table 244-1). Impaired production or excess catabolism 
of these substances can mediate dysfunctional properties of the endo­
thelium. A major homeostatic influence on the endothelium is laminar 
blood flow, and the measurement of flow-mediated dilatation directly 
assesses endothelial vasodilator function in humans (Fig. 244-3). 

Endothelial cells also produce potent 
vasoconstrictor substances such as 
endothelin. Excessive production of 
reactive oxygen species, such as super­
oxide anion (O2

CHAPTER 244
–), by endothelial or 
smooth-muscle cells under pathologic 
conditions (e.g., excessive exposure to 
angiotensin II) can promote local oxi­
dative stress and inactivate NO.
Vascular
smooth-muscle cell
Endothelial cells also regulate cel­
lular traffic through tissues. Normal 
endothelium exhibits limited interac­
tion with circulating leukocytes, but 
bacterial products such as endotoxin or 
proinflammatory cytokines can induce 
endothelial cells to express an array 
of adhesion molecules that selectively 
bind various classes of leukocytes in 
different pathologic conditions. The 
adhesion molecules and chemokines 
generated during acute bacterial infec­
tion tend to recruit granulocytes, while 
in chronic inflammatory diseases such 
as tuberculosis or atherosclerosis, the 
adhesion molecules expressed favor 
monocyte recruitment. Endothelial 
cell injury participates in the patho­
physiology of many immune-mediated 
diseases. For example, complementmediated lysis of endothelial cells con­
tributes to tissue injury. The foreign 
histocompatibility complex antigens 
on endothelial cells in solid-organ 
allografts can promote allograft arte­
riopathy, while immune-mediated endothelial injury also plays a 
role in thrombotic thrombocytopenic purpura or hemolytic-uremic 
syndrome.
Basic Biology of the Cardiovascular System
E. Large elastic artery
The endothelium also regulates the balance between thrombosis 
and hemostasis through a highly tuned set of regulatory pathways. For 
example, inflammatory cytokines, bacterial endotoxin, or angiotensin 
II can activate endothelial cells to produce substantial quantities of 
plasminogen activator inhibitor 1 (PAI-1), the major inhibitor of fibri­
nolysis. Inflammatory stimuli also induce endothelial expression of the 
potent procoagulant tissue factor, a contributor to disseminated intra­
vascular coagulation in sepsis; similar effects are observed in hyper­
glycemia. Thus, in pathologic circumstances, endothelial dysfunction 
tends to promote local thrombus accumulation rather than combat it.
Endothelial cells regulate the growth of subjacent smooth-muscle 
cells by elaborating heparan sulfate glycosaminoglycans that inhibit 
smooth-muscle proliferation. In the setting of vascular injury, endo­
thelium-derived growth factors and chemoattractants (e.g., plateletderived growth factor) induce the migration and proliferation of 
vascular smooth-muscle cells. Dysregulation of these growth-stimula­
tory molecules may promote smooth-muscle accumulation in athero­
sclerotic lesions.
TABLE 244-1  Endothelial Functions in Health and Disease
HOMEOSTATIC PROPERTIES
DYSFUNCTIONAL PROPERTIES
Optimize balance between vasodilation 
and vasoconstriction
Impaired dilation, vasoconstriction
Antithrombotic, profibrinolytic
Prothrombotic, antifibrinolytic
Anti-inflammatory
Proinflammatory
Antiproliferative
Proproliferative
Antioxidant
Prooxidant
Selective permeability
Impaired barrier function

PART 6
Disorders of the Cardiovascular System
FIGURE 244-3  Assessment of endothelial function in vivo using blood pressure cuff 
occlusion and release. Upon deflation of the cuff, an ultrasound probe monitors 
changes in diameter (A) and blood flow (B) of the brachial artery (C). (Reproduced 
with permission of J. Vita, MD.)
Vascular Smooth-Muscle Cell 
Contraction and relaxation of 
vascular smooth-muscle cells in muscular arteries determine blood 
pressure, regional flow, and the afterload experienced by the left ven­
tricle (see below). Venous tone regulates venous tree capacitance and 
influences ventricular preload. Smooth-muscle cells in the adult vessel 
seldom replicate in the absence of arterial injury or inflammatory acti­
vation, but proliferation and migration of arterial smooth-muscle cells 
contribute to arterial stenoses in atherosclerosis, arteriolar remodeling 
in hypertension, and the hyperplastic response of arteries to injury. In 
the pulmonary circulation, smooth-muscle migration and prolifera­
tion underlie the vascular pathology that occurs in sustained high-flow 

