▷ Human Body Disease

The designation chronic ischemic heart disease (CIHD) is
used here to describe the cardiac findings in patients, often but
not exclusively elderly, who develop progressive heart failure
as a consequence of ischemic myocardial damage. The term
ischemic cardiomyopathy is often used by clinicians to describe
CIHD. In most instances, there has been prior MI and sometimes
previous coronary arterial bypass graft surgery or other
interventions. CIHD usually constitutes postinfarction cardiac
decompensation owing to exhaustion of the compensatory
hypertrophy of noninfarcted viable myocardium that is itself
in jeopardy of ischemic injury (see earlier discussion of
cardiac hypertrophy). However, in other cases severe obstructive
CAD may be present without acute or healed infarction
but with diffuse myocardial dysfunction.

Hearts from patients with CIHD are
usually enlarged and heavy, secondary to left ventricular
hypertrophy and dilation. Invariably there is moderate
to severe stenosing atherosclerosis of the
coronary arteries and sometimes total occlusion. Discrete,
gray-white scars of healed infarcts are usually
present. The mural endocardium is generally normal
except for some superficial, patchy, fibrous thickenings,
although mural thrombi may be present. The
major microscopic findings include myocardial hypertrophy,
diffuse subendocardial vacuolization, and
scars of previously healed infarcts.

The clinical diagnosis is made largely by the insidious onset
of CHF in patients who have had past episodes of MI or
anginal attacks. In some individuals, however, progressive
myocardial damage is entirely silent, and heart failure is the
first indication of CIHD. The diagnosis rests largely on the
exclusion of other forms of cardiac involvement. Such patients
make up nearly half of cardiac transplant recipients.

Ischemic heart disease (IHD) is the generic designation for
a group of closely related syndromes resulting from myocardial
ischemia—an imbalance between the supply (perfusion)
and demand of the heart for oxygenated blood. Ischemia comprises
not only insufficiency of oxygen, but also reduced availability
of nutrient substrates and inadequate removal of
metabolites. Isolated hypoxemia (i.e., diminished
transport of oxygen by the blood) induced by cyanotic
congenital heart disease, severe anemia, or advanced lung
disease is less deleterious than ischemia because perfusion
(including metabolic substrate delivery and waste removal) is
maintained.

In more than 90% of cases, the cause of myocardial ischemia
is reduction in coronary blood flow due to atherosclerotic coronary
arterial obstruction. Thus, IHD is often termed coronary
artery disease (CAD) or coronary heart disease. In most cases,
there is a long period (decades) of silent, slowly progressive,
coronary atherosclerosis before these disorders become manifest.
Thus, the syndromes of IHD are only the late manifestations
of coronary atherosclerosis that probably began during
childhood or adolescence. The clinical manifestations of IHD can be divided into four  syndromes:

■ Myocardial infarction (MI), the most important form of
IHD, in which the duration and severity of ischemia is sufficient
to cause death of heart muscle.
■ Angina pectoris, in which the ischemia is less severe and
does not cause death of cardiac muscle. Of the three variants—
stable angina, Prinzmetal angina, and unstable
angina—the latter is the most threatening as a frequent harbinger
of MI.
■ Chronic IHD with heart failure.
■ Sudden cardiac death.

As will be discussed in more detail later, acute myocardial
infarction, unstable angina, and sudden cardiac death are
sometimes referred to as acute coronary syndromes.
Certain conditions aggravate ischemia through either an
increase in cardiac energy demand (e.g., hypertrophy) or by
diminished availability of blood or oxygen due to lowered systemic
blood pressure (e.g., shock) or hypoxemia as discussed
above. Moreover, increased heart rate not only increases
demand through more contractions per unit time but also
decreases supply (by decreasing the relative time spent in diastole—
when coronary perfusion occurs).

The risk of an individual developing detectable IHD
depends in part on the number, distribution, and structure of
atheromatous plaques, and the degree of narrowing they
cause. However, the clinical manifestations of IHD are not
entirely predicted by these anatomic observations of disease
burden. Moreover, there is an extraordinarily broad spectrum
of the expression of disease from elderly individuals with
extensive coronary atherosclerosis who have never had a
symptom, to the previously asymptomatic young adult in
whom modestly obstructive disease cones unexpectedly to
medical attention as a result of acute MI or sudden cardiac
death. The reasons for clinical heterogeneity of the disease are
complex, but the often precipitous and variable onset and
natural history largely depend on the pathologic basis of the
so-called acute coronary syndromes of IHD (comprising
unstable angina, acute MI, and sudden death). The acute coronary
syndromes are frequently initiated by an unpredictable and
abrupt conversion of a stable atherosclerotic plaque to an unstable
and potentially life-threatening atherothrombotic lesion
through superficial erosion, ulceration, fissuring, rupture, or deep
hemorrhage, usually with superimposed thrombosis. For purposes
of simplicity, this spectrum of alteration in atherosclerotic
lesions will be termed either plaque disruption or acute
plaque change.

Epidemiology. I HD in its various forms is the leading
cause of death for both males and females in the United States
and other industrialized nations. Each year, nearly 500,000
Americans die of IHD. Awesome as these numbers may be,
they represent an improvement over those that prevailed
several decades ago. Since its peak in 1963, the overall death
rate from IHD has fallen in the United States by approximately
50%. This decline is a spectacular achievement that has
resulted primarily from (1) prevention achieved by modification
of determinants of risk, such as smoking, elevated blood
cholesterol, hypertension, and a sedentary lifestyle, and (2)
diagnostic and therapeutic advances, allowing earlier, more
effective, and safer treatments, including new medications,
coronary care units, thrombolysis for MI, percutaneous transluminal
coronary angioplasty (PTCA), endovascular stents,
coronary artery bypass graft (CABG) surgery, and improved
control of arrhythmias. 3h Additional risk reduction may
potentially be associated with maintenance of normal blood
glucose levels in diabetic patients, control of obesity, and
aspirin prophylaxis in middle-aged men:” Nevertheless, continuing
this progress in the 21st century will be particularly
challenging, in view of a predicted increased longevity of
“baby boomers” and others. The anticipated doubling of the
population of individuals over age 65 by 2050 is expected to
contribute to a dramatic increase in IHD and associated
deaths.

Pathogenesis.

The dominant influence in the causation of
the IHD syndromes is diminished coronary perfusion relative
to myocardial demand, owing largely to a complex and
dynamic interaction among fixed atherosclerotic narrowing of
the epicardial coronary arteries, intraluminal thrombosis overlying
a disrupted atherosclerotic plaque, platelet aggregation,
and vasospasm. The individual elements and their interactions
are discussed below.
More than 90% of patients with IHD have atherosclerosis
of one or more of the coronary arteries. The clinical manifestations
of coronary atherosclerosis are generally due to progressive
encroachment of the lumen leading to stenosis
(chronic, “fixed” obstructions) or to acute plaque disruption
with thrombosis (generally both sudden and dynamic), which
compromises blood flow. A fixed obstructive lesion of 75%
or greater (i.e., only 25% or less lumen remaining) generally
causes symptomatic ischemia induced by exercise; with this
degree of obstruction, the augmented coronary flow provided
by compensatory vasodilation is no longer sufficient to meet
even moderate increases in myocardial demand. A 90% stenosis
can lead to inadequate coronary blood flow even at rest.
Slowly developing occlusions may stimulate collateral vessels
over time, which protect against distal myocardial ischemia
and infarction even with an eventual high-grade stenosis.
Although only a single major coronary epicardial trunk
may be affected, two or all three—lateral anterior descending
(LAD), left circumflex (LCX), and right coronary artery
(RCA)—are often involved. Clinically significant stenosing
plaques may be located anywhere within these vessels but tend
to predominate within the first several centimeters of the LAD
and LCX and along the entire length of the RCA. Sometimes
the major secondary epicardial branches are also involved (i.e.,
diagonal branches of the LAD, obtuse marginal branches of
the LCX, or posterior descending branch of the RCA), but atherosclerosis
of the intramural branches is rare. However, as
mentioned above, the onset of symptoms and prognosis of
IHD depend not only on the extent and severity of fixed,
chronic anatomic disease, but also critically on dynamic
changes in coronary plaque morphology (discussed below).

Atherosclerotic plaque rupture. A, Plaque rupture without superimposed thrombus, in patient who died suddenly. B,
Acute coronary thrombosis superimposed on an atherosclerotic plaque with focal disruption of the fibrous cap, triggering fatal myocardial
infarction. C, Massive plaque rupture with superimposed thrombus, also triggering a fatal myocardial infarction (special stain highlighting
fibrin in red). In both A and B, an arrow points to the site of plaque rupture.

Role of Acute Plaque Change.

In most patients the myocardial
ischemia underlying unstable angina, acute MI, and (in
many cases) sudden cardiac death is precipitated by abrupt
plaque change followed by thrombosis (Fig). Thus, these important manifestations are termed
the acute coronary syndromes. Most often, the initiating event
is disruption of previously only partially stenosing plaques
with any of the following:
■ Rupture/fissuring, exposing the highly thrombogenic
plaque constituents
■ Erosion/ulceration, exposing the thrombogenic subendothelial
basement membrane to blood
■ Hemorrhage into the atheroma, expanding its volume.

The events that trigger abrupt changes in plaque configuration
and superimposed thrombosis are complex and poorly
understood. Influences, both intrinsic (e.g., plaque structure
and composition) and extrinsic (e.g., blood pressure, platelet
reactivity) are important.”‘” Acute alterations in plaque imply
the inability of a plaque to withstand mechanical stresses.
The structure and composition of a plaque are dynamic and
contribute to a propensity to disruption. Plaques that contain
large areas of foam cells and extracellular lipid, and those in
which the fibrous caps are thin or contain few smooth muscle
cells or have clusters of inflammatory cells, are more likely to
rupture, and are therefore called “vulnerable plaques.” Fissures
frequently occur at the junction of the fibrous cap and the
adjacent normal plaque-free arterial segment, a location at
which the blood flow—inducing mechanical stresses within the
plaque are highest and the fibrous cap is thinnest. It is now
recognized that the fibrous cap can undergo continuous
remodeling. The balance of synthetic and degradative activity
of collagen, the major structural component of the fibrous
cap, accounts for its mechanical strength and determines
plaque stability and prognosis. Collagen is produced by
smooth muscle cells and degraded by the action of metalloproteinases,
enzymes elaborated by macrophages in atheroma.
Thus, there is considerable evidence that inflammation destabilizes
the mechanical integrity of plaques (see below). Moreover,
drugs such as statins (inhibitors of HMG Co-A
reductase, a key enzyme in the synthesis of cholesterol) that
reduce clinical events associated with IHD, are thought to stabilize
plaques by their lipid-lowering effect, as well as by
reducing plaque inflammation.

Influences extrinsic to plaque are also important. Adrenergic
stimulation can elevate physical stresses on the plaque
through systemic hypertension or local vasospasm. Indeed, the
adrenergic stimulation associated with awakening and arising
induces a pronounced circadian periodicity for the time of
onset of acute MI, with a peak incidence between 6 a.m. and 12
noon, concurrent with a surge in blood pressure and immediately
following heightened platelet reactivity. Intense emotional
stress can also contribute to plaque disruption; this is
most dramatically illustrated by the marked increase in the
incidence of sudden death that is associated with natural or
other disasters such as earthquakes or the sex.
It is now recognized that the preexisting culprit lesion in
patients who develop myocardial infarction and other acute
coronary syndromes is not necessarily a severely stenotic and
hemodynamically significant lesion prior to its acute change.
Pathologic and clinical studies show that plaques that undergo
abrupt disruption leading to coronary occlusion often are
those that previously produced only mild to moderate luminal
stenosis. Approximately two thirds of plaques that rupture
with subsequent occlusive thrombosis caused occlusion of
only 50% or less before plaque rupture, and 85% had initial
stenosis less than 70%.’” Thus, the worrisome conclusion is
that a rather large number of now asymptomatic adults in the
industrial world have a real but unpredictable risk of a catastrophic
coronary event. Regrettably, it is presently impossible
to reliably predict plaque disruption or subsequent thrombosis
in an individual patient.
Accumulating evidence indicates that plaque disruption
and the ensuing platelet aggregation and intraluminal thrombosis
are common, repetitive, and often clinically silent complications
of atheroma. Moreover, healing of subclinical
plaque disruption and overlying thrombosis is an important
mechanism of growth of atherosclerotic lesions.

Role of Inflammation.

