Download Ischemic Heart Disease

Ischemic Heart Disease
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 (see Chapter 1 ).
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 (see Chapter 11 ).
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 comes 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.
IHD 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,[33][34] 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.[35][36] 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.
[37]
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).
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.
12-11 and Fig. 12-12 ).[38][39][40] 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.
Figure 12-11 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. (B, reproduced from Schoen FJ: Interventional and Surgical
Cardiovascular Pathology: Clinical Correlations and Basic Principles. Philadelphia, W.B.
Saunders, 1989, p. 61.)
Figure 12-12 Schematic representation of sequential progression of coronary artery lesion
morphology, beginning with stable chronic plaque responsible for typical angina and leading to
the various acute coronary syndromes. (Modified and redrawn from Schoen FJ:
Interventional and Surgical Cardiovascular Pathology: Clinical Correlations and Basic
Principles. Philadelphia, W.B. Saunders Co., 1989, p. 63.)
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.[41][42] 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.[43]
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 and the September 11, 2001 attacks in New York and Washington, DC.[44]
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%.[45] 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
[46][47]
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, E-selectin and P-selectin) in these cells. T cells located in the arterial wall
produce cytokines such as TNF, IL-6 and IFN-γ 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.[48] 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.[49][50] In some, but not all, studies CRP predicts risk independently from
risk estimates provided by serum lipid levels.[51][52][52a] 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 (see Chapter 11 ).
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 (see Chapter 11 ), and possibly (4) mediators released from perivascular
inflammatory cells.
To summarize ( Fig. 12-12 and Table 12-3 ), the acute coronary syndromes—angina, acute MI,
and sudden death—share a common pathophysiologic basis in coronary atherosclerotic plaque
disruption and associated intraluminal platelet-fibrin thrombus formation. The critical consequence
is downstream myocardial ischemia. Stable angina results from increases in myocardial oxygen
demand that outstrip the ability of markedly stenosed coronary arteries to increase oxygen delivery
but is not usually associated with plaque disruption. Unstable angina derives from a sudden
change in plaque morphology, which induces partially occlusive platelet aggregation or mural
thrombus, and vasoconstriction leading to severe but transient reductions in coronary blood flow. In
some cases, distal microinfarcts occur secondary to thromboemboli. In MI, acute plaque change
induces total thrombotic occlusion. Finally, sudden cardiac death frequently involves a coronary
lesion in which disrupted plaque and often partial thrombus and possibly embolus have led to
regional myocardial ischemia that induces a fatal ventricular arrhythmia. Each of these important
syndromes is discussed in detail first. Then we turn to the important consequences in the
myocardium.
Table 12-3
-- Coronary Artery Pathology in Ischemic Heart Disease
Syndrome
Plaque
Stenoses
Plaque-Associated Thrombus
Disruption
Stable angina
>75%
No
No
Unstable angina
Variable
Frequent
Nonocclusive, often with thromboemboli
Variable
Frequent
Occlusive
Variable
Variable
Transmural myocardial
infarction
Subendocardial myocardial
infarction
Sudden death
Usually
severe
Frequent
Widely variable, may be absent,
partial/complete, or lysed
Often small platelet aggregates or thrombi
and/or thromboemboli
ANGINA PECTORIS
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 coronary 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.
MYOCARDIAL INFARCTION (MI)
MI, also known as "heart attack," is the death of cardiac muscle 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 predispositionsto 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.[53]
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.[54] 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 ( Fig. 12-13 ), which induces profound functional, biochemical, and morphologic
consequences. Occlusion of a major coronary artery results in ischemia and, potentially, cell death
throughout 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.
Figure 12-13 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. Photograph courtesy of Lewis L. Lainey.
(Reproduced by permission from Schoen FJ: Interventional and Surgical Cardiovascular
Pathology: Clinical Correlations and Basic Principles. Philadelphia, WB Saunders, 1989, p.
60.)
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).[56] With prolonged ischemia, injury to the microvasculature then follows. This time frame is
summarized in Table 12-4 .
Table 12-4
-- Approximate Time of Onset of Key Events in Ischemic Cardiac Myocytes
Feature
Time
Onset of ATP depletion Seconds
Loss of contractility
<2 min
ATP reduced
to 50% of normal
10 min
to 10% of normal
40 min
Irreversible cell injury
20–40 min
Microvascular injury
>1 hr
ATP, adenosine triphosphate.
