Basic Biology of the Cardiovascular System

1801CHAPTER 237

A. Capillary B. Vein C. Small muscular artery

D. Large muscular artery

Vascular

smooth-muscle cell

E. Large elastic artery

Internal elastic

lamina

External elastic

lamina

Adventitia

Pericyte

Endothelial cell

FIGURE 237-2 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.

cells known as pericytes (Fig. 237-2A). Arteries typically have a trilaminar structure (Fig. 237-2B–E). The intima consists of a monolayer

of endothelial cells continuous with those of the capillaries. The middle

layer, or tunica media, consists of smooth-muscle cells and, in veins,

consists of just a few layers of smooth-muscle cells (Fig. 237-2B).

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. 237-2E).

Arterioles are small muscular arteries (Fig. 237-2C) that regulate

blood pressure and flow through arterial beds. Medium-size muscular

arteries also contain prominent smooth-muscle layers (Fig. 237-2D)

that participate in atherosclerosis. 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. 237-2E). Larger arteries form an internal elastic lamina between

intima and media, while an external elastic lamina partitions the media

from surrounding adventitia.

■ VASCULAR CELL BIOLOGY

Endothelial Cell The endothelium forms the interface between

tissues and the blood compartment, regulating the passage of molecules 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 (H2

O2

), provide tonic

stimulation of endothelial homeostatic properties under physiologic

conditions in vivo (Table 237-1). Impaired production or excess catabolism of these substances can mediate dysfunctional properties of

the endothelium. A major homeostatic influence on the endothelium

is laminar blood flow, and the measurement of flow-mediated dilatation can

assess endothelial vasodilator function

in humans (Fig. 237-3). Endothelial

cells also produce potent vasoconstrictor substances such as endothelin.

Excessive production of reactive oxygen species, such as superoxide anion

(O2

–

), by endothelial or smooth-muscle

cells under pathologic conditions (e.g.,

excessive exposure to angiotensin II)

can promote local oxidative stress and

inactivate NO.

Endothelial cells also regulate leukocyte traffic through tissues. Normal

endothelium exhibits limited interaction 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 infection 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 pathophysiology of

many immune-mediated diseases. For

example, complement-mediated lysis of

endothelial cells contributes to tissue

injury. The foreign histocompatibility complex antigens on endothelial

cells in solid-organ allografts can promote allograft arteriopathy, while

immune-mediated endothelial injury also plays a role in thrombotic

thrombocytopenic purpura or hemolytic-uremic syndrome.

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

fibrinolysis. Inflammatory stimuli also induce endothelial expression

of the potent procoagulant tissue factor, a contributor to disseminated

intravascular coagulation in sepsis. Thus, in pathologic circumstances,

endothelial dysfunction tends to promote local thrombus accumulation rather than combat it.

Endothelial cells regulate the growth of subjacent smoothmuscle cells by elaborating heparan sulfate glycosaminoglycans that

inhibit smooth-muscle proliferation. In the setting of vascular injury,

endothelium-derived growth factors and chemoattractants (e.g., plateletderived growth factor) induce the migration and proliferation of vascular smooth-muscle cells. Dysregulation of these growth-stimulatory

molecules may promote smooth-muscle accumulation in atherosclerotic lesions.

TABLE 237-1 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

1802 PART 6 Disorders of the Cardiovascular System

FIGURE 237-3 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). (Courtesy of

Joseph A. Vita, MD.)

migration and proliferation underlie the vascular disease that occurs

in sustained high-flow states such as left-to-right shunts in congenital

heart disease.

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, evident in a widening pulse pressure,

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. 237-4). In vascular 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, promoting homeostasis, which is tightly regulated by neural and metabolic

influences.