Inflammatory processes play
important roles at all stages of atherosclerosis, from its inception
to the development of complications.”‘ The establishment
of the initial lesion requires the interaction between
endothelial cells and circulating leukocytes, leading to the
accumulation of T cells and macrophages in the arterial wall.
Entry of leukocytes into the wall is a consequence of the
release of chemokines by endothelial cells, and the increased
expression of adhesion proteins (ICAM-1, VCAM-1, Eselectin
and P-selectin) in these cells. T cells located in the
arterial wall produce cytokines such as TNF, IL-6 and IFN-y
that stimulate endothelial cells and activate macrophages,
which become loaded with oxidized LDL. At later stages of
atherosclerosis, destabilization and rupture of the plaque may
involve the secretion of metalloproteinases by macrophages. ”
These enzymes weaken the plaque by digesting collagen at the
fibrous cap or the shoulder of the lesion.
Because of the important role of inflammation in the
pathogenesis of atherosclerosis, several proteins involved in
inflammation may serve as potential markers of atherosclerosis.
C-reactive protein (CRP), an acute phase reactant made in
the liver, has been suggested as a predictor of risk of coronary
heart disease. In some, but not all, studies CRP predicts
risk independently from risk estimates provided by serum
lipid levels. It could be used to estimate the risk of
myocardium infarct in patients with angina, and the risk of
new infarcts in patients who are infarct survivors.

Role of Coronary Thrombus. As mentioned above, partial
or total thrombosis associated with a disrupted plaque is critical to the pathogenesis of the acute coronary syndromes. In
the most serious form, acute transmural MI (see later for distinction
of transmural vs. subendocardial infarcts), thrombus
superimposed on a disrupted but previously only partially
stenotic plaque converts it to a total occlusion. In contrast,
with unstable angina, acute subendocardial infarction, or
sudden cardiac death, the extent of luminal obstruction by
thrombosis is usually incomplete (mural thrombus), and it
may wax and wane with time.
Mural thrombus in a coronary artery can also embolize.
Indeed, small fragments of thrombotic material in the distal
intramyocardial circulation or microinfarcts may be found at
autopsy of patients who have had unstable angina or sudden
death. Finally, thrombus is a potent activator of multiple
growth-related signals in smooth muscle cells, which
can contribute to the growth of atherosclerotic lesions.

Role of Vasoconstriction. Vasoconstriction compromises
lumen size, and, by increasing the local mechanical forces,
can potentiate plaque disruption. Vasoconstriction at sites of
atheroma is stimulated by: (1) circulating adrenergic agonists,
(2) locally released platelet contents, (3) impaired secretion of
endothelial cell relaxing factors relative to contracting factors
(e.g., endothelin) due to atheroma-associated endothelial dysfunction , and possibly (4) mediators released
from perivascular inflammatory cells.

MI, also known as “heart attack,” is the death of cardiac
m uscle resulting from ischemia. It is by far the most important
form of IHD and alone is the leading cause of death in the
United States and industrialized nations. About 1.5 million
individuals in the United States suffer an acute MI annually
and approximately one third of them die. At least 250,000
people a year die of a heart attack before they reach the hospital.

Transmural versus Subendocardial Infarction. Most
myocardial infarcts are transmural, in which the ischemic
necrosis involves the full or nearly full thickness of the ventricular
wall in the distribution of a single coronary artery.
This pattern of infarction is usually associated with coronary
atherosclerosis, acute plaque change, and superimposed
thrombosis (as discussed previously). In contrast, a subendocardial
(nontransmural) infarct constitutes an area of ischemic
necrosis limited to the inner one third or at most one half of
the ventricular wall; under some circumstances, it may extend
laterally beyond the perfusion territory of a single coronary
artery. As previously pointed out, the subendocardial zone is
normally the least well-perfused region of myocardium and
therefore is most vulnerable to any reduction in coronary flow.
A subendocardial infarct can occur as a result of a plaque disruption
followed by coronary thrombus that becomes lysed
before myocardial necrosis extends across the major thickness
of the wall; in this case the infarct will be limited to the distribution
of one coronary artery with plaque change.
However, subendocardial infarcts can also result from sufficiently
prolonged and severe reduction in systemic blood pressure,
as in shock, often superimposed on chronic, otherwise
noncritical, coronary stenoses. In cases of global hypotension,
resulting subendocardial infarcts are usually circumferential
or nearly so, rather than limited to the distribution of a single
major coronary artery.

Incidence and Risk Factors. The risk factors for atherosclerosis,
the major underlying cause of IHD in general, are
discussed in Chapter 11 and are not reiterated here. Suffice it
to say that MI may occur at virtually any age, but the frequency
rises progressively with increasing age and when predispositions
to atherosclerosis are present, such as hypertension, cigarette
smoking, diabetes mellitus, genetic hypercholesterolemia, and
other causes of hyperlipoproteinemia. Nearly 10% of myocardial
infarcts occur in people under age 40, and 45% occur in
people under age 65. Blacks and whites are equally affected.

Throughout life, men are at significantly greater risk of MI
than women; the differential progressively declines with
advancing age. Except for those having some predisposing
atherogenic condition, women are remarkably protected against
MI during the reproductive years. Nevertheless, the decrease of
estrogen following menopause can permit rapid development
of coronary artery disease (CAD), and IHD is the overwhelming
cause of death in elderly women. Moreover, recent
epidemiologic evidence suggests that postmenopausal
hormone replacement therapy does not protect women
against MI.’

Pathogenesis.

We now consider the basis for and subsequent
consequences of myocardial ischemia, particularly as
they relate to the typical transmural myocardial infarct.

Coronary Arterial Occlusion. As discussed above, transmural
acute MI results from a dynamic interaction among
several or all of the following—coronary atherosclerosis, acute
atheromatous plaque change (such as rupture), superimposed
platelet activation, thrombosis, and vasospasm—resulting in
an occlusive intracoronary thrombus overlying a disrupted
plaque. In addition, either increased myocardial demand (as
with hypertrophy or tachycardia) or hemodynamic compromise
(as with a drop in blood pressure) can worsen the situation.
Recall also that collateral circulation may provide
perfusion to ischemic zones from a relatively unobstructed
branch of the coronary tree, bypassing the point of obstruction
and protecting against the effects of an acute coronary
occlusion.

In the typical case of MI, the following sequence of events
can be proposed:

■ The initial event is a sudden change in the morphology of
an atheromatous plaque, that is, disruption—manifest as
intraplaque hemorrhage, erosion or ulceration, or rupture
or fissuring.

■ Exposed to subendothelial collagen and necrotic plaque
contents, platelets undergo adhesion, aggregation, activation,
and release of potent aggregators including thromboxane
A2 , serotonin, and platelet factors 3 and 4.

■ Vasospasm is stimulated by platelet aggregation and the
release of mediators.

■ Other mediators activate the extrinsic pathway of coagulation,
adding to the bulk of the thrombus.

■ Frequently within minutes, the thrombus evolves to completely
occlude the lumen of the coronary vessel.

The evidence for this sequence is compelling and derives
from (1) autopsy studies of patients dying with acute MI, (2)
angiographic studies demonstrating a high frequency of
thrombotic occlusion early after MI, (3) the high success rate
of therapeutic thrombolysis and primary angioplasty, and (4)
the demonstration of residual disrupted atherosclerotic
lesions by angiography after thrombolysis. Although coronary
angiography performed within 4 hours of the onset of apparent
MI shows a thrombosed coronary artery in almost 90% of
cases, the observation of occlusion is seen in only about 60%
when angiography is delayed until 12 to 24 hours after onset.’
Thus with the passage of time, at least some occlusions appear
to clear spontaneously owing to lysis of the thrombus or relaxation
of spasm or both.
In approximately 10% of cases, transmural acute MI is not
associated with atherosclerotic plaque thrombosis stimulated
by disruption. In such situations, other mechanisms may be
involved:

■ Vasospasm: isolated, intense, and relatively prolonged,
with or without coronary atherosclerosis, perhaps in association
with platelet aggregation (sometimes related to
cocaine abuse).

■ Emboli: from the left atrium in association with atrial fibrillation,
a left-sided mural thrombus or vegetative endocarditis;
or paradoxical emboli from the right side of the
heart or the peripheral veins which cross to the systemic circulation,
through a patent foramen ovale, causing coronary
occlusion.

■ Unexplained: cases without detectable coronary atherosclerosis
and thrombosis may be caused by diseases of small
intramural coronary vessels such as vasculitis, hematologic
abnormalities such as hemoglobinopathies, amyloid deposition
in vascular walls, or other unusual disorders, such as
vascular dissection and inadequate protection during
cardiac surgery.

Myocardial Response. The consequence of coronary arterial
obstruction is the loss of critical blood supply to the myocardium
(figure)  which induces profound functional, biochemical,
and morphologic consequences. Occlusion of a major coronary
artery results in ischemia and, potentially, cell death through
out the anatomic region supplied by that artery (called the
area at risk), most pronounced in the subendocardium. The
outcome depends largely on the severity and duration of flow
deprivation.

Postmortem angiogram showing the posterior
aspect of the heart of a patient who died during the evolution of
acute myocardial infarction, demonstrating total occlusion of the
distal right coronary artery by an acute thrombus (arrow) and a
large zone of myocardial hypoperfusion involving the posterior left
and right ventricles, as indicated by arrowheads, and having
almost absent filling of capillaries, that is, less white. The heart has
been fixed by coronary arterial perfusion with glutaraldehyde and
cleared with methyl salicylate, followed by intracoronary injection
of silicone polymer.

The principal early biochemical consequence of myocardial
ischemia is the cessation of aerobic glycolysis (and therefore
initiating anaerobic glycolysis) within seconds, leading to inadequate
production of high-energy phosphates (e.g., creatine
phosphate and adenosine triphosphate) and accumulation of
potentially noxious breakdown products (such as lactic acid).
Myocardial function is exceedingly sensitive to severe ischemia;
striking loss of contractility occurs within 60 seconds of onset
of ischemia. This can precipitate acute heart failure long before
myocardial cell death.                Ultrastructural
changes (including myofibrillar relaxation, glycogen depletion,
cell and mitochondrial swelling) also develop within a few
minutes after onset of ischemia. Nevertheless, these early
changes are potentially reversible, and cell death is not immediate.

As demonstrated experimentally, only severe ischemia
lasting at least 20 to 40 minutes or longer leads to irreversible
damage (necrosis) of some cardiac myocytes. Ultrastructural
evidence of irreversible myocyte injury (primary structural
defects in the sarcolemmal membrane) develops only after 20
to 40 minutes in severely ischemic myocardium (with blood
flow of 10% or less of normal).With prolonged ischemia,
injury to the microvasculature then follows.

The principal early biochemical consequence of myocardial
ischemia is the cessation of aerobic glycolysis (and therefore
initiating anaerobic glycolysis) within seconds, leading to inadequate
production of high-energy phosphates (e.g., creatine
phosphate and adenosine triphosphate) and accumulation of
potentially noxious breakdown products (such as lactic acid).
Myocardial function is exceedingly sensitive to severe ischemia;
striking loss of contractility occurs within 60 seconds of onset
of ischemia. This can precipitate acute heart failure long before
myocardial cell death. As detailed in Chapter 1, ultrastructural
changes (including myofibrillar relaxation, glycogen depletion,
cell and mitochondrial swelling) also develop within a few
minutes after onset of ischemia. Nevertheless, these early
changes are potentially reversible, and cell death is not immediate.

As demonstrated experimentally, only severe ischemia
lasting at least 20 to 40 minutes or longer leads to irreversible
damage (necrosis) of some cardiac myocytes. Ultrastructural
evidence of irreversible myocyte injury (primary structural
defects in the sarcolemmal membrane) develops only after 20
to 40 minutes in severely ischemic myocardium (with blood
flow of 10% or less of normal).”‘ With prolonged ischemia,
injury to the microvasculature then follows

Irreversible injury of ischemic
myocytes occurs first in the subendocardial zone. With more
extended ischemia, a wavcfront of cell death moves through
the myocardium to involve progressively more of the transmural
thickness of the ischemic zone. The precise location,
size, and specific morphologic features of an acute myocardial
infarct depend on:
■ The location, severity, and rate of development of coronary
atherosclerotic obstructions
■ The size of the vascular bed perfused by the obstructed
vessels
■ The duration of the occlusion
■ The metabolic/oxygen needs of the myocardium at risk
■ The extent of collateral blood vessels
■ The presence, site, and severity of coronary arterial spasm
■ Other factors, such as alterations in blood pressure, heart
rate, and cardiac rhythm.
The necrosis is largely complete within 6 hours in experimental
models and humans, involving nearly all of the
ischemic myocardial bed at risk supplied by the occluded
coronary artery. Progression of necrosis, however, may follow
a more protracted course in some patients (possibly over 6 to
12 hours or longer) in whom the coronary arterial collateral
system, stimulated by chronic ischemia, is better developed
and thereby more effective.