Thus, myocardial necrosis begins at approximately 30 minutes after coronary occlusion. Classic
acute MI with extensive damage occurs when the perfusion of the myocardium is reduced severely
below its needs for an extended interval (usually at least 2 to 4 hours), causing profound,
prolonged ischemia and resulting in permanent loss of function of large regions in which cell death
has occurred. The predominant mechanism of cell death is coagulation necrosis; apoptosis may
also be important, but this is as yet uncertain. In contrast, if restoration of myocardial blood flow
(known as reperfusion) follows briefer periods of flow deprivation (less than 20 minutes in the most
severely ischemic myocardium), loss of cell viability can be prevented. This provides the rationale
for the very early clinical detection of acute MI—to permit early therapy such as thrombolysis,
establish reperfusion of the area at risk, salvage as much ischemic but not yet dead myocardium
as possible, and consequently minimize infarct size.
Myocardial ischemia contributes to arrhythmias through complex and poorly understood
mechanisms, probably involving electrical instability (irritability).[56] Sudden death, a leading cause
of mortality in IHD patients, can be caused by massive cell injury with mechanical failure but is
most often due to ventricular fibrillation caused by myocardial irritability induced by ischemia or
infarction. Interestingly, studies of resuscitated survivors of "sudden death" show that the majority
do not develop acute MI; in such cases, myocardial irritability induced by ischemia presumably led
directly to the serious arrhythmia.
The progression of ischemic necrosis in the myocardium is summarized in Figure 12-14 .
Irreversible injury of ischemic myocytes occurs first in the subendocardial zone. With more
extended ischemia, a wavefront 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.
Figure 12-14 Schematic representation of the progression of myocardial necrosis after
coronary artery occlusion. Necrosis begins in a small zone of the myocardium beneath the
endocardial surface in the center of the ischemic zone. This entire region of myocardium
(shaded) depends on the occluded vessel for perfusion and is the area at risk. Note that a very
narrow zone of myocardium immediately beneath the endocardium is spared from necrosis
because it can be oxygenated by diffusion from the ventricle. The end result of the obstruction
to blood flow is necrosis of the muscle that was dependent on perfusion from the coronary
artery obstructed. Nearly the entire area at risk loses viability. The process is called myocardial
infarction, and the region of necrotic muscle is a myocardial infarct.
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.
Morphology.
The evolution of the morphologic changes in acute MI and its healing are summarized in Table
12-5 .
Table 12-5
Time
-- Evolution of Morphologic Changes in Myocardial Infarction
Gross Features
Light Microscope
Electron Microscope
Reversible Injury
Relaxation of
0–? hr
None
None
myofibrils; glycogen
loss; mitochondrial
swelling
Irreversible Injury
Sarcolemmal
?–4 hr
None
Usually none; variable waviness of fibers at
disruption;
border
mitochondrial
amorphous densities
4–12
Occasionally dark
Beginning coagulation necrosis; edema;
hr
mottling
hemorrhage
Ongoing coagulation necrosis; pyknosis of
12–24
hr
Dark mottling
nuclei; myocyte hypereosinophilia; marginal
contraction band necrosis; beginning
neutrophilic infiltrate
1–3
Mottling with yellow-tan Coagulation necrosis, with loss of nuclei and
days
infarct center
striations; interstitial infiltrate of neutrophils
Hyperemic border;
Beginning disintegration of dead myofibers,
central yellow-tan
with dying neutrophils; early phagocytosis of
softening
dead cells by macrophages at infarct border
3–7
days
Maximally yellow-tan
7–10
and soft, with
days
depressed red-tan
margins
Well-developed phagocytosis of dead cells;
early formation of fibrovascular granulation
tissue at margins
10–14
Red-gray depressed
Well-established granulation tissue with new
days
infarct borders
blood vessels and collagen deposition
Time
Gross Features
Light Microscope
Electron Microscope
Gray-white scar,
2–8 wk
progressive from
Increased collagen deposition, with
border toward core of
decreased cellularity
infarct
>2 mo
Scarring complete
Dense collagenous scar
Nearly all transmural infarcts involve at least a portion of the left ventricle (including the ventricular
septum). About 15% to 30% of those that affect the posterior free wall and posterior portion of the
septum transmurally extend into the adjacent right ventricular wall. Isolated infarction of the right
ventricle, however, occurs in only 1% to 3% of cases. Associated infarction of atrial tissue
accompanies a large posterior left ventricular infarct in some cases. Transmural infarcts usually
encompass nearly the entire perfusion zone of the occluded coronary artery. Almost always there
is a narrow rim (approximately 0.1 mm) of preserved subendocardial myocardium sustained by
diffusion of oxygen and nutrients from the lumen.