Vasoconstricting agonists also increase intracellular [Ca2+] by various

mechanisms including receptor-dependent phospholipase C activation 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 sarcoplasmic

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 autonomic 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 neurotransmitter

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, leading

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

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

ventricle (see below). Venous tone regulates venous tree capacitance

and, thus, influences ventricular preload. Smooth-muscle cells in

the adult vessel seldom replicate in the absence of arterial injury or

inflammatory activation, 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

Basic Biology of the Cardiovascular System

1803CHAPTER 237

PIP2

NE, ET-1, Ang II

PLC

NO ANP

pGC AC

RhoA

Ca2+

“Spark”

Ca2+

Rho

Kinase

IP3

G G

SR

Calcium

MLCK

MLCP

IP3R

RyrR

Plb

ATPase

cGMP

GTP ATP

DAG cAMP

PKC

Caldesmon

Calponin

K+ Ch Na-K ATPase

sGC

BetaAgonist

PKG PKA

VDCC

FIGURE 237-4 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.)

parasympathetic neurons may bind to muscarinic receptors on either

vascular smooth-muscle cells, causing vasoconstriction, or endothelial

cells, causing NO-dependent vasorelaxation. Nitrergic neurons release

NO, which relaxes vascular smooth-muscle cells 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. 440.

The release of endothelial effectors of vascular smooth-muscle cell

tone integrates the smooth-muscle response to mechanical (shear

stress, cyclic strain, etc.) 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 modulates 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 factor (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 preexisting 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 (Chaps. 96 and 484).

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. 237-5A). Each

cell contains multiple myofibrils that run the length of the cell and are

composed of series of repeating sarcomeres. The cytoplasm between

the myofibrils 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 varies

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

1804 PART 6 Disorders of the Cardiovascular System

M

yocyte

Myofibril

Myofibril

Myofibril

Mitochondrion

T tubule

10 µm

SR

Myofiber

Myocyte

Ca2+

enters

Ca2+

leaves

Na+

Exchange

Ca2+

Pump

Free

Ca2+

Ca2+

“trigger”

Contract Relax

Systole

Diastole

Head

43 nm

Myosin

Titin

Actin

Z

Z

D

C

B

A

M

FIGURE 237-5 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.

(Courtesy of L.H. Opie.)

and thin filaments overlap only within the (dark) A band, whereas the

(light) I band contains only thin filaments. On electron-microscopic

examination, 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

length during both contraction and relaxation. With activation, the

actin filaments are propelled farther into the A band. In the 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. 237-5B).

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. 237-6). In contrast to myosin, actin lacks intrinsic enzymatic activity, but combines reversibly with myosin in the presence of

ATP and Ca2+. Calcium activates the myosin ATPase, which breaks

down ATP to supply the energy for contraction (Fig. 237-6). The activity 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. 237-5D) an enormous, flexible, myofibrillar protein, connects

myosin to the Z line; its elasticity contributes to the passive mechanical

characteristics of the heart. Dystrophin, a cytoskeletal protein that

Basic Biology of the Cardiovascular System

1805CHAPTER 237

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).

During activation of the cardiac myocyte, Ca2+ binds the heterotrimer troponin C, resulting in regulatory conformational changes

in tropomyosin and exposing actin cross-bridge interaction sites

(Fig. 237-6). 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 development of tension. The splitting of ATP then dissociates the myosin

cross-bridge from actin. In the presence of ATP (Fig. 237-6), actin and

myosin filaments bind and dissociate cyclically if sufficient Ca2+ is present; these processes cease when [Ca2+] falls below a critical level, and

the troponin-tropomyosin complex once more inhibits actin-myosin

interactions (Fig. 237-7).

Cytoplasmic [Ca2+] is a principal determinant of the inotropic state

of the heart. Most agents that stimulate myocardial contractility (positive inotropic stimuli), including digitalis glycosides and β-adrenergic

agonists, increase cytoplasmic [Ca2+], triggering cross-bridge cycling.

Increased adrenergic neuronal activity stimulates myocardial contractility 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. 237-7).

Cyclic AMP in turn activates protein kinase A (PKA), which phosphorylates sarcolemmal Ca2+ channels, thereby enhancing the influx of

Ca2+ into the myocyte.