Acute myocardial infarct, predominantly of the
posterolateral left ventricle, demonstrated histochemically by a
lack of staining by the triphenyltetrazolium chloride (TTC) stain in
areas of necrosis (arrow). The staining defect is due to the enzyme
leakage that follows cell death. Note the myocardial hemorrhage
at one edge of the infarct that was associated with cardiac
rupture, and the anterior scar (arrowhead), indicative of old
infarct. (Specimen the oriented with the posterior wall at the top.)

Infarct Modification by Reperfusion. The most effective
way to salvage ischemic myocardium threatened by infarction
is to restore tissue perfusion as rapidly as possible. This is best
accomplished by restoration of coronary flow (reperfusion) by
thrombolysis, balloon angioplasty (also known as percutaneous
transluminal coronary angioplasty, or PTCA), or coronary
arterial bypass graft (CABG). Reperfusion-associated
pathologies, including reperfusion-induced arrhythmias,
myocardial hemorrhage with contraction bands, irreversible
cell damage distinct from and additional to the injury associated
with the original ischemic event (reperfusion injury),
microvascular injury, and prolonged ischemic dysfunction
(myocardial stunning), are discussed below and summarized in
Figure.

FROM ROBBINS

Schematic illustration of the progression of myocardial
ischemic injury and its modification by restoration of flow (reperfusion). Hearts suffering brief periods of ischemia of <20 minutes
followed by reperfusion do not develop necrosis (reversible injury). Brief ischemia followed by reperfusion results in stunning. If coronary
occlusion is extended beyond 20 minutes’ duration, a wavefront of necrosis progresses from subendocardium to subepicardium
over time. Reperfusion before 3 to 6 hours of ischemia salvages ischemic but viable tissue. (This salvaged tissue may demonstrate
stunning.) Reperfusion beyond 6 hours does not appreciably reduce myocardial infarct size. Late reperfusion may still have a beneficial
effect on reducing or preventing myocardial infarct expansion and left ventricular remodeling.

Thrombolytic therapy (dissolution of the
offending thrombus by streptokinase or tissue-type plasminogen
activator [t-PA] through activation of the fibrinolytic
system) or PTCA is often used in an attempt to dissolve or
mechanically disrupt the thrombus that initiated acute MI.
The purpose of these treatments is to restore blood flow to the area
at risk for infarction and possibly rescue the ischemic (but not
yet necrotic) heart muscle. Removal of thrombus re-establishes
flow through the occluded coronary artery in most cases; early
reperfusion can salvage myocardium and thereby limit infarct
size, with consequent improvement in both short- and longterm
function and survival.” As discussed above, loss of
myocardial viability in infarction is progressive, occurring over
a period of at least several hours. Thus, reperfusion of at risk
myocardium offers an effective approach for restoring the
balance between myocardial perfusion and need. The potential
benefit is clearly related to the rapidity with which the coronary symptoms are critical.

Moreover, thrombolysis can at best
remove a thrombus occluding a coronary artery; it does not significantly
alter the underlying disrupted atherosclerotic plaque
that initiated it. In contrast, PTCA not only eliminates a thrombotic
occlusion, but also can relieve some of the original
obstruction caused by the underlying plaque.” CABG provides
flow around it.
Recall that severe ischemia does not cause immediate cell
death even in the most severely affected regions of
myocardium, and not all regions of myocardium are equally
ischemic. Therefore, the outcome distal to the occlusion following
restoration of flow to previously ischemic myocardium
may vary from region to region. Reperfusion of myocardium sufficiently early (within  15 to 20 minutes) after onset of ischemia may prevent all
necrosis. Reperfusion after a longer interval may not prevent
all necrosis but can salvage (i.e., prevent necrosis of) at least
some myocytes that would have died with more prolonged or
permanent ischemia.

A partially
completed then reperfused infarct usually has hemorrhage
because the vasculature injured during the period of ischemia
becomes leaky on restoration of flow. Moreover, disintegration
of myocytes that were lethally damaged by the
preceding ischemia may be accentuated or accelerated by
reperfusion. Microscopic examination reveals that myocytes
already irreversibly injured at the time of reflow often have
necrosis with contraction bands. Contraction bands are
intensely eosinophilic transverse bands composed of closely
packed hypercontracted sarcomeres. They are most likely produced
by exaggerated contraction of myofibrils at the instant
perfusion is reestablished, at which time the internal portions
of an already dead cell whose membranes have been damaged
by ischemia are exposed to a high concentration of calcium
ions from the plasma. Thus reperfusion not only salvages
reversibly injured cells but also alters the morphology of cells
already lethally injured at the time of reflow.

However, despite the potential for myocardial salvage by
reperfusion of ischemic myocardium, some small amount of
new cellular damage may occur that blunts the beneficial effect
of reperfusion itself (reperfusion injury). The clinical significance
of myocardial reperfusion injury is uncertain. Reperfusion injury is mediated, at least in
part, by the generation of oxygen free radicals from infiltrating
leukocytes during reperfusion. Recent advances in the understanding
of cell death in ischemia and reperfusion suggest that
apoptosis may be prominent at reperfusion; thus, prevention
of apoptosis maybe a potential therapeutic target to limit reperfusion
injury.” Reperfusion-induced microvascular injury
causes not only hemorrhage, but also endothelial swelling that
occludes capillaries and may prevent local reperfusion to areas
of critically injured myocardium (called no-reflow).
Ischemic myocardium may have profound functional
changes despite complete salvage of viability.’ Although most
of the viable myocardium existing at the time of reflow ultimately
recovers after alleviation of ischemia, critical abnormalities
in cellular biochemistry and function of myocytes
salvaged by reperfusion may persist for as long as several days
(prolonged postischemic ventricular dysfunction, or stunned
myocardium). Stunning may induce a state of reversible
cardiac failure that may benefit from temporary cardiac assist.

Paradoxically, short-lived transient severe ischemia, as might
occur in repetitive angina pectoris or silent ischemia, may
protect the myocardium against a greater subsequent ischemic
insult (a phenomenon known as preconditioning) by mechanisms
that are not well known. Myocardium that is subjected
to persistently low flow has chronically depressed function
and is said to be hibernating.” This portion of the
myocardium may undergo profound restoration of function
following revascularization by CABG surgery or balloon
angioplasty.

Clinical Features

MI is diagnosed classically by typical
symptoms, biochemical evidence, and by the ECG pattern.
Patients with MI have rapid, weak pulse and are often sweating
profusely (diaphoretic). Dyspnea due to impaired contractility
of the ischemic myocardium and the resultant
pulmonary congestion and edema is common. In about 10%
to 15% of MI patients, the onset is entirely asymptomatic
and the disease is discovered only later by ECG
changes, usually consisting of new Q waves. Such “silent” Mls
are particularly common in patients with diabetes mellitus
and in elderly patients.

Laboratory evaluation is based on measuring the blood
levels of intracellular macromolecules that leak out of fatally
injured myocardial cells through damaged cell membranes;
these molecules include myoglobin, cardiac troponins T and
I (TnT, TnI), creatine kinase (CK), lactate dehydrogenase, and
many others. Although these markers have become increasingly
sensitive indicators of myocardial damage, they do not
reflect its mechanism.From a biochemical perspective, the
diagnosis of myocardial injury is established when blood
levels of sensitive and specific biomarkers, such as cardiac troponin
and the MB fraction of creatine kinase (CK-MB), are
increased in the clinical setting of acute ischemia. The preferred
biomarkers for myocardial damage are cardiac-specific
proteins, particularly Troponin-I (TnI) and Troponin-T. Troponins
are proteins that regulate calcium-mediated contraction
of cardiac and skeletal muscle. These markers have nearly
complete tissue specificity and high sensitivity. TnI and TnT
are not normally detectable in the circulation, but after acute
MI, levels of both cardiac troponins rise at 2 to 4 hours and
peak at 48 hours. Troponin levels remain elevated for 7 to 10
days after the acute event.
Formerly the “gold standard,” cardiac creatine kinase (CKMB)
remains the best alternative to troponin measurement.

Creatine kinase is an enzyme that is highly concentrated in
brain, myocardium, and skeletal muscle and is composed of
two dimers, designated “M” and “B.” The isoenzyme CK-MM
is derived predominantly from skeletal muscle and heart; CKBB
from brain, lung, and many other tissues; and CK-MB
principally from myocardium, although variable amounts of
the MB form are also present in skeletal muscle. Total CK
activity is sensitive but not specific, as CK is elevated in other
conditions such as skeletal muscle injury. CK-MB activity
begins to rise within 2 to 4 hours of onset of MI, peaks at
about 24 hours, and returns to normal within approximately
72 hours. Although the diagnostic sensitivities of cardiac troponin
and CK-MB measurements are similar in the early
stages of MI, persistence of elevated troponin levels for
approximately 10 days allows the diagnosis of acute MI long
after CK-MB levels have returned to normal. The peak of
either troponin or CK-MB is accelerated in patients who have had reperfusion, owing to washing out of the enzyme from
the necrotic tissue. An absence of a change in the levels of CK
and CK-MB during the first 2 days of chest pain and of troponin
in the days following essentially excludes the diagnosis of MI.
As discussed, C-reactive protein (CRP) may serve as a
marker to predict the risk of myocardial infarct in patients
with angina, and the risk of new infarcts in patients who
recover from infarcts.Using highly sensitive methods,
serum CRP, levels of more than 3 mg/L are associated with the
highest risk of cardiovascular disease, while levels of 1 to 3
mg/L are associated with moderate risk

Other diagnostic modalities such as echocardiography (for
visualization of abnormalities of regional wall motion),
radioisotope studies such as radionuclide angiography (for
chamber configuration), perfusion scintigraphy (for regional
perfusion), and magnetic resonance imaging (for structural
characterization) sometimes provide additional anatomic,
biochemical, and functional data.

Consequences and Complications of Myocardial Infarction.

Extraordinary progress has been made in improving
the outcome of patients with acute MI. Concurrent with the
marked decrease in the overall mortality of IHD since the
1960s, the in-hospital death rate has declined from approximately
30% to an overall rate of between 10% and 13% today
(and to approximately 7% for patients receiving aggressive
reperfusion therapy). Nevertheless, half of the deaths associated
with acute MI occur within 1 hour of onset; these individuals
never reach the hospital. In general, factors associated
with a poor prognosis include advanced age, female gender,
diabetes mellitus and, owing to a loss of functional
myocardium, previous MI.
Nearly three-fourths of patients have one or more complications
following acute MI, which include the :

■ Contractile dysfunction. Myocardial infarcts produce
abnormalities in left ventricular function approximately proportional
to their size. Most often, there is some degree of
left ventricular failure with hypotension, pulmonary vascular
congestion, and transudation into the interstitial pulmonary
spaces, which may progress to pulmonary edema
with respiratory impairment. Severe “pump failure” (cardiogenic
shock) occurs in 10% to 15% of patients following
acute MI, generally with a large infarct (often greater than
40% of the left ventricle). Cardiogenic shock has a nearly
70% mortality rate and accounts for two thirds of inhospital
deaths.

■ Arrhythmias. Many patients have conduction disturbances
and myocardial irritability following MI, which undoubtedly
are responsible for many of the sudden deaths. MIassociated
arrhythmias include sinus bradycardia, heart
block (asystole), tachycardia, ventricular premature contractions
or ventricular tachycardia, and ventricular
fibrillation. Owing to the location of portions of the atrioventricular
conduction system (bundle of His) in the
inferoseptal myocardium, infarcts of this region may also
be associated with heart block. Prompt intervention by
mobile and hospital coronary care units can control potentially
lethal arrhythmias in many patients.

■ Myocardial rupture. The cardiac rupture syndromes result
from the mechanical weakening that occurs in necrotic and
subsequently inflamed myocardium and include (1)
rupture of the ventricular free wall (most commonly), with
hemopericardium and cardiac tamponade, usually fatal);
(2) rupture of the ventricular septum (less
commonly), leading to a left-to-right shunt and
(3) papillary muscle rupture (least commonly),
resulting in the acute onset of severe mitral regurgitation. Free-wall rupture may occur at almost any time after MI but is most frequent 3 to 7 days
after onset, when coagulative necrosis, neutrophilic infiltration,
and lysis of the myocardial connective tissue have
appreciably weakened the infarcted myocardium (mean, 4
to 5 days; range, 1 to 10 days). However, as many as one
quarter of cardiac ruptures occur within 24 hours. The
lateral wall at the midventricular level is the most common
site for postinfarction free-wall rupture. Risk factors for
free-wall rupture include age older than 60, female gender,
pre-existing hypertension, and lack of left ventricular
hypertrophy. Moreover, this complication occurs more
readily in patients without prior MI owing to an absence of
fibrosis, which tends to block myocardial tearing. Acute
free-wall ruptures are usually rapidly fatal. However, a
strategically located pericardial adhesion that aborts a
rupture may result in the formation of a false aneurysm
(that is, a contained rupture that results in a hematoma
communicating with the ventricular cavity). The wall
of a false aneurysm consists only of epicardium and
adherent parietal pericardium. Many false aneurysms are
filled with mural thrombus, and half ultimately rupture.
Postinfarction rupture of septal myocardium causing an
(acute) ventricular septal defect complicates 1% to 2% of
infarcts.