The frequencies of critical narrowing (and thrombosis) of each of the three main arterial trunks and
the corresponding sites of myocardial lesions resulting in infarction (in the typical right dominant
heart) are as follows:
?
Left anterior descending coronary artery (40% to 50%): infarct involves anterior wall of left
ventricle near apex; anterior portion of ventricular septum; apex circumferentially
?
Right coronary artery (30% to 40%): infarct involves inferior/posterior wall of left ventricle;
posterior portion of ventricular septum; inferior/posterior right ventricular free wall in some
cases
?
Left circumflex coronary artery (15% to 20%): infarct involves lateral wall of left ventricle
except at apex
Other locations of critical coronary arterial lesions causing infarcts are sometimes encountered,
such as the left main coronary artery or the secondary branches (e.g., diagonal branches of the
LAD artery or marginal branches of the LCX artery). In contrast, stenosing atherosclerosis or
thrombosis of a penetrating intramyocardial branch of the coronary arteries is almost never
encountered. Occasionally the observation of multiple severe stenoses or thromboses in the
absence of myocardial damage suggests that formation of collateral connections between
coronary arteries was protective.
The gross and microscopic appearance of an infarct at autopsy depends on the duration of survival
of the patient following the MI. Areas of damage undergo a progressive sequence of morphologic
changes that consist of typical ischemic coagulative necrosis, followed by inflammation and repair
that closely parallels that occurring after injury at other, noncardiac sites.
Early recognition of acute myocardial infarcts by pathologists can be difficult, particularly when
death has occurred within a few hours after the onset of symptoms.
[57]
Myocardial infarcts less than
12 hours old are usually not apparent on gross examination. It is often possible, however, to
highlight the area of necrosis that first becomes apparent after 2 to 3 hours after the infarct, by
immersion of tissue slices in a solution of triphenyltetrazolium chloride (TTC). This histochemical
stain imparts a brick-red color to intact, noninfarcted myocardium where the dehydrogenase
enzymes are preserved. Because dehydrogenases are depleted in the area of ischemic necrosis
(they leak out through the damaged cell membranes), an infarcted area is revealed as an
unstained pale zone (while old scarred infarcts appear white and glistening) ( Fig. 12-15 ).
Subsequently, by 12 to 24 hours, an infarct can be identified in routinely fixed gross slices owing to
a red-blue hue caused by stagnated, trapped blood. Progressively thereafter, the infarct becomes
a more sharply defined, yellow-tan, somewhat softened area that by 10 days to 2 weeks is rimmed
by a hyperemic zone of highly vascularized granulation tissue. Over the succeeding weeks, the
injured region evolves to a fibrous scar.
Figure 12-15 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.)
The histopathologic changes also have a fairly predictable sequence (summarized in Table 12-5
and Figure 12-16 ). Using light microscopic examination of routinely stained tissue sections, the
typical changes of coagulative necrosis become detectable variably in the first 4 to 12 hours.
"Wavy fibers" may be present at the periphery of the infarct; these changes probably result from
the forceful systolic tugs by the viable fibers immediately adjacent to the noncontractile dead fibers,
thereby stretching and buckling them. An additional but sublethal ischemic change may be seen in
the margins of infarcts: so-called vacuolar degeneration or myocytolysis, involving large vacuolar
spaces within cells, probably containing water. This potentially reversible alteration is particularly
frequent in the thin zone of viable subendocardial cells. Subendocardial myocyte vacuolization in
other contexts may signify severe chronic ischemia.
Figure 12-16 Microscopic features of myocardial infarction and its repair. A, One-day-old
infarct showing coagulative necrosis along with wavy fibers (elongated and narrow), compared
with adjacent normal fibers (at right). Widened spaces between the dead fibers contain edema
fluid and scattered neutrophils. B, Dense polymorphonuclear leukocytic infiltrate in area of
acute myocardial infarction of 3 to 4 days' duration. C, Nearly complete removal of necrotic
myocytes by phagocytosis (approximately 7 to 10 days). D, Granulation tissue characterized
by loose collagen and abundant capillaries. E, Well-healed myocardial infarct with
replacement of the necrotic fibers by dense collagenous scar. A few residual cardiac muscle
cells are present.