states such as left-to-right shunts in congenital heart disease with 
resulting pulmonary hypertension.
Smooth-muscle cells secrete the bulk of vascular extracellular 
matrix. Excessive production of collagen and glycosaminoglycans 
contributes to the remodeling, altered biomechanics, and physiology 
of arteries affected by hypertension or atherosclerosis. In larger elastic 
arteries, such as the aorta, the ability to store the kinetic energy of 
systole promotes tissue perfusion during diastole. Arterial stiffness, 
associated with aging or disease, increases left ventricular afterload and 
portends a poor outcome.
Like endothelial cells, vascular smooth-muscle cells not only 
respond to paracrine stimuli from other cells but can themselves serve 
as a source of such stimuli. For example, proinflammatory stimuli 
induce smooth-muscle cells to elaborate cytokines and other mediators 
that drive thrombosis and fibrinolysis as well as proliferation.
Vascular Smooth-Muscle Cell Contraction 
The principal 
mechanism for vascular smooth-muscle cell contraction is increased 
cytoplasmic calcium concentration due to transmembrane influx and 
triggered release from intracellular calcium stores (Fig. 244-4). In vas­
cular smooth-muscle cells, voltage-dependent L-type calcium channels 
open with membrane depolarization. Local influx of calcium, termed 
calcium sparks, can trigger release from intracellular stores, which 
results in more contraction and increased vessel tone (see below). 
Opposing currents balance the effects of individual ionic fluxes pro­
moting homeostasis, which is tightly regulated by neural and metabolic 
influences.
Vasoconstricting agonists also increase intracellular [Ca2+] by vari­
ous mechanisms including receptor-dependent phospholipase C acti­
vation producing hydrolysis of phosphatidylinositol 4,5-bisphosphate 
to generate diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). 
These membrane lipid derivatives, in turn, activate protein kinase C 
and increase intracellular [Ca2+]. In addition, IP3 binds specific sarco­
plasmic reticulum (SR) receptors to increase calcium efflux from this 
storage pool into the cytoplasm.
Vascular smooth-muscle cell contraction depends on myosin light 
chain phosphorylation that reflects the balance between the activity 
of relevant kinases and phosphatases. Calcium activates myosin light 
chain kinase via calmodulin, augmenting myosin ATPase activity and 
enhancing contraction. Conversely, myosin light chain phosphatase 
reduces myosin ATPase activity and contractile force. Other kinase/
phosphorylase combinations result in a complex regulatory network 
that refines vascular tone and links it to physiologic requirements.
Control of Vascular Smooth-Muscle Cell Tone 
The auto­
nomic nervous system and endothelial cells modulate vascular smoothmuscle cells through similar convergent pathways. Autonomic neurons 
enter vessel media and modulate vascular smooth-muscle cell tone in 
response to baroreceptors and chemoreceptors within the aortic arch 
or carotid bodies and to thermoreceptors in the skin. Rapidly acting 
reflex arcs modulated by central inputs respond to multiple sensory 
inputs as well as emotional stimuli through three neuronal classes: 
sympathetic, whose principal neurotransmitters are epinephrine and 
norepinephrine; parasympathetic, whose principal neurotransmit­
ter is acetylcholine; and nonadrenergic/noncholinergic, which include 
two subgroups—nitrergic, whose principal neurotransmitter is NO, 
and peptidergic, whose principal neurotransmitters are substance P, 
vasoactive intestinal peptide, calcitonin gene-related peptide, and the 
nonpeptide, adenosine triphosphate (ATP).
Each of these neurotransmitters acts through specific receptors on 
the vascular smooth-muscle cell to modulate intracellular Ca2+ and, 
consequently, contractile tone. Norepinephrine activates α-adrenergic 
receptors, and epinephrine activates both α and β receptors. In most 
blood vessels, norepinephrine activates postjunctional α1 receptors in 
large arteries and α2 receptors in small arteries and arterioles, lead­
ing to vasoconstriction. Most blood vessels express β2-adrenergic 
receptors on their vascular smooth-muscle cells and respond to β 
agonists by cyclic AMP–dependent relaxation. Acetylcholine released 
from parasympathetic neurons may bind to muscarinic receptors on 
either vascular smooth-muscle cells, causing vasoconstriction, or on

Ca2+
NE, ET-1, Ang II
VDCC
PIP2
G
G
PLC
RhoA
Ca2+
“Spark”
cAMP
DAG
IP3R
RyrR
Plb
ATPase
IP3
PKC
Rho
Kinase
Caldesmon
Calponin
FIGURE 244-4  Regulation of vascular smooth-muscle cell calcium concentration and actomyosin ATPase-dependent contraction. AC, adenylyl cyclase; Ang II, angiotensin 
II; ANP, atrial natriuretic peptide; DAG, diacylglycerol; ET-1, endothelin-1; G, G protein; IP3, inositol 1,4,5-trisphosphate; MLCK, myosin light chain kinase; MLCP, myosin light 
chain phosphatase; NE, norepinephrine; NO, nitric oxide; pGC, particular guanylyl cyclase; PIP2, phosphatidylinositol 4,5-bisphosphate; PKA, protein kinase A; PKC, protein 
kinase C; PKG, protein kinase G; PLC, phospholipase C; sGC, soluble guanylyl cyclase; SR, sarcoplasmic reticulum; VDCC, voltage-dependent calcium channel. Solid lines 
depict stimulatory interaction, and dashed lines represent inhibition. (Reproduced with permission from B Berk, in Vascular Medicine, 3rd ed. Philadelphia, Saunders, 
Elsevier; 2006.)
endothelial cells, causing NO-dependent vasorelaxation. Nitrergic 
neurons release NO, which relaxes vascular smooth-muscle cell via 
the cyclic GMP–dependent and –independent mechanisms outlined, 
and other peptidergic inputs that regulate vascular tone. For the 
detailed molecular physiology of the autonomic nervous system, 
see Chap. 451.
The release of endothelial effectors of vascular smooth-muscle cell 
tone integrates the smooth-muscle response to mechanical (e.g., shear 
stress, cyclic strain) and biochemical stimuli (purinergic agonists, 
muscarinic agonists, peptidergic agonists). In addition to these local 
paracrine modulators, a complex system of circulating modulators 
ranging from norepinephrine to the natriuretic peptides also modify 
vascular smooth-muscle cell tone.
■
■ARTERIOGENESIS AND ANGIOGENESIS
Recruitment and growth of blood vessels (arteriogenesis) and new 
capillaries (angiogenesis) can occur in response to conditions such 
as chronic hypoxemia and tissue ischemia. Growth factors, including 
vascular endothelial growth factor (VEGF) and fibroblast growth fac­
tor (FGF), can activate a signaling cascade that stimulates endothelial 
proliferation and tube formation, defined as angiogenesis. Guidance 
molecules, including members of the semaphorin family of secreted 
peptides, direct blood vessel patterning by attracting or repelling 
nascent endothelial tubes. The recruitment and expansion of preexist­
ing collateral vascular networks in response to a blocked artery, an 
example of arteriogenesis, can result from selective activation of both 
growth factors and, perhaps, local or circulating endothelial progenitor 
cells. True vascular regeneration, or the development of a new blood 
vessel that includes all three cell layers, normally does not occur in 
adult mammals, but recent scientific advances might help obviate such 
limitations.