■ Pericarditis. A fibrinous or fibrohemorrhagic pericarditis
usually develops about the second or third day following a
transmural infarct and usually resolves over time. Pericarditis is the epicardial manifestation of the
underlying myocardial inflammation.

■ Infarct extension. New necrosis may occur adjacent to an
existing infarct.

■ Infarct expansion. Owing to the weakening of necrotic
muscle, there may be disproportionate stretching, thinning,
and dilation of the infarct region (especially with
anteroseptal infarcts), which is often associated with mural
thrombus (see Fig. 12—19E).

■ Ventricular aneurysm. In contrast to false aneurysms
mentioned above, true aneurysms of the ventricular wall
are bounded by myocardium that has become scarred. A
late complication, aneurysms of the ventricular wall most
commonly result from a large transmural anteroseptal
infarct (often one that has undergone expansion) that heals into a large region of thin scar tissue, which paradoxically bulges during systole. Complications of ventricular aneurysms include mural thrombus, arrhythmias and heart failure, but rupture of the fibrotic wall does not occur.

■ Papillary muscle dysfunction. A s mentioned above, rarely, early dysfunction of a papillary muscle following MI occurs due to its rupture. More frequently, postinfarct mitral regurgitation results from early ischemic dysfunction of a papillary muscle and underlying myocardium and later from papillary muscle fibrosis and shortening or ventricular dilation.

■ Progressive late heart failure is discussed as chronic IHD
below.

The propensity toward specific complications and the prognosis
afterMI depend primarily on infarct size, site, and fractional
thickness of the myocardial wall that is damaged (subendocardial
or transmural infarct). Large transmural infarcts yield a
higher probability of cardiogenic shock, arrhythmias, and late
CHF. Patients with anterior transmural infarcts are at greatest
risk for free-wall rupture, expansion, mural thrombi, and
aneurysm. In contrast, posterior transmural infarcts are more
likely to be complicated by serious conduction blocks, right
ventricular involvement, or both, and when acute ventricular
septa] defects occur in this area, they are more difficult to
manage. Overall, however, patients with anterior infarcts have
a substantially worse clinical course than those with inferior
(posterior) infarcts. With subendocardial infarcts, thrombi
may form on the endocardial surface, but pericarditis,
rupture, and aneurysms rarely occur.
Multiple dynamic structural changes maintain cardiac
output after acute MI. Both the necrotic zone and the noninfarcted
segments of the ventricle undergo progressive changes
in size, shape and thickness comprising early wall thinning,
healing, hypertrophy and dilation, and late aneurysm formation,
collectively termed ventricular remodeling.”‘ Clearly,
the initial compensatory hypertrophy of noninfarcted
myocardium is hemodynamically beneficial. However, the
adaptive effect of remodeling may be overwhelmed by expansion
and ventricular aneurysm or late depression of regional
and global contractile function owing to degenerative changes
in viable myocardium. This may lead to late impairment of
ventricular performance.
Long-term prognosis after MI depends on many factors, the
most important of which are the quality of left ventricular
function and the extent of vascular obstructions in vessels
that perfuse viable myocardium. The overall total mortality
within the first year is about 30%, including those victims
who die before reaching the hospital. Thereafter there is a 3%
to 4% mortality among survivors with each passing year.
Infarct prevention through control of risk factors in individuals
who have never experienced MI (primary prevention) and
prevention of rein farction in those who have recovered from an
acute MI (secondary prevention) are important strategies that
have received much attention and have achieved considerable
success.

Complications of myocardial infarction. Cardiac rupture syndromes (A, B, and C). A , Anterior myocardial rupture in an
acute infarct (arrow). B, Rupture of the ventricular septum (arrow). C, Complete rupture of a necrotic papillary muscle

Angina pectoris is a symptom complex of IHD characterized
by paroxysmal and usually recurrent attacks of substernal or precordial
chest discomfort (variously described as constricting,
squeezing, choking, or knifelike) caused by transient (15 seconds
to 15 minutes) myocardial ischemia that falls short of inducing
the cellular necrosis that defines infarction. There are three overlapping
patterns of angina pectoris:

(1) stable or typical angina,
(2) Prinzmetal or variant angina, and
(3) unstable or crescendo angina.

They are caused by varying combinations
of increased myocardial demand and decreased myocardial
perfusion, owing to fixed stenosing plaques, disrupted
plaques, vasospasm, thrombosis, platelet aggregation, and
embolization. Moreover, it is being increasingly recognized
that not all ischemic events are perceived by patients, even
though such events may have adverse prognostic implications
(silent ischemia).

Stable angina, the most common form and therefore called
typical angina pectoris, appears to be caused by the reduction of
coronary perfusion to a critical level by chronic stenosing coronary
atherosclerosis; this renders the heart vulnerable to
further ischemia whenever there is increased demand, such as
that produced by physical activity, emotional excitement, or
any other cause of increased cardiac workload. Typical angina
pectoris is usually relieved by rest (thereby decreasing
demand) or nitroglycerin, a strong vasodilator. Although the
coronary arteries are usually maximally dilated by intrinsic
regulatory influences, nitroglycerin also decreases cardiac
work by dilating the peripheral vasculature. In particular
instances, local vasospasm may contribute to the imbalance
between supply and demand.

Prinzmetal variant angina is an uncommon pattern of
episodic angina that occurs at rest and is due to co ronary artery
spasm. Usually there is an elevated ST segment on the electrocardiogram
(ECG), indicative of transmural ischemia.
Although individuals with this form of angina may well have
significant coronary atherosclerosis, the anginal attacks are
unrelated to physical activity, heart rate, or blood pressure.
Prinzmetal angina generally responds promptly to vasodilators,
such as nitroglycerin and calcium channel blockers.

Unstable or crescendo angina refers to a pattern of pain that
occurs with progressively increasing frequency, is precipitated
with progressively less effort, often occurs at rest, and tends to
be of more prolonged duration. As discussed above, in most
patients, unstable angina is induced by disruption of an atherosclerotic
plaque with superimposed partial (mural) thrombosis
and possibly embolization or vasospasm (or both). Although
the ischemia that occurs in unstable angina falls precariously
close to inducing clinically detectable infarction, unstable
angina is often the prodrome of subsequent acute MI. Thus
this syndrome is sometimes referred to as preinfarction angina,
and in the spectrum of IHD, unstable angina lies intermediate
between stable angina on the one hand and MI on the
other.

Composed of diverse cell lineages, the heart is
among the first organs to form and function in vertebrate
embryos. Cardiac morphogenesis involves a myriad of genes
and is tightly regulated to ensure an effective embryonic circulation.
Key steps involve specification of cardiac cell fate,
morphogenesis and looping of the heart tube, segmentation
and growth of the cardiac chambers, cardiac valve formation,
and connection of the great vessels to the heart. The genetic
regulation of heart formation has been widely studied in
model organisms, including chick, frog, mouse, and zebrafish.
In recent years, the zebrafish, an organism that is transparent
and has external fertilization, a brief generation time, and no
requirement of a functional cardiovascular system for survival
during embryogenesis, has permitted detailed genetic analysis
of both normal development and cardiac defects.The molecular
pathways controlling cardiac development provide a
foundation for understanding the basis of some congenital
heart defects and can be used to reveal pathways and interactions
important in human disease.

Several congenital heart diseases are associated with mutations
in transcription factors. For example, mutation of the
gene that encodes the transcription factor, TBX5, has been
shown to cause the ASD and VSD observed in the Holt-Oram
syndrome, a rare hereditary condition associated with heart,
arm, and hand defects.”‘ Another gene, encoding the transcription
factor NKX2.5, causes nonsyndromic (isolated) ASD
in humans when one copy is missing. This gene is the human
counterpart of the tinman gene of the fruit fly (so named
because, like the Tin Man in The Wizard of Oz, fruit fly
embryos lacking both copies of tinman have no hearts). Nevertheless,
most ASDs do not have an identifiable genetic etiology,
and the mechanisms by which mutated transcription
factors cause clinically important heart defects are just beginning
to be understood.

Until recently, in most studies, defects were classified by
their pathology; for example, all VSDs were considered as one
group. A major advance has been to examine familial aggregation
of defects based on presumed pathogenesis. Since some
cardiac structures share developmental pathways, anatomically
and clinically distinct lesions may be related by a
common genetic defect. Thus, the occurrence of distinct
defects in the same family remains consistent with a genetic
model. Defects unrelated by pathogenesis would require a different
interpretation.
Developmental errors in mesenchymal tissue migration
exemplify the concept that distinct syndromes share a
common pathogenesis. Included in this category is a wide
range of anomalies of the outflow tract, some due to failure
of fusion and others due to failure of septation. These lesions
include isolated interruption of the aortic arch, persistent
truncus arteriosus (failure of separation of aorta and pulmonary
arteries), and tetralogy of Fallot (malalignment of
aorta and pulmonary artery with the ventricles). Comprising
15% of congenital heart defects, outflow tract defects may be
caused by the abnormal development of neural crest—derived
cells, whose migration into the embryonic heart is required
for formation of the outflow tracts of the heart (Fig).

Considerable progress has been made during the past few
years in identifying a region of chromosome 22 that has a
major role in development of the conotruncus, the branchial
arches, and the face. Chromosome 22gl1.2 deletions are seen
in 15% to 50% of these disorders, rendering this abnormality
a common genetic cause of congenital heart defects.
This condition includes developmental anomalies
of the fourth branchial arch and derivatives of the third and
fourth pharyngeal pouches. Hypoplasia of the thymus and
parathyroids causes immune deficiency (Di George syndrome),and hypocalcemia.
Other common mechanisms of congenital heart disease
include extracellular matrix abnormalities and situs and
looping defects. The endocardial cushions have received the
most attention as an area where defects in cell—cell and
cell—extracellular matrix interactions might produce malformations,
as evidenced by a high frequency of endocardial
cushion defects and atrioventricular septal defects in Down
syndrome. Situs and looping defects may arise from single
genes that have a major effect on determining laterality.

Clinical Features.

The varied structural anomalies in congenital
heart disease fall primarily into three major categories:

■ Malformations causing a left-to-right shunt

■ Malformations causing a right-to-left shunt

■ Malformations causing an obstruction.

A shunt is an abnormal communication between chambers
or blood vessels. Abnormal channels permit the flow of blood
from left to right or the reverse, depending on pressure relationships.
When blood from the right side of the heart enters
the left side (right-to-left shunt), a dusky blueness of the skin
and mucous membranes (cyanosis) results because there is
diminished pulmonary blood flow, and poorly oxygenated
blood enters the systemic circulation (called cyanotic congenital
heart disease). The most important examples of right-toleft
shunts are tetralogy of Fallot, transposition of the great
arteries, persistent truncus arteriosus, tricuspid atresia, and
total anomalous pulmonary venous connection. Moreover,
with right-to-left shunts, bland or septic emboli arising in
peripheral veins can bypass the normal filtration action of the
lungs and thus directly enter the systemic circulation (paradoxical
embolism); brain infarction and abscess are potential
consequences. Clinical findings frequently associated with
severe, long-standing cyanosis include clubbing of the tips of
the fingers and toes (hypertrophic osteoarthropathy) and
polycythemia.

In contrast, left-to-right shunts (such as ASD, VSD, and
patent ductus arteriosus [PDAI) increase pulmonary blood
flow and are not initially associated with cyanosis. However,
they expose the postnatal, low-pressure, low-resistance pulmonary
circulation to increased pressure and/or volume,
which can result in right ventricular hypertrophy and, potentially,
failure. Shunts associated with increased pulmonary
blood flow include ASDs; shunts associated with both
increased pulmonary blood flow and pressure include VSDs
and PDA. The muscular pulmonary arteries (<1 mm diameter)
first respond to increased pressure by medial hypertrophy
and vasoconstriction, which maintains relatively normal distal
pulmonary capillary and venous pressures, helping to prevent
pulmonary edema. Prolonged pulmonary arterial vasoconstriction,
however, stimulates the development of irreversible
obstructive intimal lesions. Eventually pulmonary vascular
resistance increases toward systemic levels, thereby reversing
the shunt to right-to-left with unoxygenated blood in the systemic
circulation (late cyanotic congenital heart disease, or
Eisenmenger syndrome).