The necrotic muscle elicits acute inflammation (typically most prominent at 2 to 3 days). Thereafter
macrophages remove the necrotic myocytes (most pronounced at 5 to 10 days), and the damaged
zone is progressively replaced by the ingrowth of highly vascularized granulation tissue (most
prominent at 2 to 4 weeks), which progressively becomes less vascularized and more fibrous. In
most instances, scarring is well advanced by the end of the sixth week, but the efficiency of repair
depends on the size of the original lesion. As healing requires the participation of inflammatory
cells that migrate to the region of damage through intact blood vessels, which often survive only at
the infarct margins, the infarct heals from its borders toward the center. Thus, a large infarct may
not heal as readily nor as completely as a small one. A healing infarct may appear nonuniform, with
the most advanced healing at the periphery. Once a lesion is completely healed, it is impossible to
distinguish its age (i.e., the dense fibrous tissue scar of an 8-week-old and a 10-year-old lesion
may look similar).
Several infarcts of varying age are frequently found in the same heart. Repetitive necrosis of
adjacent regions yields progressive extension of an individual infarct over a period of days to
weeks. Examination of the heart in such cases often reveals a central zone of repairing infarct that
is days to weeks older and whose healing is more advanced than that of a peripheral margin of
more recent ischemic necrosis. This contrasts with the appearance of a single-event infarct
described above, in which the most advanced repair was peripheral. An initial infarct may extend
because of retrograde propagation of a thrombus, proximal vasospasm, progressively impaired
cardiac contractility that renders flow through moderate stenoses critically insufficient, the
development of platelet-fibrin microemboli, the appearance of an arrhythmia that impairs cardiac
function, or poor perfusion owing to progressively impaired myocardial function. In general, the
sequential morphology of evolving subendocardial and transmural infarcts is qualitatively similar,
but subendocardial infarcts tend to be smaller.
The temporal sequence of morphologic events in MI is summarized in Figure 12-17 , emphasizing
the possibility of interventions that might limit infarct size, since myocardium that is not yet necrotic
is potentially salvageable.
Figure 12-17 Temporal sequence of early biochemical, ultrastructural, histochemical, and
histologic findings after onset of severe myocardial ischemia. For approximately 30 minutes
after the onset of even the most severe ischemia, myocardial injury is potentially reversible.
Thereafter, progressive loss of viability occurs that is complete by 6 to 12 hours. The benefits
of reperfusion are greatest when it is achieved early, with progressively smaller benefit
occurring as reperfusion is delayed. (Modified with permission from Antman E: Acute
myocardial infarction. In Braunwald E, Zipes DP, Libby P (eds): Heart Disease: A Textbook of
Cardiovascular Medicine, 6th ed. Philadelphia, WB Saunders, 2001, pp. 1114–1231.)
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 12-18 . 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 long-term function and survival.[58] 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 occlusion is alleviated; the first 3 to 4 hours following
onset of 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.[59] CABG provides flow around it.
Figure 12-18 Consequences of myocardial ischemia followed by reperfusion. A, 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. B, Gross and C, microscopic
appearance of myocardium modified by reperfusion. B, Large, densely hemorrhagic, anterior
wall acute myocardial infarction from patient with left anterior descending artery thrombus
treated with streptokinase intracoronary thrombolysis (triphenyl tetrazolium chloride-stained
heart slice). (Specimen oriented with posterior wall at top.) C, Myocardial necrosis with
hemorrhage and contraction bands, visible as dark bands spanning some myofibers (arrow).
This is the characteristic appearance of markedly ischemic myocardium that has been
reperfused.
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. As indicated in Figure 12-18A , 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.
The typical appearance of ischemic then reperfused myocardium is illustrated in Figure 12-18B
and C . 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).[60][61] The clinical significance of myocardial reperfusion injury
is uncertain. As discussed in Chapter 1 , 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 may be a potential therapeutic target to limit
reperfusion injury.[62] 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.
[63]
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.[64] 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" MIs 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.[65] 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 (CK-MB) 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; CK-BB 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.[49][50] 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.
[51][52]
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 following (some of which are illustrated in Fig. 12-19 ):
?
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. MI-associated
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 (see Fig. 12-19A ); (2) rupture of the ventricular septum (less commonly), leading to a
left-to-right shunt (see Fig. 12-19B ); and (3) papillary muscle rupture (least commonly),
resulting in the acute onset of severe mitral regurgitation (see Fig. 12-19C ). 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.[66]
?