BetaAgonist
ANP
NO
CHAPTER 244
K+ Ch
Na-K ATPase
pGC
AC
GTP
ATP
sGC
SR
Basic Biology of the Cardiovascular System
cGMP
PKG
PKA
Calcium
MLCK
MLCP
CELLULAR BASIS OF CARDIAC 
CONTRACTION
■
■CARDIAC ULTRASTRUCTURE
Most of the ventricular mass is composed of cardiomyocytes, normally 
60–140 μm in length and 17–25 μm in diameter (Fig. 244-5A). Each cell 
contains multiple myofibrils that run the length of the cell and are com­
posed of series of repeating sarcomeres. The cytoplasm between the myo­
fibrils contains other cell constituents, including a single centrally located 
nucleus, mitochondria, and the intracellular membrane system, the SR.
The sarcomere, the structural and functional unit of contraction, lies 
between adjacent Z lines, which on transmission electron microscopy 
are seen as dark repeating bands. The distance between Z lines var­
ies with the degree of contraction or stretch of the muscle and ranges 
between 1.6 and 2.2 μm. At the center of the sarcomere is a dark band 
of constant length (1.5 μm), the A band, which is flanked by two lighter 
bands, the I bands, which are of variable length. The sarcomere of heart 
muscle, like that of skeletal muscle, consists of interdigitating thick and 
thin myofilaments. Thicker filaments, composed principally of the 
protein myosin, traverse the A band; they are about 10 nm (100 Å) in 
diameter, with tapered ends. Thinner filaments, composed primarily of 
actin, course from the Z lines through the I band into the A band; they 
are ~5 nm (50 Å) in diameter and 1.0 μm in length. Thus, thick and thin 
filaments overlap only within the (dark) A band, whereas the (light) I 
band contains only thin filaments. On electron-microscopic examina­
tion, bridges extend between the thick and thin filaments within the 
A band; these are myosin heads (see below) bound to actin filaments.
■
■THE CONTRACTILE PROCESS
The sliding filament model for muscle contraction rests on the central 
observation that both the thick and the thin filaments are constant in

Myofiber
PART 6
Disorders of the Cardiovascular System
A
Na+
Exchange
Ca2+
Pump
Myofibril
e
t
y
c
o
y
M
Myofibril
Mitochondrion
B
Myofibril
C
Diastole
Actin
Myosin
Titin
M
Z
D
FIGURE 244-5  A shows the branching myocytes making up the cardiac myofibers. B illustrates the critical role played by the changing [Ca2+] in the myocardial cytosol. Ca2+ 
ions are schematically shown as entering through the calcium channel that opens in response to the wave of depolarization that travels along the sarcolemma. These Ca2+ 
ions “trigger” the release of more calcium from the sarcoplasmic reticulum (SR) and thereby initiate a contraction-relaxation cycle. Eventually the small quantity of Ca2+ 
that has entered the cell leaves predominantly through an Na+/Ca2+ exchanger, with a lesser role for the sarcolemmal Ca2+ pump. The varying actin-myosin overlap is shown 
for (B) systole, when [Ca2+] is maximal, and (C) diastole, when [Ca2+] is minimal. D. The myosin heads, attached to the thick filaments, interact with the thin actin filaments. 
(Reproduced with permission from LH Opie: Heart Physiology: From Cell to Circulation, 4th ed. Philadelphia, Lippincott, Williams & Wilkins, 2004.)
length during both contraction and relaxation. With activation, the 
actin filaments are propelled farther into the A band. In this process, 
the A band remains constant in length, whereas the I band shortens 
and the Z lines move toward one another.
The myosin molecule is a complex, asymmetric protein with a 
molecular mass of about 500,000 Da; it has a rod-like portion that is 
about 150 nm (1500 Å) in length with a globular portion (head) at its 
end. The globular portions of myosin form the bridges to actin and 
are the site of ATPase activity. In thick myofilaments, composed of 
~300 longitudinally stacked myosin molecules, the rod-like segments 
of myosin assume an orderly, polarized orientation, with outwardly 
projecting globular heads interacting with actin to generate force and 
shorten (Fig. 244-5B).
Actin has a molecular mass of about 47,000 Da. Thin filaments 
consist of a double helix of two chains of actin molecules wound about 
each other on a larger molecule, tropomyosin. A group of regulatory 
proteins—troponins C, I, and T—localize at regular intervals on this 
filament (Fig. 244-6). In contrast to myosin, actin lacks intrinsic enzy­
matic activity but combines reversibly with myosin in the presence of 