Once significant irreversible pulmonary hypertension develops,
the structural defects of congenital heart disease are considered
irreparable. The secondary pulmonary vascular
changes can eventually lead to the patient’s death. This is the
rationale for early intervention, either surgical or nonsurgical.
Some developmental anomalies of the heart (e.g., coarctation
of the aorta, aortic valvular stenosis, and pulmonary
valvular stenosis) produce obstructions to flow because of
abnormal narrowing of chambers, valves, or blood vessels and
therefore are called obstructive congenital heart disease. A complete
obstruction is called an atresia. In some disorders (e.g.,
tetralogy of Fallot), an obstruction (pulmonary stenosis) is
associated with a shunt (right-to-left through a VSD).
In congenital heart disease, altered hemodynamics usually
cause cardiac dilation or hypertrophy (or both). A decrease in
the volume and muscle mass of a cardiac chamber is called
hypoplasia if it occurs before birth and atrophy if it develops
after birth.

The diseases in this group cause cyanosis several months or
years after birth. The most commonly encountered left-to-right
shunts include atrial septal defects, ventricular septa]
defects, patent (or persistent) ductus arteriosus, and AV septal
defects, and are shown in figure.

Schematic diagram of congenital left-to-right shunts. A, Atrial septa) defect (ASD). B, Ventricular septal defect (VSD). With VSD the shunt is left-to-right, and the pressures are the same in both ventricles. Pressure hypertrophy of the right ventricle and volume hypertrophy of the left ventricle are generally present. C, Patent ductus arteriosus (PDA). D, Atrioventricular septal defect (AVSD). E, Large VSD with irreversible pulmonary hypertension. The shunt is right-to-left (shunt reversal). Volume hypertrophy and pressure hypertrophy of the right ventricle are present. Arrow indicates the direction of blood flow. The right
ventricular pressure is now sufficient to yield a right-to-left shunt (Ao, aorta; LA, left atrium; LV, left ventricle; PT, pulmonary trunk; RA, right atrium; RV, right ventricle.)

Atrial Septal Defect

An ASD is an abnormal opening in the atrial septum that
allows communication of blood between the left and right
atria (not to be confused with a patent foramen ovale, present
in up to one-third of normal individuals). ASD is the most
common congenital cardiac anomaly and is usually asymptomatic
until adulthood

Morphology. The three major types of ASDs, classified
according to their location in the septum, are
secundum, primum, and sinus venosus. The secundum
ASD, accounting for approximately 90% of all
ASDs, is a defect located at and resulting from a deficient
or fenestrated oval fossa. ASDs are usually isolated
(i.e., not associated with other anomalies). When
associated with another defect, such as tetralogy of
Fallot, the other defect is usually hemodynamically
dominant. The atrial aperture may be of any size and
may be single, multiple, or fenestrated. Primum
anomalies (5% of ASDs) occur adjacent to the AV
valves and are usually associated with a cleft anterior
mitral leaflet. This combination is known as a partial
AV septa) defect (see later). Sinus venosus defects
(5%) are located near the entrance of the superior
vena cava. They are commonly accompanied by
anomalous connections of right pulmonary veins to
the superior vena cava or right atrium.
ASDs result in a left-to-right shunt, largely because
pulmonary vascular resistance is considerably less
than systemic vascular resistance and because the
compliance (distensibility) of the right ventricle is
much greater than that of the left. Pulmonary blood
flow may be 2 to 4 times normal. Although some
neonates may be in profound CHF, most isolated
ASDs are well tolerated and usually do not become
symptomatic before age 30. A murmur is often
present as a result of excessive flow through the pulmonary
valve. Eventually, volume hypertrophy of the
right atrium and right ventricle develops

Irreversible pulmonary hypertension develops in fewer
than 10% of subjects with an isolated uncorrected ASD. The
objectives of surgical closure of an ASD are the reversal of the
hemodynamic abnormalities and the prevention of complications,
including heart failure, paradoxical embolization, and
irreversible pulmonary vascular disease. Mortality is low,
and postoperative survival is comparable to that of a normal
population.

Ventricular Septal Defect

Incomplete closure of the ventricular septum, allowing
free communication and thus a shunt from left to right ventricles,
is the most common congenital cardiac anomaly (see
Fig. B). Frequently, VSD is associated with other structural
defects, such as tetralogy of Fallot. About 30% occur as
isolated anomalies. Depending on the size of the defect, it may
produce difficulties virtually from birth or, with smaller
lesions, may not be recognized until later or may even spontaneously
close.
Morphology. VSDs are classified according to size
and location. Most are about the size of the aortic
valve orifice. About 90% involve the region of the
membranous septum (membranous VSD).

The remainder lie below the pulmonary valve
(infundibular VSD) or within the muscular septum.
Although most often single, VSDs in the muscular
septum may be multiple (so-called Swiss-cheese
septum).
The functional significance of a VSD depends on the
size of the defect and the presence of other anomalies.
About 50% of small muscular VSDs close spontaneously,
and the remainder are generally well tolerated
for years. Large defects are usually membranous
or infundibular, and they generally remain patent and
permit a significant left-to-right flow. Right ventricular
hypertrophy and pulmonary hypertension are present
from birth. Over time, irreversible pulmonary vascular
disease develops in virtually all patients with large
unoperated VSDs, leading to shunt reversal, cyanosis,
and death.
Large defects may become manifest virtually at birth
with signs of cardiac failure accompanying the
murmur. Surgical closure of asymptomatic VSDs is
generally not attempted during infancy, in hope of
spontaneous closure. Correction, however, is indicated
at age 1 year with large defects, before obstructive pulmonary
vascular disease becomes irreversible.

Patent Ductus Arteriosus

Patent (also called persistent) ductus arteriosus (PDA)
results when the ductus arteriosus remains open after birth
(see Fig C). About 90% of PDAs occur as an isolated
anomaly. The remainder are most often associated with VSD,
coarctation of the aorta, or pulmonary or aortic stenosis. The
length and diameter of the ductus vary widely.
Most often PDA does not produce functional difficulties at
birth. Indeed, a narrow ductus may have no effect on growth
and development during childhood. Its existence, however,
can generally be detected by a continuous harsh murmur,
described as “machinery-like.” Because the shunt is at first leftto-
right, there is no cyanosis. Obstructive pulmonary vascular
disease eventually ensues, however, with ultimate reversal
of flow and its associated consequences.
There is general agreement that an isolated PDA should
be closed as early in life as is feasible. Conversely, preservation
of ductal patency (by administering prostaglandin E)
assumes great importance in the survival of infants with
various forms of congenital heart disease with obstructed pulmonary
or systemic blood flow, such as aortic valve atresia.
Ironically, therefore, the ductus may be either life-threatening
or life-saving.
Atrioventricular Septal Defect (AVSD)

AVSD (also called complete atrioventricular canal defect)
results from abnormal development of the embryologic AV
canal, in which the superior and inferior endocardial cushions
fail to fuse adequately, resulting in incomplete closure of
the AV septum and inadequate formation of the tricuspid
and mitral valves (see Fig D). The two most common
forms are partial AVSD (consisting of a primum ASD and a
cleft anterior mitral leaflet, causing mitral insufficiency) and
complete AVSD (consisting of a large combined AV septal
defect and a large common AV valve—essentially a hole in
the center of the heart). In the complete form, all four
cardiac chambers freely communicate, inducing volume
hypertrophy of each. More than one-third of all patients with
the complete AVSD have Down syndrome. Surgical repair is
possible.

The diseases in this group cause cyanosis early in postnatal
life. Although a VSD is the most common congenital cardiac
malformation, tetralogy of Fallot constitutes the most
common form of cyanotic congenital heart disease. Other relatively
frequently encountered anomalies in this category
include transposition of the great arteries, tricuspid atresia,
total anomalous pulmonary venous connection, and truncus
arteriosus (note that each entity begins with the letter “T”).
Tetralogy of Fallot and transposition of the great arteries are
illustrated schematically in Figure.

figure A

figure B

figure B

Tetralogy of Fallot
The four features of the tetralogy of Fallot are (1) VSD, (2)
obstruction to the right ventricular outflow tract (subpulmonary
stenosis), (3) an aorta that overrides the VSD, and (4) right ventricolar hypertrophy (see Fig. A). All of the features result
embryologically from anterosuperior displacement of the
infundibular septum. Even untreated, some patients with
tetralogy of Fallot often survive into adult life (in a large series
of untreated patients with this condition, 10% were alive at 20
years and 3% at 40 years). The clinical consequences of tetralogy
of Fallot depend primarily on the severity of subpulmonary
stenosis.

Morphology. The heart is often enlarged and may
be “boot-shaped” owing to marked right ventricular
hypertrophy, particularly of the apical region. The VSD
is usually large and approximates the diameter of the
aortic orifice. The aortic valve forms the superior
border of the VSD, thereby overriding the defect and
both ventricular chambers. The obstruction to right
ventricular outflow is most often due to narrowing of
the infundibulum (subpulmonic stenosis) but is often
accompanied by pulmonary valvular stenosis. Sometimes
there is complete atresia of the pulmonary valve
and variable portions of the pulmonary arteries, such
that blood flow through a patent ductus or dilated
bronchial arteries, or through both, is necessary for
survival. Aortic valve insufficiency or ASD may also
be present, and a right aortic arch is present in about
25% of cases.

The severity of obstruction to right ventricular outflow
determines the direction of blood flow. If the subpulmonary
stenosis is mild, the abnormality resembles an isolated VSD,
and the shunt may be left-to-right, without cyanosis (so-called
pink tetralogy). As the obstruction increases in severity, there is
commensurately greater resistance to right ventricular outflow. As
it approaches the level of systemic vascular resistance, right-to-left
shunting predominates and, along with it, cyanosis (classic
tetralogy of Fallot). With increasing severity of subpulmonic
stenosis, the pulmonary arteries are progressively smaller and
thinner walled (hypoplastic), and the aorta is progressively
larger in diameter. As the child grows and the heart increases
in size, the pulmonic orifice does not expand proportionally,
making the obstruction progressively worse. Thus most infants
with tetralogy are cyanotic from birth or soon thereafter. The
subpulmonary stenosis, however, protects the pulmonary vasculature
from pressure overload, and right ventricular failure
is rare because the right ventricle is decompressed into the left
ventricle and aorta. Complete surgical repair is possible for
classic tetralogy of Fallot but is more complicated for patients
with pulmonary atresia and dilated bronchial arteries.

Transposition of the Great Arteries (TGA)
Transposition of the great arteries implies ventriculoarterial
discordance, such that the aorta arises from the right ventricle
and the pulmonary artery emanates from the left ventricle (see
Fig. B). The AV connections are normal (concordant),
with right atrium joining right ventricle and left atrium emptying
into left ventricle.
The essential embryologic defect in complete TGA is abnormal
formation of the truncal and aortopulmonary septa. The
aorta arises from the right ventricle and lies anterior and to
the right of the pulmonary artery; in contrast, in the
normal heart, the aorta is posterior and to the left.

The result is separation of the systemic and pulmonary circulations, a condition
incompatible with postnatal life unless a shunt exists
for adequate mixing of blood. Patients with TGA and a VSD
(about 35%) have a stable shunt. Those with only a patent
foramen ovale or PDA (about 65%), however, have unstable
shunts that tend to close and therefore require immediate
intervention to create a shunt (such as balloon atrial septostomy)
within the first few days of life. Right ventricular
hypertrophy becomes prominent because this chamber functions
as the systemic ventricle. Concurrently the left ventricle
becomes thin-walled (atrophic) as it supports the lowresistance
pulmonary circulation.

The outlook for infants with TGA depends on the degree
of “mixing” of the blood, the magnitude of the tissue hypoxia,
and the ability of the right ventricle to maintain the systemic
circulation. Without surgery, most patients die within the first
months of life. Currently, most patients undergo a reparative
operation (usually entailing transection and “switching ” of the
great arteries as well as of the coronary arteries) during the
first several weeks of life.

Truncus Arteriosus
The persistent truncus arteriosus anomaly arises from a
developmental failure of separation of the embryologic
truncus arteriosus into the aorta and pulmonary artery. This
results in a single great artery that receives blood from both
ventricles, accompanied by an underlying VSD, and that gives
rise to the systemic, pulmonary, and coronary circulations.
Because blood from the right and left ventricles mixes, there
is early systemic cyanosis as well as increased pulmonary
blood flow, with the danger of irreversible pulmonary
hypertension.

Tricuspid Atresia
Complete occlusion of the tricuspid valve orifice is known
as tricuspid atresia. It results embryologically from unequal
division of the AV canal, and thus the mitral valve is larger
than normal. This lesion is almost always associated with
underdevelopment (hypoplasia) of the right ventricle. The circulation
is maintained by a right-to-left shunt through an
interatrial communication (ASD or patent foramen ovale). A
VSD is also present and affords communication between the
left ventricle and the great artery that arises from the
hypoplastic right ventricle. Cyanosis is present virtually from
birth, and there is a high mortality in the first weeks or months
of life.