Pericarditis. A fibrinous or fibrohemorrhagic pericarditis usually develops about the second or
third day following a transmural infarct and usually resolves over time (see Fig. 12-19D ).
Pericarditis is the epicardial manifestation of the underlying myocardial inflammation.
?
Right ventricular infarction. Although isolated infarction of the right ventricle is unusual,
infarction of the right ventricular myocardium often accompanies ischemic injury of the
adjacent posterior left ventricle and ventricular septum. A right ventricular infarct of either type
can yield serious functional impairment.
?
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 ).
?
Mural thrombus. With any infarct, the combination of a local myocardial abnormality in
contractility (causing stasis) with endocardial damage (causing a thrombogenic surface) can
foster mural thrombosis ( Chapter 4 ) and, potentially, thromboembolism.
?
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 (see Fig. 12-19F ). Complications of
ventricular aneurysms include mural thrombus, arrhythmias and heart failure, but rupture of
the fibrotic wall does not occur.
?
Papillary muscle dysfunction. As 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 (see below).
?
Progressive late heart failure is discussed as chronic IHD below.
Figure 12-19 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. D, Fibrinous pericarditis,
showing a dark, roughened epicardial surface overlying an acute infarct. E, Early expansion of
anteroapical infarct with wall thinning (arrow) and mural thrombus. F, Large apical left
ventricular aneurysm. The left ventricle is on the right in this apical four-chamber view of the
heart. (A–E, Reproduced by permission from Schoen FJ: Interventional and Surgical
Cardiovascular Pathology: Clinical Correlations and Basic Principles, Philadelphia, WB
Saunders, 1989.) (F, Courtesy of William D. Edwards, M.D., Mayo Clinic, Rochester, MN.)
The propensity toward specific complications and the prognosis after MI 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 septal 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.[67][68][69] 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 reinfarction in those who have recovered
from an acute MI (secondary prevention) are important strategies that have received much
attention and have achieved considerable success.
CHRONIC ISCHEMIC HEART 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.
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.
Morphology.
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.
SUDDEN CARDIAC DEATH
This catastrophe strikes down about 300,000 to 400,000 individuals annually in the United States.
Sudden cardiac death (SCD) is most commonly defined as unexpected death from cardiac causes
early after symptom onset (usually within 1 hour) or without the onset of symptoms. In many adults,
SCD is a complication and often the first clinical manifestation of IHD. With decreasing age of the
victim, the following nonatherosclerotic causes of SCD become increasingly probable:[70][71]
?
Congenital structural or coronary arterial abnormalities
?
Aortic valve stenosis
?
Mitral valve prolapse
?
Myocarditis
?
Dilated or hypertrophic cardiomyopathy
?
Pulmonary hypertension
?
Hereditary or acquired abnormalities of the cardiac conduction system
?
Isolated hypertrophy, hypertensive or unknown cause. Increased cardiac mass is an
independent risk factor for cardiac death; thus, some young patients who die suddenly,
including athletes, have hypertensive hypertrophy or unexplained increased cardiac mass as
the only finding.
The ultimate mechanism of SCD is most often a lethal arrhythmia (e.g., asystole, ventricular
fibrillation). Although ischemic injury can impinge on the conduction system and create
electromechanical cardiac instability, in most cases the fatal arrhythmia is triggered by electrical
irritability of myocardium that may be distant from the conduction system, induced by ischemia or
other cellular abnormalities. The prognosis of patients vulnerable to SCD, especially those with
chronic IHD, is markedly improved by implantation of an automatic cardioverter defibrillator, which
senses and electrically counteracts an episode of ventricular fibrillation.[72]
Arrhythmias that occur in the absence of structural cardiac pathology can also precipitate sudden
death. The most important cause is the autosomal dominant long QT syndrome (Romano-Ward
syndrome), which causes heightened cardiac excitability and episodic ventricular arrhythmias.
Mutations causing this disorder have been demonstrated in at least five different genes that
encode components of cardiac ion channels including potassium and sodium channels.[73]
Morphology.
Marked coronary atherosclerosis with critical (>75%) stenosis involving one or more of the three
major vessels is present in 80% to 90% of SCD victims; only 10% to 20% of cases are of
nonatherosclerotic origin. Usually there are high-grade stenoses (>90%), and acute plaque
disruption is common. A healed myocardial infarct is present in about 40%, but in those who were
successfully resuscitated from sudden cardiac arrest, new MI is found in only 25% or less.
Subendocardial myocyte vacuolization indicative of severe chronic ischemia is common.
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