10 µm
Myocyte
Ca2+
enters
T tubule
Ca2+
“trigger”
Ca2+
leaves
Free
Ca2+
SR
Contract
Relax
Systole
Z
Head
43 nm
ATP and Ca2+. Calcium activates the myosin ATPase, which breaks 
down ATP to supply the energy for contraction (Fig. 244-6). The activ­
ity of myosin ATPase determines the rate of actomyosin cross-bridge 
formation and breakdown, and ultimately determines contraction 
velocity. In relaxed muscle, tropomyosin inhibits this interaction. Titin 
(Fig. 244-5D) an enormous, flexible, myofibrillar protein, connects 
myosin to the Z line; its elasticity contributes to the passive mechani­
cal characteristics of the heart. Dystrophin, a cytoskeletal protein that 
binds to the dystroglycan complex at membrane adherens junctions, 
tethers the sarcomere to the cell membrane at these regions of tight 
coupling to adjacent myocytes. Mutations in multiple sarcomeric and 
cytoskeletal proteins cause different Mendelian disorders involving 
the heart and skeletal muscle and also sensitize individuals to toxic 
cardiomyopathies (e.g., due to alcohol or chemotherapy) and to those 
caused by other acquired stressors, such as inflammatory or peripar­
tum cardiomyopathy.
During activation of the cardiac myocyte, Ca2+ binds the hetero­
trimer troponin C, resulting in regulatory conformational changes 
in tropomyosin and exposing actin cross-bridge interaction sites

ATP
Relaxed, energized
Relaxed
Actin
2.
4.
Dissociation of
actin and myosin
ATP
Rigor complex
Active complex
FIGURE 244-6  Four steps in cardiac muscle contraction and relaxation. In relaxed muscle (upper left), ATP bound to the myosin cross-bridge dissociates the thick and 
thin filaments. Step 1: Hydrolysis of myosin-bound ATP by the ATPase site on the myosin head transfers the chemical energy of the nucleotide to the activated cross-bridge 
(upper right). When cytosolic Ca2+ concentration is low, as in relaxed muscle, the reaction cannot proceed because tropomyosin and the troponin complex on the thin 
filament do not allow the active sites on actin to interact with the cross-bridges. Therefore, even though the cross-bridges are energized, they cannot interact with actin. 
Step 2: When Ca2+ binding to troponin C has exposed active sites on the thin filament, actin interacts with the myosin cross-bridges to form an active complex (lower right) in 
which the energy derived from ATP is retained in the actin-bound cross-bridge, whose orientation has not yet shifted. Step 3: The muscle contracts when ADP dissociates 
from the cross-bridge. This step leads to the formation of the low-energy rigor complex (lower left) in which the chemical energy derived from ATP hydrolysis has been 
expended to perform mechanical work (the “rowing” motion of the cross-bridge). Step 4: The muscle returns to its resting state, and the cycle ends when a new molecule of 
ATP binds to the rigor complex and dissociates the cross-bridge from the thin filament. This cycle continues until calcium is dissociated from troponin C in the thin filament, 
which causes the contractile proteins to return to the resting state with the cross-bridge in the energized state. ADP, adenosine diphosphate; ATP, adenosine triphosphate; 
ATPase, adenosine triphosphatase. (Reproduced with permission from AM Katz: Heart failure: Cardiac function and dysfunction, in Atlas of Heart Diseases, 3rd ed, WS 
Colucci [ed]. Philadelphia, Current Medicine, 2002.)
(Fig. 244-6). Repetitive interaction between myosin heads and actin 
filaments is termed cross-bridge cycling and results in sliding of the actin 
along the myosin filaments, with muscle shortening and/or the devel­
opment of tension. The splitting of ATP then dissociates the myosin 
cross-bridge from actin. In the presence of ATP (Fig. 244-6), actin and 
myosin filaments bind and dissociate cyclically if sufficient Ca2+ is pres­
ent; these processes cease when [Ca2+] falls below a critical level, and 
the troponin-tropomyosin complex once more inhibits actin-myosin 
interactions (Fig. 244-7).
Cytoplasmic [Ca2+] is a principal determinant of the inotropic state 
of the heart. Most agents that stimulate myocardial contractility (posi­
tive inotropic stimuli), including digitalis glycosides and β-adrenergic 
agonists, increase cytoplasmic [Ca2+], triggering cross-bridge cycling. 
Increased adrenergic neuronal activity stimulates myocardial con­
tractility through norepinephrine release, activation of β-adrenergic 
receptors, and, via Gs-stimulated guanine nucleotide-binding proteins, 
activation of the adenylyl cyclase, which leads to the formation of the 
intracellular second messenger cyclic AMP from ATP (Fig. 244-7). 
Cyclic AMP in turn activates protein kinase A (PKA), which phos­
phorylates sarcolemmal Ca2+ channels, thereby enhancing the influx of 
Ca2+ into the myocyte.
The SR (Fig. 244-8), a complex network of anastomosing intracel­
lular channels, invests the myofibrils. The transverse tubules, or T sys­
tem, closely related to the SR, both structurally and functionally, arise 
as sarcolemmal invaginations that extend into the myofibrillar bundles 
along the Z lines, i.e., the ends of the sarcomeres.
■
■CARDIAC ACTIVATION
In the inactive state, the cardiomyocyte membrane is electrically 
polarized; i.e., the interior has a negative charge relative to the outside 
of the cell, with a transmembrane potential of –80 to –100 mV 
(Chap. 250). The sarcolemma, which in the resting state is largely 
impermeable to Na+, and a Na+- and K+-pump energized by ATP 
extrudes Na+ from the cell and maintains the resting potential. In this 
resting state, intracellular [K+] is relatively high and [Na+] is far lower; 