Total Anomalous Pulmonary Venous Connection (TAPVC)
TAPVC, in which no pulmonary veins directly join the left
atrium, results embryologically when the common pulmonary
vein fails to develop or becomes atretic, causing primitive systemic
venous channels from the lungs to remain patent.
TAPVC usually drains into the left innominate vein or to the
coronary sinus. Either a patent foramen ovale or an ASD is
always present, allowing pulmonary venous blood to enter the
left atrium. Consequences of TAPVC include volume and
pressure hypertrophy of the right atrium and right ventricle,
and these chambers and the pulmonary trunk are dilated. The
left atrium is hypoplastic, but the left ventricle is usually
normal in size. Cyanosis may be present, owing to mixing of
well-oxygenated and poorly oxygenated blood at the site of
anomalous pulmonary venous connection and a large rightto-
left shunt at the ASD.

Congenital obstruction to blood flow may occur at the level
of the heart valves or within a great vessel. Relatively common
examples include stenosis of the pulmonary valve, stenosis or
atresia of the aortic valve, and coarctation of the aorta.
Obstruction can also occur within a chamber, as with subpulmonary
stenosis in tetralogy of Fallot.

Coarctation of the Aorta
Coarctation (narrowing, constriction) of the aorta ranks
high in frequency among the common structural anomalies.
Males are affected twice as often as females, although females
with Turner syndrome frequently have a coarctation (see
Chapter 5). Two classic forms have been described: (1) an
“infantile ” form with tubular hypoplasia of the aortic arch
proximal to a PDA that is often symptomatic in early childhood
and (2) an “adult” form in which there is a discrete ridgelike
infolding of the aorta, just opposite the closed ductus
arteriosus (ligamentum arteriosum) distal to the arch vessels
(Fig).

Diagram showing coarctation of the aorta with  and without PDA. (Ao, aorta; LA, left atrium; LV, left ventricle; PT. pulmonary trunk; RA. right atrium; RV, right ventricle; PDA. persistent ductus arteriosus.)

Encroachment on the aortic lumen is of variable
severity, sometimes leaving only a small channel and at
other times producing only minimal narrowing. Clinical
manifestations depend almost entirely on the severity of the
narrowing and the patency of the ductus arteriosus. Although
coarctation of the aorta may occur as a solitary defect, it is
accompanied by a bicuspid aortic valve in 50% of cases and
may also be associated with congenital aortic stenosis, ASD,
VSD, mitral regurgitation, and berry aneurysms of the circle
of Willis.
Coarctation of the aorta with a PDA usually leads to manifestations
early in life; indeed, it may cause signs and symptoms immediately after birth. Many infants with this anomaly
do not survive the neonatal period without surgical or
catheter-based intervention. In such cases, the delivery of
unsaturated blood through the ductus arteriosus produces
cyanosis localized to the lower half of the body.
The outlook is different with coarctation of the aorta
without a PDA, unless it is very severe. Most of the children
are asymptomatic, and the disease may go unrecognized until
well into adult life. Typically there is hypertension in the upper
extremities, but there are weak pulses and a lower blood pressure
in the lower extremities, associated with manifestations
of arterial insufficiency (i.e., claudication and coldness).
Particularly characteristic in adults is the development of collateral
circulation between the precoarctation arterial
branches and the postcoarctation arteries through enlarged
intercostal and internal mammary arteries and the radiographically
visible erosions (“notching”) of the undersurfaces of the ribs.

With all significant coarctations, murmurs are often present
throughout systole. Sometimes a thrill may be present, and
there is cardiomegaly owing to left ventricular hypertrophy.
With uncomplicated coarctation of the aorta, surgical resection
and end-to-end anastomosis or replacement of the
affected aortic segment by a prosthetic graft yields excellent
results.

Pulmonary Stenosis and Atresia
This relatively frequent malformation constitutes an
obstruction at the pulmonary valve, which may be mild to
severe. It may occur as an isolated defect, or as part of a more
complex anomaly—either tetralogy of Fallot or TGA. Right
ventricular hypertrophy often develops, and there is sometimes
poststenotic dilation of the pulmonary artery owing to
jetstream injury to the wall. With coexistent subpulmonary
stenosis (as in tetralogy of Fallot), the high ventricular pressure
is not transmitted to the valve, and the pulmonary trunk
is not dilated and may in fact be hypoplastic. When the valve
is entirely atretic, there is no communication between the
right ventricle and lungs, and so the anomaly is commonly
associated with a hypoplastic right ventricle and an ASD; flow
enters the lungs through a PDA. Mild stenosis may be asymptomatic
and compatible with long life. The smaller the valvular
orifice, the more severe is the cyanosis and the earlier its
appearance.

Aortic Stenosis and Atresia
Here we are concerned with the narrowings and obstructions
of the aortic valve present from birth. There are three
major types of stenosis: valvular, subvalvular, and supravalvular.

With valvular aortic stenosis, the cusps may be hypoplastic
(small), dysplastic (thickened, nodular), or abnormal in
number (usually acommissural or unicommissural). In severe
congenital aortic stenosis or atresia, obstruction of the left
ventricular outflow tract leads to underdevelopment
(hypoplasia) of the left ventricle and ascending aorta. There
may be dense, porcelain-like left ventricular endocardial fibroelastosis
(see section on restrictive cardiomyopathy, later in
this chapter). The ductus must be open to allow blood flow to
the aorta and coronary arteries. This constellation of findings,
called the hypoplastic left heart syndrome, is nearly always fatal
in the first week of life, when the ductus closes. Less severe
degrees of congenital aortic stenosis may be compatible with
long survival. Cogenital aortic stenosis is an isolated lesion in
80% of cases.

Subaortic stenosis represents either a thickened ring (discrete
type) or collar (tunnel type) of dense endocardial
fibrous tissue below the level of the cusps. Supravalvular aortic
stenosis represents an inherited form of aortic dysplasia in
which the ascending aortic wall is greatly thickened, causing
luminal constriction. It may be related to a developmental
disorder affecting multiple organ systems, including the
vascular system, which includes hypercalcemia of infancy
(Williams syndrome). Mutations in the elastin gene cause
supravalvular aortic stenosis, probably via disruption of an
important elastin-smooth muscle cell interactions in arterial
morphogenesis.

A prominent systolic murmur is usually detectable and
sometimes a thrill, which does not distinguish the site of
stenosis. Pressure hypertrophy of the left ventricle develops as
a consequence of the obstruction to blood flow. In general,
congenital stenoses are well tolerated unless very severe. Mild
stenoses can be managed conservatively with antibiotic prophylaxis
and avoidance of strenuous activity, but the threat of
sudden death with exertion always looms.

In heart failure, often called congestive heart failure
(CHF), the heart is unable to pump blood at a rate commensurate
with the requirements of the metabolizing tissues or
can do so only at an elevated filling pressure. Although usually
caused by a slowly developing intrinsic deficit in myocardial
contraction, a similar clinical syndrome is present in some
patients with heart failure caused by conditions in which the
normal heart is suddenly presented with a load that exceeds
its capacity (e.g., fluid overload, acute myocardial infarction,
acute valvular dysfunction) or in which ventricular filling is
impaired (see below). CHF is a common and often recurrent
condition with a poor prognosis. The magnitude of the
problem is exemplified by the impact of CHF in the United
States, where each year it affects nearly 5 million individuals,
is the underlying or contributing cause of death of an estimated
300,000, and necessitates over 1 million hospitalizations.
‘° Moreover, CHF is the leading discharge diagnosis in
hospitalized patients over age 65 and has an associated annual
cost of $18 billion. In many pathologic states, the onset of
heart failure is preceded by cardiac hypertrophy, the compensatory
response of the myocardium to increased mechanical
work.

The cardiovascular system maintains arterial pressure and
perfusion of vital organs in the presence of excessive hemodynamic
burden or disturbance in myocardial contractility by
a number of mechanisms.” The most important are:

■ The Frank-Starling mechanism, in which the increased
preload of dilation (thereby increasing cross-bridges within
the sarcomeres) helps to sustain cardiac performance by
enhancing contractility

■ Myocardial structural changes, including augmented
muscle mass (hypertrophy) with or without cardiac chamber
dilation, in which the mass of contractile tissue is
augmented

■ Activation of neurohumoral systems, especially (1) release
of the neurotransmitter norepinephrine by adrenergic
cardiac nerves (which increases heart rate and augments
myocardial contractility and vascular resistance), (2) activation
of the renin-angiotensin-aldosterone system, and (3)
release of atrial natriuretic peptide.

These adaptive mechanisms may be adequate to maintain
the overall pumping performance of the heart at relatively
normal levels, but their capacity to sustain cardiac performance
may ultimately be exceeded. Moreover, pathologic
changes, such as apoptosis, cytoskeletal alterations, and extracellular
matrix (particularly collagen) synthesis and remodeling,
may also occur, causing structural and functional
disturbances. Most instances of heart failure are the consequence
of progressive deterioration of myocardial contractile
function (systolic dysfunction), as often occurs with ischemic
injury, pressure or volume overload, or dilated cardiomyopathy.
The most frequent specific causes are ischemic heart
disease and hypertension. Sometimes, however, failure results
from an inability of the heart chamber to relax, expand, and
fill sufficiently during diastole to accommodate an adequate
ventricular blood volume (diastolic dysfunction), as can occur
with massive left ventricular hypertrophy, myocardial fibrosis,
deposition of amyloid, or constrictive pericarditis.’ Whatever
its basis, CHF is characterized by diminished cardiac output
(sometimes called forward failure) or damming back of blood in
the venous system (so-called backward failure), or both.
The molecular, cellular, and structural changes in the heart
that occur as a response to injury, and cause changes in size,
shape, and function, are often called left ventricular remodeling.
Our discussion focuses on structural changes and considers
heart failure to be a progressive disorder, which can
culminate in a clinical syndrome characterized by impaired
cardiac function and circulatory congestion. Nevertheless, we
recognize that the modern treatment of chronic heart failure
emphasizes the neurohumoral hypothesis, in which neuroendocrine
activation is important in the progression of heart
failure. Thus, inhibition of neurohormones may have longterm
beneficial effects on morbidity and mortality.” In the
future, patients with CHF may be helped by implanted
mechanical cardiac assist devices, an area in which considerable
progress has recently been made.’

CARDIAC HYPERTROPHY: PATHOPHYSIOLOGY AND PROGRESSION
TO FAILURE

The cardiac myocyte is generally considered a terminally
differentiated cell that has lost its ability to divide. Under
normal circumstances, functionally useful augmentation of
myocyte number (hyperplasia) cannot occur. Increased
mechanical load causes an increase in the content of subcellular
components and a consequent increase in cell size
(hypertrophy). Increased mechanical work owing to pressure
or volume overload or trophic signals (e.g., hyperthyroidism
through stimulation of beta-adrenergic receptors) increases
the rate of protein synthesis, the amount of protein in each
cell, the number of sarcomeres and mitochondria, the dimension
and mass of myocytes and, consequently, the size of the
heart. Nevertheless, the extent to which adult cardiac myocytes
have some capacity to synthesize DNA and whether this leads
to some degree of cell division is an area of considerable recent
attention and debate.’
The extent of hypertrophy varies for different underlying
causes. Heart weight usually ranges from 350 to 600 gm (up
to approximately two times normal) in pulmonary hypertension
and ischemic heart disease; from 400 to 800 gm (up to
two to three times normal) in systemic hypertension, aortic
stenosis, mitral regurgitation, or dilated cardiomyopathy;
from 600 to 1000 gm (three or more times normal) in aortic
regurgitation or hypertrophic cardiomyopathy. Hearts weighing
more than 1000 gm are rare.

The pattern of hypertrophy reflects the nature of the stimulus
(Fig. ).

Pressure-overloaded ventricles (e.g., in hypertension or aortic stenosis) develop pressure-overload
(also called concentric) hypertrophy of the left ventricle, with
an increased wall thickness. In the left ventricle the augmented
muscle may reduce the cavity diameter. In pressure overload,
the predominant deposition of sarcomeres is parallel to the
long axes of cells; cross-sectional area of myocytes is expanded
(but cell length is not). In contrast, volume overload stimulates
deposition of new sarcomeres and cell length (as well as width) is increased. Thus, volume-overload hypertrophy is
characterized by dilation with increased ventricular diameter.
In volume overload, muscle mass and wall thickness are
increased approximately in proportion to chamber diameter.

