Incidence.

With an incidence of approximately 1% (estimates range from 4 to 50 per 1000 live births), congenital cardiovascular defects are among the most prevalent malformations and are the most common type of heart disease among children.²⁴ 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.

TABLE 12-2 Frequencies of Congenital Cardiac Malformations^*

* Presented as upper quartile of 44 published studies. Percentages do not add up to 100% because of rounding.

Source: Hoffman JIE, Kaplan S: The incidence of congenital heart disease. J Am Coll Cardiol 39:1890, 2002.

The number of individuals who have survived with congenital heart disease into adulthood is increasing rapidly and is presently estimated at nearly 1 million individuals in the United States.²⁵ Many of those with congenital heart disease have benefited greatly from rapid advances in the surgical and interventional repair of various structural heart defects. Nevertheless, such repairs may not restore the heart to normal; in such instances, patients may suffer from arrhythmias or ventricular dysfunction, and require additional surgery.²⁶ Other factors that impact the long-term outcome include risks associated with the use of prosthetic materials and devices,²⁷ such as substitute valves or myocardial patches, and maternal risks associated with childbearing.²⁸

Cardiac Development.

The diverse malformations seen in congenital heart disease are caused by errors that occur during cardiac development; thus, a brief review how the heart normally forms is in order before discussing the specific defects (Fig. 12-3). The fine details of this complex process are beyond our scope here. Suffice it to say that the earliest cardiac precursors originate in lateral mesoderm and move to the mid-line in two migratory waves to create a crescent of cells consisting of the first and second heart fields by about day 15 of development.^29,30 Each heart field is marked by the expression of different sets of genes; for example, the first heart field expresses the transcription factors TBX5 and Hand1, whereas the second heart field expresses the transcription factor Hand2 and fibroblast growth factor-10. Both fields contain multipotent progenitor cells that can produce all of the major cell types of the heart; endocardium, myocardium, and smooth muscle cells. As an aside, there is considerable interest in the therapeutic potential of such early cardiac progenitors, which could conceivably be used to regenerate portions of the adult heart that are damaged or otherwise dysfunctional.

FIGURE 12-3 Human cardiac development, emphasizing the three sources of cells. A, Day 15. First heart field (FHF) cells (shown in red) form a crescent shape in the anterior embryo with second heart field (SHF) cells (shown in yellow) near the FHF. B, Day 21. SHF cells lie dorsal to the straight heart tube and begin to migrate (arrows) into the anterior and posterior ends of the tube to form the right ventricle (RV), conotruncus (CT), and part of the atria (A). C, Day 28. Following rightward looping of the heart tube, cardiac neural crest cells (shown in blue) also migrate (arrow) into the outflow tract from the neural folds to septate the outflow tract and pattern the bilaterally symmetric aortic arch arteries (III, IV, and VI). D, Day 50. Septation of the ventricles, atria, and atrioventricular valves (AVV) results in the appropriately configured four-chambered heart. Ao, aorta; AS, aortic sac; DA, ductus arteriosus; LA, left atrium; LCA, left carotid artery; LSCA, left subclavian artery; LV, left ventricle; PA, pulmonary artery; RA, right atrium; RCA, right carotid artery; RSCA, right subclavian artery; V, ventricle.

(Modified by permission from Srivastava D: Making or breaking the heart: from lineage determination to morphogenesis. Cell 126:1037, 2006.)

Even at this very early stage of development, each heart field is destined to give rise to particular portions of the heart. Cells derived from the first heart field mainly give rise to the left ventricle, whereas cells derived from the second heart field give rise to the outflow tract, right ventricle, and most of the atria. By day 20, the initial cell crescent develops into a beating tube, which loops to the right and begins to form the heart chambers by day 28. Around this time, two other critical events occur: (1) cells derived from the neural crest migrate into the outflow tract, where they participate in the septation of the outflow tract and the formation of the aortic arches; and (2) the extracellular matrix (ECM) underlying the future atrioventricular canal and outflow tract enlarges to produce swellings known as endocardial cushions. This process depends on the delamination of a subset of endocardial cells, which invade the ECM and subsequently proliferate and differentiate into the mesenchymal cells that are responsible for valve development. By day 50, further septation of the ventricles, atria, and atrioventricular valves produces the fourchambered heart.

Proper orchestration of these remarkable transformations depends on a network of transcription factors that are regulated by a number of signaling pathways, particularly the Wnt, VEGF, bone morphogenetic factor, TGF-β, fibroblast growth factor, and Notch pathways. It should also be remembered that the heart is a mechanical organ that is exposed to flowing blood from its earliest stages of development. It is likely that hemodynamic forces play an important role in cardiac development, just as they influence adaptations in the adult heart such as hypertrophy and dilation. In addition, specific micro-RNAs play critical roles in cardiac development by coordinating patterns and levels of transcription factor expression.¹⁸

Many of the genetic defects that affect heart development are autosomal dominant mutations that cause partial loss of function in one or another required factor, which are often transcription factors (discussed below). Thus, even relatively minor changes in the activity of one of the many factors necessary for normal development can lead to defects in the final product, the fully developed heart. It can be imagined (but is unproved) that transient environmental stresses during the first trimester of pregnancy that alter the activity of these same genes might give rise to defects resembling those produced by inherited mutations.

Etiology and Pathogenesis.