ADP
Pi
1. ATP hydrolysis
CHAPTER 244
Actin
Formation of 
active complex
Basic Biology of the Cardiovascular System
Pi
ADP
ADP
3.
Product
dissociation
conversely, extracellular [Na+] is high and [K+] is low. At the same 
time, extracellular [Ca2+] greatly exceeds free intracellular [Ca2+].
The action potential has four phases (see Fig. 250-1B). Depolariz­
ing current spreads across the cell membrane, penetrating deeply into 
the cell via the T tubular system. During the action potential plateau 
(phase 2), there is a slow inward current through sarcolemmal L-type 
Ca2+ channels (Fig. 244-8). The absolute quantity of Ca2+ traversing 
sarcolemmal and T tubular membranes is modest and insufficient to 
fully activate contraction. However, this initial Ca2+ current, through 
Ca2+-induced Ca2+ release, triggers substantial Ca2+ release from the SR, 
inducing contraction.
Ca2+ is released from the SR through a Ca2+ release channel, a 
cardiac isoform of the ryanodine receptor (RyR2). Several regulatory 
proteins inhibit RyR2 and thus SR Ca2+ release. Inherited disorders or 
exogenous factors affecting the efficiency or stability of SR Ca2+ han­
dling can impair contraction, leading to heart failure or to ventricular 
arrhythmias.
The Ca2+ released from the SR diffuses to interact with myofi­
brillar troponin C (Fig. 244-7), repressing this protein’s inhibition 
of contraction, and so activating myofilaments to shorten. During 
repolarization, the activity of the SR Ca2+-ATPase (SERCA2A) leads 
to Ca2+ uptake against a concentration gradient into the SR where it 
complexes with another specialized protein, calsequestrin. The uptake 
of Ca2+ is ATP (energy)-dependent and lowers cytoplasmic [Ca2+] 
to a level where actomyosin interaction is inhibited and myocardial 
relaxation occurs. There is also a sarcolemmal exchange of Ca2+ for 
Na+ (Fig. 244-8), reducing cytoplasmic [Ca2+]. Additional control of 
calcium compartmentalization results from cyclic AMP–dependent 
PKA phosphorylation of the SR protein phospholamban, permit­
ting SERCA2A activation, increasing SR Ca2+ uptake, and so accelerating 
relaxation rates, and loading the SR with Ca2+ for subsequent cycles of 
release and contraction.
Thus, the combination of the cell membrane, transverse tubules, and 
SR, transmitting the action potential, releasing and then re-accumulating 
Ca2+, controls the cyclic contraction and relaxation of heart muscle.

β - Adrenergic agonist
PART 6
Disorders of the Cardiovascular System
β
γ
αs
Adenyl
cyclase
SL
GTP
β
Receptor
cAMP
Via protein kinase A
Metabolic
• glycolysis
• lipolysis
• citrate cycle
ADP + Pi
+
ATP
Troponin C
Myosin
ATPase
ADP + Pi
Increased
1. rate of contraction
2. peak force
3. rate of relaxation
β
Force
FIGURE 244-7  Signal systems involved in positive inotropic and lusitropic (enhanced relaxation) effects of α-adrenergic stimulation. When the β-adrenergic agonist 
interacts with the β receptor, a series of G protein–mediated changes leads to activation of adenylyl cyclase and the formation of cyclic adenosine monophosphate 
(cAMP). The latter acts via protein kinase A to stimulate metabolism (left) and phosphorylate the Ca2+ channel protein (right). The result is an enhanced opening probability 
of the Ca2+ channel, thereby increasing the inward movement of Ca2+ ions through the sarcolemma (SL) of the T tubule. These Ca2+ ions release more calcium from the 
sarcoplasmic reticulum (SR) to increase cytosolic Ca2+ and activate troponin C. Ca2+ ions also increase the rate of breakdown of adenosine triphosphate (ATP) to adenosine 
diphosphate (ADP) and inorganic phosphate (Pi). Enhanced myosin ATPase activity explains the increased rate of contraction, with increased activation of troponin C 
explaining increased peak force development. An increased rate of relaxation results from the ability of cAMP to activate as well the protein phospholamban, situated on 
the membrane of the SR, that controls the rate of uptake of calcium into the SR. The latter effect explains enhanced relaxation (lusitropic effect). P, phosphorylation; PL, 
phospholamban; TnI, troponin I. (Reproduced with permission from LH Opie: Heart Physiology: From Cell to Circulation, 4th ed. Philadelphia, Lippincott, Williams & Wilkins, 
2004.)
Genetic or pharmacologic alterations of any component can disturb 
any of the functions of this finely tuned system.
CONTROL OF CARDIAC PERFORMANCE 
AND OUTPUT
The extent of shortening of heart muscle and, therefore, ventricular 
stroke volume in the intact heart depends on three major influences: 
(1) the length of the muscle at the onset of contraction, i.e., the preload; 
(2) the tension that the muscle must develop during contraction, i.e., 
the afterload; and (3) muscle contractility, i.e., the extent and velocity 
of shortening at any given preload and afterload. Table 244-2 lists the 
major determinants of preload, afterload, and contractility.
■
■THE ROLE OF MUSCLE LENGTH (PRELOAD)
Preload determines sarcomere length at the onset of contraction. 
Contractile force is optimal at specific sarcomere lengths (~2.2 μm) 
where both myofilament Ca2+ sensitivity is maximal, and myofilament 
interactions and activation of contraction are most efficient. The rela­
tionship between initial muscle fiber length and the developed force is 
the basis of Starling’s law of the heart, which states that, within limits, 

Ca2+
P
Ca2+
+
+
SR
+
P
Ca2+
+
cAMP
via Tnl
+

+
cAMP
via PL

+

Control
Time
Pattern of contraction
the ventricular contraction force depends on the end-diastolic length 
of the cardiac muscle; in vivo, end-diastolic length relates closely to the 
ventricular end-diastolic volume.
■
■CARDIAC PERFORMANCE
Ventricular end-diastolic or “filling” pressure can serve as a surrogate 
for end-diastolic volume. In isolated heart and heart-lung prepara­
tions, stroke volume varies directly with the end-diastolic fiber 
length (preload) and inversely with the arterial resistance (afterload), 
and as the heart fails—i.e., as its contractility declines—it delivers a 
progressively smaller stroke volume from a normal or even elevated 
end-diastolic volume. The relation between ventricular end-diastolic 
pressure and the stroke work of the ventricle (the ventricular func­
tion curve) provides a working definition of cardiac contractility in 
the intact organism. An increase in contractility is accompanied by a 
shift of the ventricular function curve upward and to the left (greater 
stroke work at any level of ventricular end-diastolic pressure, or lower 
end-diastolic volume at any level of stroke work), whereas a shift 
downward and to the right characterizes reduction of contractility 
(Fig. 244-9).