However, owing to dilation, wall thickness of a heart in which
both hypertrophy and dilation have occurred is not necessarily
increased, and it may be normal or less than normal. Thus,
wall thickness is by itself not an adequate measure of volumeoverload
hypertrophy.
Cardiac hypertrophy is also accompanied by numerous
transcriptional and morphologic changes. With prolonged
hemodynamic overload, gene expression is altered, leading to
re-expression of a pattern of protein synthesis analogous to
that seen in fetal cardiac development; other changes are analogous
to events that occur during mitosis of normally proliferating
cells. Early mediators of hypertrophy
include the immediate-early genes (e.g., c-fos, c-myc, c-jun and
EGR1). Selective up-regulation or re-expression of embryonic/
fetal forms of contractile and other proteins also occurs,
including f3-myosin heavy chain, ANP, and collagen. The increased myocyte size that occurs in cardiac
hypertrophy is usually accompanied by decreased capillary
density, increased intercapillary distance, and deposition of
fibrous tissue. Nevertheless, the enlarged muscle mass has
increased metabolic requirements and increased wall tension,
both major determinants of the oxygen consumption of the
heart. The other major factors in oxygen consumption are
heart rate and contractility (inotropic state, or force of contraction),
both of which are often increased in hypertrophic
states.

Thus, the geometry, structure, and composition (cells and
extracellular matrix) of the hypertrophied heart are not normal.
Cardiac hypertrophy constitutes a tenuous balance between
adaptive characteristics (including new sarcomeres) and potentially
deleterious structural and biochemical/molecular alterations (inclding decreased capillary-to-mryocyte ratio, increased
fibrous tissue, and synthesis of abnormal proteins). Thus, sustained
cardiac hypertrophy often evolves to cardiac failure. Ultimately,
the primary cardiac disease and the superimposed
compensatory burdens further encroach on the myocardial
reserve. Then begins the downward slide of stroke volume and
cardiac output that often ends in death. The proposed sequence
of initially beneficial and later harmful events in the response
to increased cardiac work is summarized in Figure.

The structural, biochemical, and molecular basis for
myocardial contractile failure is obscure in many cases. Nevertheless,
in some instances (e.g., myocardial infarction), there
is obvious death of myocytes and loss of vital elements of the
“pump”; consequently, noninfarcted regions of cardiac muscle
are overworked. In contrast, in valvular heart disease,
increased pressure or volume work affects the myocardium
globally. The molecular and cellular changes in hypertrophied
hearts that initially mediate enhanced function may contribute
to the development of heart failure.’- ‘” Proteins related to contractile
elements, excitation—contraction coupling, and energy
utilization may be significantly altered through production of
different isoforms that either may be less functional than
normal or may be reduced or increased in amount. Alterations
of intracellular handling of calcium ions may also contribute
to impaired contraction and relaxation.’ Loss of myocytes
due to apoptosis may contribute to progressive myocardial
dysfunction in cardiac disease with hypertrophy.’ ”
Increased heart mass predicts excess cardiac mortality and
morbidity. Indeed, besides predisposing to CHF, left ventricular
hypertrophy is an independent risk factor for sudden
death.” Interestingly, and in contrast to the pathologic hypertrophy
just discussed, hypertrophy that is induced by regular
strenuous exercise (physiologic hypertrophy) seems to be an
extension of normal growth and has minimal or no deleterious
effect. A suitable explanation for this discrepancy is yet lacking.

The degree of structural abnormality of the heart in CHF
does not always reflect the level of dysfunction and, indeed, it
may be impossible from morphologic examination of the
heart to distinguish a damaged but compensated heart from
one that has decompensated. At autopsy, the heart of patients
having CHF is generally characterized by increased weight,
chamber dilation, thin walls, and microscopic changes of
hypertrophy, but the extent of these changes varies from one
patient to the next. Moreover, many of the significant adaptations
and morphologic changes noted in CHF are distant from
the heart and are produced by the hypoxic and congestive effects
of the failing circulation on other organs and tissues. Thus CHF
represents a clinical syndrome characterized primarily by
findings outside the cardiovascular system—in both
“forward” (e.g., poor organ perfusion) and “backward”
(dyspnea and peripheral edema) directions.
To some extent, the right and left sides of the heart act as
two distinct anatomic and functional units. Thus left-sided
and right-sided failure can occur independently. Nevertheless,
because the cardiovascular system is a closed circuit, failure of
one side (particularly the left side) often produces excessive
strain on the other, terminating in global heart failure. Despite
this interdependency, the clearest understanding of the pathologic physiology and anatomy of heart failure is derived from
a consideration of each side separately.

Isolated right-sided heart failure occurs in only a few diseases.
Usually it is a secondary consequence of left-sided heart
failure because any increase in pressure in the pulmonary circulation
incidental to left-sided heart failure inevitably produces
an increased burden on the right side of the heart. The
causes of right-sided heart failure must then include all those
that induce left-sided heart failure.
Pure right-sided heart failure most often occurs with
chronic severe pulmonary hypertension and thus is called cor
pulmonale. In this condition, the right ventricle is burdened
by a pressure workload due to increased resistance within the
pulmonary circulation. Hypertrophy and dilation are generally
confined to the right ventricle and atrium, although
bulging of the ventricular septum to the left can cause dysfunction
of the left ventricle.
The major morphologic and clinical effects of pure right sided
heart failure differ from those of left-sided heart failure
in that pulmonary congestion is minimal, whereas engorgement
of the systemic and portal venous systems may be
pronounced.

Liver and Portal System. The liver is usually increased
in size and weight (congestive hepatomegaly),
and a cut section displays prominent passive congestion. Congested red centers of the liver
lobules are surrounded by paler, sometimes fatty,
peripheral regions. In some instances, especially when
left-sided heart failure is also present, the severe central
hypoxia produces centrilobular necrosis along with
the sinusoidal congestion. With long-standing severe
right-sided heart failure, the central areas can become
fibrotic, creating so-called cardiac sclerosis or cardiac
cirrhosis.
Right-sided heart failure also leads to elevated pressure
in the portal vein and its tributaries. Congestion
produces a tense, enlarged spleen (congestive
splenomegaly). Microscopically there may be marked
sinusoidal dilation. With long-standing congestion,
the enlarged spleen may achieve a weight of 300 to
500 gm (normal, approximately 150 gm). Chronic
edema of the bowel wall can also occur and in some
patients may interfere with absorption of nutrients. In
addition, accumulations of transudate in the peritoneal
cavity may give rise to ascites.
Kidneys. Congestion of the kidneys is more marked
with right-sided heart failure than with left-sided heart
failure, leading to greater fluid retention, peripheral
edema, and more pronounced azotemia.
Brain. Symptoms essentially identical to those
described in left-sided heart failure may occur, representing
venous congestion and hypoxia of the central
nervous system.
Pleural and Pericardial Spaces. Accumulation of
fluid in the pleural space (particularly right) and pericardial
space (effusions) may appear. Thus, while
pulmonary edema indicates left-sided heart failure,
pleural effusions accompany right-sided heart failure.
Pleural effusions can range from 100 ml to well over
1 liter and can cause partial atelectasis of the corresponding
lung.
Subcutaneous Tissues. Peripheral edema of dependent
portions of the body, especially ankle (pedal) and
pretibial edema, is a hallmark of right-sided heart
failure. In chronically bedridden patients, the edema
may be primarily presacral. Generalized massive
edema is called anasarca.

The symptoms of pure left-sided heart failure are largely
due to pulmonary congestion and edema. In contrast, in
right-sided heart failure, respiratory symptoms may be absent
or quite insignificant, and there is a systemic (and portal)
venous congestive syndrome, with hepatic and splenic
enlargement, peripheral edema, pleural effusion, and ascites.
In many cases of chronic cardiac dccompensation, however, the
patient presents with the picture of biventricular CHF, encompassing
the clinical syndromes of both right-sided and left-sided
heart failure.

Congenital heart disease is a general term used to describe
abnormalities of the heart or great vessels that are present
from birth. Most such disorders arise from faulty embryogenesis
during gestational weeks 3 through 8, when major cardiovascular
structures develop. The most severe anomalies
may be incompatible with intrauterine survival. Congenital
heart defects compatible with embryologic maturation and
birth are generally morphogenetic defects of individual chambers
or regions of the heart, with the remainder of the heart
developing relatively normally. Examples are infants born with
a defect in septation (“hole in the heart” ), such as an atrial
septal defect (ASD) or a ventricular septal defect (VSD), or a
hypoplastic right or left ventricle, in which the unaffected
ventricle is morphologically, electrically, and physiologically
normal. Alternatively, the development of the muscular component
of the heart may proceed normally, but vessels that
arise from the heart may not have the appropriate connections
with specific cardiac chambers. Some forms of congenital
heart disease produce manifestations soon after birth, frequently
accompanying the change from fetal to postnatal
circulatory patterns (with reliance on the lungs, rather than
placenta, for oxygenation). Others, however, do not necessarily
become evident until adulthood (e.g., aortic coarctation or
ASD).

Owing largely to surgical advances in the correction of
simple and complex structural heart defects, the number of
adults who have survived with congenital heart disease is
increasing rapidly. It is estimated that by 2020 there will be at
least 750,000 adults with congenital heart disease who require
a very specialized form of care with novel medical, psychologic,
and social dimensions.” They include those who have
never had cardiac surgery, those who have had reparative
cardiac surgery and require no further intervention, and those
who have had incomplete or palliative surgery.”
Although surgery may fully correct the hemodynamic
abnormalities of congenital heart disease, the heart following
repair of a congenital defect may not be fully normal. Myocardial
hypertrophy and other changes of cardiac remodeling
brought about by the congenital defect may be irreversible or
even necessary for survival and growth. Although adaptive initially,
such changes can elicit late-onset arrhythmias, ischemia,
and myocardial dysfunction, sometimes after many uneventful
years subsequent to the surgery. Associated prosthetic
materials and devices, such as substitute valves or myocardial
patches, yield an additional risk of complications, most
prominently thromboembolism, infection, or dysfunction of
the material or device. Moreover, there may be specific difficulties
resulting from hyperviscosity of the blood owing to
increased hematocrit, and maternal risks associated with
childbearing in those with cyanotic congenital disease.

Incidence. Congenital heart disease is the most common
type of heart disease among children. Although figures vary,
a generally accepted incidence is approximately 1% of live
births. The incidence is higher in premature infants and in
stillborns. Twelve disorders account for about 85% of cases;
their frequencies are presented in Table 12-2.
In the past few decades, the reported incidence of structural
heart defects in newborns has increased owing to increased
diagnostic sensitivity (especially cross-sectional and Doppler

echocardiography and magnetic resonance imaging).
The enhanced resolving power of noninvasive methods should
prove particularly useful in the study of familial structural
defects, because apparently unaffected relatives can be evaluated
for subclinical evidence of anomalies.

Etiology and Pathogenesis

Congenital heart defects are caused by developmental
abnormalities. However, the genes that may be involved in
these defects have been identified in only a minority of conditions.
In fact, well-defined genetic or environmental influences
are identifiable in only about 10% of cases of congenital
heart disease, but the understanding of probable genetic links
is increasing. The obvious role of genetic factors in some cases
is demonstrated by the occurrence of familial forms of congenital
heart disease and by an association of congenital
cardiac malformations with certain chromosomal abnormalities
(e.g., trisomies 13, 15, 18, and 21, and the Turner syndrome).
Indeed, a congenital heart defect in a parent or
preceding sibling is the greatest risk factor for developing a
cardiac malformation. Trisomy 21 (associated with Down syndrome)
is the most common known genetic cause of congenital
heart disease. Environmental factors, such as congenital
rubella infection or teratogens, are responsible for some additional
cases. Multifactorial genetic, environmental, and maternal
factors probably account for the remaining majority of
cases in which a cause is not apparent.
The growing understanding of the genetics of congenital
heart disease has also led to the recognition that powerful
disease modifiers must exist. There is wide variation in the nature

and severity of lesions in patients with identical genetic
abnormalities. This suggests that altering key environmental
or maternal factors could modify disease in high-risk individuals,
whether or not the disease is caused by a distinct genetic
abnormality. For instance, this type of strategy has resulted in
marked reduction in neural tube defects by increasing maternal
dietary folate.”

As discussed, left-sided heart failure is most often caused by
(1) ischemic heart disease, (2) hypertension, (3) aortic and
mitral valvular diseases, and (4) nonischemic myocardial diseases.
The morphologic and clinical effects of left-sided CHF
primarily result from progressive damming of blood within
the pulmonary circulation and the consequences of diminished
peripheral blood pressure and flow.

The findings in the heart vary
depending on the cause of the disease process; abnormalities
such as myocardial infarction or a valvular
deformity may be present. Except with obstruction at
the mitral valve or other processes that restrict the
size of the left ventricle, this chamber is usually hypertrophied
and often dilated, sometimes quite massively.
There are usually nonspecific changes of
hypertrophy and fibrosis in the myocardium. Secondary
enlargement of the left atrium with resultant
atrial fibrillation (i.e., uncoordinated, chaotic contraction
of the atrium) may either compromise stroke
volume or cause blood stasis and possible thrombus
formation (particularly in the atrial appendage). A fibrillating
left atrium carries a substantially increased
risk of embolic stroke. The extracardiac effects of
left-sided heart failure are manifested most prominently
in the lungs, although the kidneys and brain
may also be affected.