The SR (Fig. 237-8), a complex network of anastomosing intracellular channels, invests the myofibrils. The transverse tubules, or T

system, 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 cardiac cell 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. 243). The sarcolemma, which in the resting state is largely impermeable to Na+, and

a Na+- and K+-pump energized by ATP that extrudes Na+ from the cell

and maintain the resting potential. In this resting state, intracellular

[K+] is relatively high and [Na+] is far lower; 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. 243-1B). During

the action potential plateau (phase 2), there is a slow inward current

through sarcolemmal L-type Ca2+ channels (Fig. 237-8). Depolarizing

current spreads across the cell membrane, penetrating deeply into the

cell via the T tubular system. 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,

including calstabin 2, inhibit RyR2 and thus SR Ca2+ release. Inherited

disorders or exogenous factors affecting the efficiency or stability of

SR Ca2+ handling can impair contraction, leading to heart failure or to

ventricular arrhythmias.

The Ca2+ released from the SR diffuses to interact with myofibrillar

troponin C (Fig. 237-7), 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.

237-8), reducing the cytoplasmic [Ca2+]. Additional control of calcium

ATP

Dissociation of

actin and myosin

ADP

ADP

ADP

Actin

Relaxed Relaxed, energized

Actin

ATP

Rigor complex Active complex

Formation of

active complex

Product

dissociation

Pi

Pi

1. ATP hydrolysis

3.

4. 2.

FIGURE 237-6 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 crossbridge (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, in WS Colucci [ed]: Heart failure: Cardiac function and dysfunction, in Atlas

of Heart Diseases, 3rd ed. Philadelphia, Current Medicine, 2002.)

1806 PART 6 Disorders of the Cardiovascular System

compartmentalization results from cyclic AMP–dependent PKA phosphorylation of the SR protein phospholamban, permitting 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, which transmit the action potential, release and then reaccumulate

Ca2+, controls the cyclic contraction and relaxation of heart muscle.

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 237-2 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 relationship between initial muscle fiber length and the developed force is

the basis of Starling’s law of the heart, which states that, within limits,

the ventricular contraction force depends on the end-diastolic length

of the cardiac muscle, which in vivo 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 preparations,

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 function curve)

P

P

2

1

3

β

GTP

ADP + Pi

Myosin

ATPase

cAMP

cAMP

via Tnl

cAMP

via PL

Control

Pattern of contraction

Time

Force

ATP Troponin C

ADP + Pi

Via protein kinase A

Metabolic

• glycolysis

• lipolysis

• citrate cycle

Increased

1. rate of contraction

2. peak force

3. rate of relaxation

Adenyl

cyclase SL

SR

Ca2+

Ca2+

Ca2+

β - Adrenergic agonist

β

Receptor

β

γ αs

+

+

+

+

+

+

+

+

FIGURE 237-7 Signal systems involved in positive inotropic and lusitropic (enhanced relaxation) effects of `-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. (Courtesy of L.H. Opie.)

Basic Biology of the Cardiovascular System

1807CHAPTER 237

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. 237-9).

■ 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. Afterload is determined by the aortic impedance 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 intracavitary ventricular pressure and ventricular radius

divided by wall thickness. Therefore, at any given aortic pressure, the

afterload on a dilated left ventricle exceeds that on a normal-sized 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 (and impedance) 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. 237-10). 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.

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 vasodilators has the opposite effect; when afterload falls, cardiac output rises

(Chap. 257).

Under normal circumstances, the various influences acting on cardiac performance interact in a complex fashion to maintain cardiac

output at a level responsive to the requirements of tissue metabolic

demands (Fig. 237-10). 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,

 Z-line Troponin C Thin

filament

Contractile

proteins

Thick

filament

Sarcoplasmic reticulum

Ca2+ pump

Sarcotubular network

Mitochondria

Calsequestrin

Sarcoplasmic reticulum

Intracellular

(cytosol)

Plasma

membrane

Extracellular

Cisterna

Plasma

membrane

Ca2+

channel

Ca2+- release channel

('foot' protein)

Na+

pump

Plasma membrane

Ca2+ pump

Na+/Ca2+

exchanger

T tubule

B1 B2

A

G

C

E F

D

H

A1

FIGURE 237-8 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.)