Na+
pump
Plasma membrane
Ca2+ pump
Na+/Ca2+
exchanger
B2
B1
T tubule
Cisterna
Plasma
membrane
Ca2+
channel
Ca2+-
release channel
('foot' protein)
A
A1
Mitochondria
Calsequestrin
C
E
F
  Z-line
  Troponin C
Thin
filament
Contractile
proteins
Thick
filament
FIGURE 244-8  The Ca2+ fluxes and key structures involved in cardiac excitation-contraction coupling. The arrows denote the direction of Ca2+ fluxes. The thickness of 
each arrow indicates the magnitude of the calcium flux. Two Ca2+ cycles regulate excitation-contraction coupling and relaxation. The larger cycle is entirely intracellular 
and involves Ca2+ fluxes into and out of the sarcoplasmic reticulum, as well as Ca2+ binding to and release from troponin C. The smaller extracellular Ca2+ cycle occurs when 
this cation moves into and out of the cell. The action potential opens plasma membrane Ca2+ channels to allow passive entry of Ca2+ into the cell from the extracellular fluid 
(arrow A). Only a small portion of the Ca2+ that enters the cell directly activates the contractile proteins (arrow A1). The extracellular cycle is completed when Ca2+ is actively 
transported back out to the extracellular fluid by way of two plasma membrane fluxes mediated by the sodium-calcium exchanger (arrow B1) and the plasma membrane 
calcium pump (arrow B2). In the intracellular Ca2+ cycle, passive Ca2+ release occurs through channels in the cisternae (arrow C) and initiates contraction; active Ca2+ uptake 
by the Ca2+ pump of the sarcotubular network (arrow D) relaxes the heart. Diffusion of Ca2+ within the sarcoplasmic reticulum (arrow G) returns this activator cation to the 
cisternae, where it is stored in a complex with calsequestrin and other calcium-binding proteins. Ca2+ released from the sarcoplasmic reticulum initiates systole when it 
binds to troponin C (arrow E). Lowering of cytosolic [Ca2+] by the sarcoplasmic reticulum (SR) causes this ion to dissociate from troponin (arrow F) and relaxes the heart. 
Ca2+ also may move between mitochondria and cytoplasm (H). (Reproduced with permission from AM Katz: Physiology of the Heart, 4th ed. Philadelphia, Lippincott, Williams 
& Wilkins, 2005.)
■
■VENTRICULAR AFTERLOAD
In the intact heart, as ex vivo, the extent and velocity of shortening 
of ventricular muscle fibers at any level of preload and of myocardial 
contractility relate inversely to the afterload, i.e., the instantaneous load 
opposing shortening. In the intact heart, the afterload may be defined 
as the tension developed in the ventricular wall during ejection. After­
load is determined by the aortic pressure as well as by the volume of 
the ventricular cavity and myocardial tissue characteristics including 
thickness. Laplace’s law models the tension of the myocardial fiber 
as the product of intra-cavitary ventricular pressure and ventricular 
radius divided by wall thickness. Therefore, at any given aortic pres­
sure, the afterload on a dilated left ventricle exceeds that on a normalsized ventricle. Conversely, at the same aortic pressure and ventricular 
diastolic volume, the afterload on a hypertrophied ventricle is lower 
than that on a normal chamber. Aortic pressure in turn depends on the 
peripheral vascular resistance, the biomechanics of the arterial tree, 
and the volume of blood it contains at the onset of ejection.
Ventricular afterload finely regulates cardiovascular performance 
(Fig. 244-10). As noted, elevations in both preload and contractility 
increase myocardial fiber shortening, whereas increases in afterload 
reduce it. The extent of myocardial fiber shortening and left ventricular 
size determine stroke volume. An increase in arterial pressure induced 
by vasoconstriction, for example, augments afterload, which opposes 
myocardial fiber shortening, reducing stroke volume.

Plasma
membrane
Extracellular
CHAPTER 244
Intracellular
(cytosol)
Sarcoplasmic reticulum
Basic Biology of the Cardiovascular System
Sarcotubular network
G
Sarcoplasmic reticulum
Ca2+ pump
D
H
When myocardial contractility is impaired and the ventricle dilates, 
afterload rises (Laplace’s law) and limits cardiac output. Increased 
afterload also may result from neural and humoral stimuli that occur 
in response to a fall in cardiac output. This increased afterload may 
reduce cardiac output further, thereby increasing ventricular volume 
and initiating a vicious circle, especially in patients with ischemic heart 
disease and limited myocardial O2 supply. Treatment with vasodila­
tors has the opposite effect; when afterload falls, cardiac output rises 
(Chaps. 266–270).
Under normal circumstances, the various influences acting on car­
diac performance interact in a complex fashion to maintain cardiac 
output at a level responsive to the requirements of tissue metabolic 
demands (Fig. 244-10). Interference with a single mechanism may 
not influence the cardiac output due to homeostatic adjustments. For 
example, a moderate reduction of blood volume or the loss of the 
atrial contribution to ventricular contraction can be tolerated without 
a reduction in resting cardiac output. Under these circumstances, 
other factors, such as adrenergic neuronal impulses increasing cardiac 
contractility, heart rate, and venous tone, will serve as compensa­
tory mechanisms and sustain cardiac output in a normal individual. 
Ultimately, understanding the complex interactions between so many 
different phasic variables requires rigorous models to predict relevant 
outcomes, and led to the early application of systems engineering prin­
ciples in medicine.