Lungs. Pressure in the pulmonary veins mounts and
is ultimately transmitted retrograde to the capillaries
and arteries. The result is pulmonary congestion and
edema, with heavy, wet lungs. It is sufficient to note here that the
pulmonary changes include, in sequence, (1) a perivascular
and interstitial transudate, particularly in the
interlobular septa, responsible for Kerley’s B lines on
x-ray; (2) progressive edematous widening of alveolar
septa; and (3) accumulation of edema fluid in the alveolar
spaces. Moreover, iron-containing proteins in
edema fluid and hemoglobin from erythrocytes, which
leak from congested capillaries, are phagocytosed by
macrophages and converted to hemosiderin. Hemosiderin-
containing macrophages in the alveoli (called
siderophages, or heart failure cells) denote previous
episodes of pulmonary edema.
These anatomic changes are associated with striking
clinical manifestations. Dyspnea (breathlessness),
usually the earliest and the cardinal complaint of
patients in left-sided heart failure, is an exaggeration
of the normal breathlessness that follows exertion.
With further impairment, there is orthopnea, which is
dyspnea on lying down that is relieved by sitting or
standing. Thus the orthopneic patient must sleep
while sitting upright. Paroxysmal nocturnal dyspnea
is an extension of orthopnea that consists of attacks
of extreme dyspnea bordering on suffocation, usually
occurring at night. Cough is a common accompaniment
of left-sided failure.

Kidneys. Decreased cardiac output causes a reduction
in renal perfusion, which activates the renin of salt and water with consequent expansion of the
interstitial fluid and blood volumes. This compensatory
reaction can contribute to the pulmonary
edema in left-sided heart failure and is counteracted
by the release of ANP through atrial dilation, which
acts to decrease excessive blood volume. If the perfusion
deficit of the kidney becomes sufficiently
severe, impaired excretion of nitrogenous products
may cause azotemia, in this instance prerenal
azotemia.

Brain. In far-advanced CHF, cerebral hypoxia may
give rise to hypoxic encephalopathy,
with irritability, loss of attention span, and restlessness,
which may even progress to stupor and coma.

Some of the most distressing types of heart malfunction occur not as a result of abnormal heart muscle but because of abnormal rhythm of the heart. For instance,
sometimes the beat of the atria is not coordinated with the beat of the ventricles, so that the atria no longer function as primer pumps for the ventricles. The purpose of this chapter is to discuss the physiology of common cardiac arrhythmias and their
effects on heart pumping, as well as their diagnosis by electrocardiography.The causes of the cardiac arrhythmias are usually one or a combination of the following abnormalities in the rhythmicity-conduction system of the heart:

1. Abnormal rhythmicity of the pacemaker
2. Shift of the pacemaker from the sinus node to another place in the heart
3. Blocks at different points in the spread of the impulse through the heart
4. Abnormal pathways of impulse transmission through the heart
5. Spontaneous generation of spurious impulses in almost any part of the heart

Abnormal Sinus Rhythms

Tachycardia

The term “tachycardia” means fast heart rate, usually defined in an adult person as
faster than 100 beats per minute. An electrocardiogram recorded from a patient
with tachycardia is shown in Figure.

This electrocardiogram is normal except that the heart rate, as determined from the time intervals between QRS complexes, is about 150 per minute instead of the normal 72 per minute.
The general causes of tachycardia include increased body temperature, stimulation
of the heart by the sympathetic nerves, or toxic conditions of the heart.
The heart rate increases about 10 beats per minute for each degree Fahrenheit
(18 beats per degree Celsius) increase in body temperature, up to a body temperature of about 105°F (40.5°C); beyond this, the heart rate may decrease because of progressive debility of the heart muscle as a result of the fever. Fever causes tachycardia because increased temperature increases the rate of metabolism of the sinus node, which in turn directly increases its excitability and rate of rhythm.
Many factors can cause the sympathetic nervous system to excite the heart, as we
discuss at multiple points in this text. For instance, when a patient loses blood and
passes into a state of shock or semishock, sympathetic reflex stimulation of the heart often increases the heart rate to 150 to 180 beats per minute.
Simple weakening of the myocardium usually increases the heart rate because
the weakened heart does not pump blood into the arterial tree to a normal extent,
and this elicits sympathetic reflexes to increase the heart rate.

Bradycardia

The term “bradycardia” means a slow heart rate, usually defined as fewer than 60
beats per minute. Bradycardia is shown by the electrocardiogram in Figure.

Bradycardia in Athletes. The athlete’s heart is larger and considerably stronger than that of a normal person, which allows the athlete’s heart to pump a large stroke volume output per beat even during periods of rest. When the athlete is at rest, excessive quantities of blood pumped into the arterial tree with each beat initiate feedback circulatory reflexes or other effects to cause bradycardia.

Vagal Stimulation as a Cause of Bradycardia. Any circulatory reflex that stimulates the vagus nerves causes release of acetylcholine at the vagal endings in the heart, thus giving a parasympathetic effect. Perhaps the most striking
example of this occurs in patients with carotid sinus syndrome. In these patients, the pressure receptors (baroreceptors) in the carotid sinus region of the carotid
artery walls are excessively sensitive. Therefore, even mild external pressure on the neck elicits a strong baroreceptor reflex, causing intense vagal-acetylcholine
effects on the heart, including extreme bradycardia. Indeed, sometimes this reflex is so powerful that it actually stops the heart for 5 to 10 seconds.

Sinus Arrhythmia

A cardiotachometer is an instrument that records by the height of successive spikes the duration of the interval between the successive QRS complexes in the electrocardiogram. Note from this record that the heart rate increased and decreased no more than 5 per cent during quiet respiration (left half of the record). Then, during deep respiration, the heart rate increased and decreased with each respiratory cycle by as much as 30 per cent. Sinus arrhythmia can result from any one of many circulatory conditions that alter the strengths of the sympathetic and parasympathetic nerve signals to the heart sinus node. In the “respiratory” type of sinus arrhythmia, this results mainly from “spillover” of signals from the medullary respiratory center into the adjacent vasomotor center during inspiratory
and expiratory cycles of respiration.The spillover signals cause alternate increase and decrease in the number of impulses transmitted through the sympathetic and vagus nerves to the heart.

Abnormal Rhythms That Result from Block of Heart Signals Within the Intracardiac Conduction Pathways

Sinoatrial Block

In rare instances, the impulse from the sinus node is blocked before it enters the atrial muscle. This phenomenon is demonstrated in Figure, which shows
sudden cessation of P waves, with resultant standstill of the atria. However, the ventricles pick up a new rhythm, the impulse usually originating spontaneously in the atrioventricular (A-V) node, so that the rate of the ventricular QRS-T complex is slowed but not otherwise altered.

Atrioventricular Block

The only means by which impulses ordinarily can pass from the atria into the ventricles is through the A-V bundle, also known as the bundle of His. Conditions that can either decrease the rate of impulse conduction in this bundle or block the impulse entirely are as follows:

1. Ischemia of the A-V node or A-V bundle fibers
often delays or blocks conduction from the atria to
the ventricles. Coronary insufficiency can cause
ischemia of the A-V node and bundle in the same
way that it can cause ischemia of the myocardium.

2. Compression of the A-V bundle by scar tissue or by
calcified portions of the heart can depress or block
conduction from the atria to the ventricles.

3. Inflammation of the A-V node or A-V bundle can depress conductivity from the atria to the ventricles. Inflammation results frequently from different types of myocarditis, caused, for example, by diphtheria or rheumatic fever.

4. Extreme stimulation of the heart by the vagus nerves
in rare instances blocks impulse conduction
through the A-V node. Such vagal excitation
occasionally results from strong stimulation of the
baroreceptors in people with carotid sinus
syndrome, discussed earlier in relation to bradycardia.

Incomplete Atrioventricular Heart Block

Prolonged P-R (or P-Q) Interval—First Degree Block. The usual lapse of time between beginning of the P wave and beginning of the QRS complex is about 0.16 second when the heart is beating at a normal rate. This socalled P-R interval usually decreases in length with faster heartbeat and increases with slower heartbeat. In general, when the P-R interval increases to greater than 0.20 second, the P-R interval is said to be prolonged, and the patient is said to have first degree incomplete heart block.
Figure shows an electrocardiogram with prolonged

P-R interval; the interval in this instance is about 0.30 second instead of the normal 0.20 or less.Thus, first degree block is defined as a delay of conduction from the atria to the ventricles but not actual blockage of conduction. The P-R interval seldom increases above 0.35 to 0.45 second because, by that time, conduction through the A-V bundle is depressed so much that conduction stops entirely. One means for determining the severity of some heart diseases—acute rheumatic heart disease, for instance—is to measure the P-R interval.

Second Degree Block. When conduction through the A-V bundle is slowed enough to increase the P-R interval to 0.25 to 0.45 second, the action potential sometimes is strong enough to pass through the bundle into the ventricles and sometimes is not strong enough. In this instance, there will be an atrial P wave but no QRS-T wave, and it is said that there are “dropped beats” of the ventricles. This condition is called second degree heart block.
Figure shows P-R intervals of 0.30 second, as

well as one dropped ventricular beat as a result of failure of conduction from the atria to the ventricles. At times, every other beat of the ventricles is dropped, so that a “2:1 rhythm” develops, with the atria beating twice for every single beat of the ventricles.At other times, rhythms of 3:2 or 3:1 also develop.

Complete A-V Block (Third Degree Block). When the condition causing poor conduction in the A-V node or A-V bundle becomes severe, complete block of the impulse from the atria into the ventricles occurs. In this instance, the ventricles spontaneously establish their own signal, usually originating in the A-V node or A-V bundle. Therefore, the P waves become dissociated from the

QRS-T complexes, as shown in Figure.

Note that the rate of rhythm of the atria in this electrocardiogram is about 100 beats per minute, whereas the rate of ventricular beat is less than 40 per minute. Furthermore, there is no relation between the rhythm of the P waves and that of the QRS-T complexes because the ventricles have “escaped” from control by the atria, and they are beating at their own natural rate, controlled most often by rhythmical signals generated in the A-V node or A-V bundle.

Stokes-Adams Syndrome—Ventricular Escape. In some patients with A-V block, the total block comes and goes; that is, impulses are conducted from the atria into the ventricles for a period of time and then suddenly impulses are not conducted. The duration of block may be a few seconds, a few minutes, a few hours, or even weeks or longer before conduction returns. This condition occurs in hearts with borderline ischemia of the conductive system. Each time A-V conduction ceases, the ventricles often do not start their own beating until after a delay of 5 to 30 seconds. This results from the phenomenon called overdrive suppression. This means that ventricular excitability is at first in a suppressed state because the ventricles have been driven by the atria at a rate greater than their natural rate of rhythm. However, after a few seconds, some part of the Purkinje system beyond the block, usually in the distal part of the A-V node beyond the blocked point in the node, or in the A-V bundle, begins discharging rhythmically at a rate of 15 to 40 times per minute and acting as the pacemaker of the ventricles. This is called ventricular escape.

Because the brain cannot remain active for more than 4 to 7 seconds without blood supply, most patients faint a few seconds after complete block occurs because the
heart does not pump any blood for 5 to 30 seconds, until the ventricles “escape.” After escape, however, the slowly beating ventricles usually pump enough blood to
allow rapid recovery from the faint and then to sustain the person. These periodic fainting spells are known as the Stokes-Adams syndrome.
Occasionally the interval of ventricular standstill at the onset of complete block is so long that it becomes detrimental to the patient’s health or even causes death.
Consequently, most of these patients are provided with an artificial pacemaker, a small battery-operated electrical stimulator planted beneath the skin, with electrodes usually connected to the right ventricle. The pacemaker provides continued rhythmical impulses that take control of the ventricles.

Incomplete Intraventricular Block — Electrical Alternans

Most of the same factors that can cause A-V block can
also block impulse conduction in the peripheral ventricular
Purkinje system. Figure

shows the condition known as electrical alternans, which results from partial intraventricular block every other heartbeat. This electrocardiogram also shows tachycardia (rapid heart rate), which is probably the reason the block has occurred, because when the rate of the heart is rapid, it may be impossible for some portions of the Purkinje system to recover from the previous refractory period quickly enough to respond during every succeeding heartbeat. Also, many conditions that depress the heart, such as ischemia, myocarditis, or digitalis toxicity, can cause incomplete intraventricular block, resulting in electrical alternans.