TABLE 244-2  Determinants of Stroke Volume
I.	 Ventricular Preload
A.	 Blood volume
B.	 Distribution of blood volume
1.	 Body position
2.	 Intrathoracic pressure
3.	 Intrapericardial pressure
4.	 Venous tone
5.	 Pumping action of skeletal muscles
C.	 Atrial contraction
II.	 Ventricular Afterload
PART 6
Disorders of the Cardiovascular System
A.	 Systemic vascular resistance
B.	 Elasticity of arterial tree
C.	 Arterial blood volume
D.	 Ventricular wall tension
1.	 Ventricular radius
2.	 Ventricular wall thickness
III.	 Myocardial Contractilitya
A.	 Intramyocardial [Ca2+] ↑↓
B.	 Cardiac adrenergic nerve activity ↑↓b
C.	 Circulating catecholamines ↑↓b
D.	 Cardiac rate ↑↓b
E.	 Exogenous inotropic agents ↑
F.	 Myocardial ischemia ↓
G.	 Myocardial cell death (necrosis, apoptosis, autophagy) ↓
H.	 Alterations of sarcomeric and cytoskeletal proteins ↓
1.	 Genetic
2.	 Hemodynamic overload
I.	 Myocardial fibrosis ↓
J.	 Chronic overexpression of neurohormones ↓
K.	 Ventricular remodeling ↓
L.	 Chronic and/or excessive myocardial hypertrophy ↓
aArrows indicate directional effects of determinants of contractility. bContractility 
rises initially but later becomes depressed.
Maximal activity
Normal-exercise

C

Normal-rest
Ventricular performance
Contractile state of myocardium
Walking

B
Exercise
Heart failure
3′
D
Rest
A
E

Fatal myocardial
depression
Dyspnea
Pulmonary edema
Ventricular EDV
Stretching of myocardium
FIGURE 244-9  The interrelations among influences on ventricular end-diastolic 
volume (EDV) through stretching of the myocardium and the contractile state of the 
myocardium. Levels of ventricular EDV associated with filling pressures that result 
in dyspnea and pulmonary edema are shown on the abscissa. Levels of ventricular 
performance required when the subject is at rest, while walking, and during maximal 
activity are designated on the ordinate. The broken lines are the descending limbs of 
the ventricular-performance curves, which are rarely seen during life but show the 
level of ventricular performance if end-diastolic volume could be elevated to very 
high levels. For further explanation, see text. (Reproduced with permission from WS 
Colucci, and E Braunwald: Pathophysiology of heart failure, in Braunwald’s Heart 
Disease, 7th ed, Philadelphia: Elsevier, 2005.)

Venous
return
Preload
Contractility
Stroke volume
Cardiac
output
Arterial
pressure
Heart rate
Afterload
Peripheral
resistance
Medullary
vasomotor
and cardiac
centers
Carotid and
aortic
baroreceptors
Higher
nervous
centers
FIGURE 244-10  Interactions in the intact circulation of preload, contractility, 
and afterload in producing stroke volume. Stroke volume combined with heart 
rate determines cardiac output, which, when combined with peripheral vascular 
resistance, determines arterial pressure for tissue perfusion. The characteristics 
of the arterial system also contribute to afterload, an increase that reduces 
stroke volume. The interaction of these components with carotid and aortic arch 
baroreceptors provides a feedback mechanism to higher medullary and vasomotor 
cardiac centers and to higher levels in the central nervous system to effect a 
modulating influence on heart rate, peripheral vascular resistance, venous return, 
and contractility. (Reproduced with permission from MR Starling: Physiology of 
myocardial contraction, in Atlas of Heart Failure: Cardiac Function and Dysfunction, 
3rd ed, WS Colucci and E Braunwald [eds]. Philadelphia: Current Medicine; 2002.)
■
■EXERCISE
The integrated response to exercise illustrates typical interactions 
among the three determinants of stroke volume: preload, afterload, and 
contractility (Fig. 244-9). Hyperventilation, the pumping action of the 
exercising muscles, and venoconstriction during exercise all augment 
venous return and hence ventricular filling and preload (Table 244-2). 
Simultaneously, the increase in neuronal and humoral adrenergic 
stimulation of the myocardium and the tachycardia that occur during 
exercise combine to augment the myocardial contractility (Fig. 244-9, 
curves 1 and 2), together elevating stroke volume and stroke work, with 
little or no change in end-diastolic pressure and volume (Fig. 244-9, 
points A and B). Vasodilation occurs in the exercising muscles, thus 
limiting the increase in afterload that otherwise would occur as cardiac 
output rises to levels as high as five times greater than basal levels dur­
ing maximal exercise. This vasodilation ultimately allows the achieve­
ment of elevated cardiac outputs during exercise at arterial pressures 
only moderately higher than the resting state.
ASSESSMENT OF CARDIAC FUNCTION
Several techniques can define impaired cardiac function in clinical 
practice. Cardiac output and stroke volume may decline in the pres­
ence of heart failure, but these variables are often within normal limits, 
especially at rest, even late in disease. A more sensitive index of cardiac 
function is the ejection fraction, i.e., the ratio of stroke volume to 
end-diastolic volume (normal value = 67 ± 8%), which is frequently 
depressed in systolic heart failure even when stroke volume is normal. 
Alternatively, abnormally elevated ventricular end-diastolic volume 
(normal value = 75 ± 20 mL/m2) or end-systolic volume (normal value = 
25 ± 7 mL/m2) signifies left ventricular systolic impairment.
Noninvasive techniques, particularly echocardiography, radionu­
clide scintigraphy, and cardiac magnetic resonance imaging (MRI) 
(Chap. 248), have great value in the clinical assessment of myocardial 
function. They provide measurements of end-diastolic and end-systolic 
volumes, ejection fraction, and systolic shortening rate, and they allow 
assessment of ventricular filling (see below) as well as regional contrac­
tion, relaxation, and tissue characterization. The latter measurements

ESPVR
afterload
LV pressure
preload

LV volume
FIGURE 244-11  The responses of the left ventricle to increased afterload, increased preload, and increased and reduced contractility are shown in the pressure-volume 
plane. Left. Effects of increases in preload and afterload on the pressure-volume loop. Because there has been no change in contractility, the end-systolic pressure-volume 
relationship (ESPVR) is unchanged. With an increase in afterload, stroke volume falls (1 → 2); with an increase in preload, stroke volume rises (1 → 3). Right. With increased 
myocardial contractility and constant left ventricular end-diastolic volume, the ESPVR moves to the left of the normal line (lower end-systolic volume at any end-systolic 
pressure) and stroke volume rises (1 → 3). With reduced myocardial contractility, the ESPVR moves to the right; end-systolic volume is increased, and stroke volume falls 
(1 → 2).
have particular importance in ischemic heart disease, as myocardial 
infarction causes regional myocardial damage.
Strong dependence on ventricular loading conditions influences the 
precision of measurements of cardiac output, ejection fraction, and 
ventricular volumes as indices of cardiac function. Thus, a depressed 
ejection fraction and lowered cardiac output may occur in patients 
with normal ventricular function but reduced preload, as occurs in 
hypovolemia, or with increased afterload, as occurs in acutely elevated 
arterial pressure.
The end-systolic left ventricular pressure-volume relationship has 
particular value as an index of ventricular performance as it does not 
depend on preload and afterload (Fig. 244-11). At any level of myocar­
dial contractility, left ventricular end-systolic volume varies inversely 
with end-systolic pressure; as contractility declines, end-systolic vol­
ume (at any level of end-systolic pressure) rises. Invasive measurement 
of end-systolic left ventricular pressure-volume loops adds rigor to 
research studies of left ventricular function, but these techniques are 
less pragmatic than the more readily assessed indices obtained in rou­
tine clinical practice, such as ventricular volumes and ejection fraction. 
Integrated cardiopulmonary exercise testing with formal analysis of 
exhaled gases is now more broadly available and can estimate maximal 
oxygen delivery as an indirect metric of physiologic reserve. Longitu­
dinal measurements of some aspects of cardiovascular physiology are 
increasingly feasible with implantable or wearable devices.
■
■DIASTOLIC FUNCTION
Ventricular filling is influenced by several characteristics of the myo­
cardium including: (1) the extent and speed of myocardial relaxation; 
and (2) the passive stiffness of the ventricular wall. The former is 
largely a function of the rate of uptake of Ca2+ by the SR that may be 
enhanced by adrenergic activation and reduced by ischemia due to 
limited ATP available for pumping Ca2+ into the SR (see above). For 
the latter, ventricular stiffness increases with hypertrophy, fibrosis, 
and conditions that infiltrate the ventricle, such as amyloid, or can 
result from an extrinsic constraint (e.g., pericardial constriction) 
(Fig. 244-12).
Ventricular filling can be assessed by measuring flow velocity across 
the mitral valve using Doppler ultrasound. Normally, inflow velocity is 
more rapid in early diastole than during atrial systole. However, with 
mild to moderately impaired relaxation, the rate of early diastolic filling 
declines, as presystolic filling rates rise. With further stiffening, flow is 
“pseudo-normalized,” as early ventricular filling becomes more rapid 
with rising left atrial pressure upstream of the left ventricle.

Normal
  contractility
Contractility
CHAPTER 244
Contractility
LV pressure

Basic Biology of the Cardiovascular System

LV volume
■
■CARDIAC METABOLISM
The heart requires a continuous supply of energy (ATP) not only to 
drive mechanical contraction, but also to maintain ionic and biochemi­
cal homeostasis. The development of tension, the frequency of contrac­
tion, and myocardial contractility levels are the principal determinants 
of the heart’s energy and oxygen requirements, representing ~15% of 
that of the entire organism.
The heart’s ATP production requires the generation of acetyl coen­
zyme A that can be derived from (in descending order) free fatty acids 
(FFAs), glucose, lactate, amino acids, and ketone bodies. Myocardial 
FFAs derive from circulating FFAs, whereas the cardiomyocyte’s glu­
cose derives from plasma as well as from myocardial glycogen stores 
(via glycogenolysis). These two principal sources of acetyl coenzyme 
Abnormal relaxation
Pericardial restraint
Left ventricular pressure
Chamber
dilation
Increased chamber
stiffness
Left ventricular volume
FIGURE 244-12  Mechanisms that cause diastolic dysfunction reflected in the 
pressure-volume relation. The bottom half of the pressure-volume loop is depicted. 
Solid lines represent normal subjects; broken lines represent patients with diastolic 
dysfunction. (Reproduced with permission from JD Carroll et al: The differential 
effects of positive inotropic and vasodilator therapy on diastolic properties in 
patients with congestive cardiomyopathy. Circulation; 1986; 74: 815.)