The main known causes of congenital heart disease consist of sporadic genetic abnormalities, which can take the form of single gene mutations, small chromosomal deletions, and additions or deletions of whole chromosomes (trisomies and monosomies). In the case of single gene mutations, the affected genes encode proteins belonging to several different functional classes, examples of which are provided in Table 12-3. Many of these mutations affect genes encoding transcription factors that are required for normal heart development. Since the affected patients are heterozygous for these mutations, it follows that a 50% reduction in the activity of these factors is probably sufficient to derange cardiac development. Some of the affected transcription factors appear to work together in large protein complexes, providing an explanation for why mutations in any one of several genes produce similar defects. For example, GATA4, TBX5, and NKX2-5, three transcription factors that are mutated in some patients with atrial and ventricular septal defects, all bind to one another and co-regulate the expression of target genes that are required for the proper development of the heart. Of further interest, GATA4 and TBX20 are also mutated in rare forms of adult-onset cardiomyopathy (discussed later), indicating that they are not only important developmentally but are also needed to maintain the function of the postnatal heart.

TABLE 12-3 Selected Examples of Genetic Causes of Congenital Heart Disease

Other single gene mutations associated with congenital heart disease affect proteins within signaling pathways or that have structural roles. Mutations in genes encoding various components of the Notch pathway, such as JAGGED1, NOTCH1, and NOTCH2, are associated with a number of different congenital heart defects, including bicuspid aortic valve (NOTCH1, discussed later) and Tetralogy of Fallot (JAGGED1 and NOTCH2).^29,30 As you will recall from Chapter 11, fibrillin mutations underlie Marfan syndrome, which is associated with valvular defects and aortic aneurysms. Although fibrillin was initially described as a structural protein, it is also an important negative regulator of TGFβ signaling, and hyperactive TGFβ signaling is at least partially responsible for the cardiovascular abnormalities in Marfan syndrome.

A notable example of a small chromosomal lesion that causes congenital heart disease is deletion of chromosome 22q11.2, which is found in up to 50% of patients with DiGeorge syndrome. In this syndrome the fourth branchial arch and the derivatives of the third and fourth pharyngeal pouches, which contribute to the formation of the thymus, parathyroids, and heart, develop abnormally. One candidate gene in the deleted region is TBX1, which encodes a transcription factor that regulates the expansion of cardiac progenitors in the second heart field. Other important genetic causes of congenital heart disease include chromosomal aneuplodies, particularly Turner syndrome (monosomy X) and trisomies 13, 18, and 21.³¹ Indeed, the most common genetic cause of congenital heart disease is trisomy 21 (Down syndrome),³² in which about 40% of patients have one or more heart defects, most often affecting structures derived from the endocardial cushions (e.g., the atrioventricular septae and valves). The mechanisms by which aneuploidy leads to congenital heart defects remain largely unknown, but are likely to involve the dysregulated expression of multiple genes.

Beyond these known associations, more subtle forms of genetic variation probably also contribute to congenital heart disease. This assertion is based in part on the recognition that first-degree relatives of affected patients are at increased risk for congenital heart defects compared to the general population. For example, a child of a father with a VSD has a risk of 2%; if the VSD occurred in the mother, the risk to her offspring is 6% to 10%.

Despite these genetic clues, it must be acknowledged that our understanding of the mechanisms that lead to heart defects remains rudimentary. Most affected patients have no identifiable genetic risk factor, and even in those that do, the nature and severity of the defect are highly variable. As a result, it is thought that environmental factors, alone or in combination with genetic factors, also contribute to congenital heart disease and in some cases may be the primary cause. Examples of known exposures that are associated with heart defects include congenital rubella infection, gestational diabetes, and exposure to teratogens (including some therapeutic drugs).³³ There is also great interest in identifying nutritional factors that may modify risk. For instance, intake of multivitamin supplements containing folate may reduce the risk of congenital heart defects.³⁴

Clinical Features.

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

A shunt is an abnormal communication between chambers or blood vessels. Abnormal channels permit the flow of blood down pressure gradients from the left (systemic) side to the right (pulmonary) side of the circulation or vice versa. When blood from the right side of the circulation flows directly into the left side (right-to-left shunt), hypoxemia and cyanosis (a dusky blueness of the skin and mucous membranes) result because of the admixture of poorly oxygenated venous blood with systemic arterial blood (called cyanotic congenital heart disease). The most important congenital causes of right-to-left 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, emboli arising in peripheral veins can bypass the lungs and directly enter the systemic circulation (paradoxical embolism); brain infarction and abscess are potential consequences. Severe, long-standing cyanosis also causes clubbing of the tips of the fingers and toes (called hypertrophic osteoarthropathy) and polycythemia.

In contrast, left-to-right shunts (such as ASD, VSD, and patent ductus arteriosus) increase pulmonary blood flow and are not initially associated with cyanosis. However, leftto-right shunts raise both flow volumes and pressures in the normally low-pressure, low-resistance pulmonary circulation, which can lead to right ventricular hypertrophy and atherosclerosis of the pulmonary vasculature. The muscular pulmonary arteries (<1 mm diameter) first respond to increased pressure and flow by undergoing medial hypertrophy and vasoconstriction, which maintains relatively normal distal pulmonary capillary and venous pressures, and prevents pulmonary edema. Prolonged pulmonary arterial vasoconstriction, however, stimulates the proliferation of the vascular wall cells and the consequent development of irreversible obstructive intimal lesions analogous to the arteriolar changes seen in systemic hypertension (Chapter 11). Eventually, pulmonary vascular resistance approaches systemic levels, thereby producing a new right-to-left shunt that introduces unoxygenated blood into the systemic circulation (late cyanotic congenital heart disease, or Eisenmenger syndrome).

Once 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 provides the rationale for early intervention, either surgical or nonsurgical, in those with left-to-right shunts.

Some developmental anomalies of the heart (e.g., coarctation of the aorta, aortic valvular stenosis, and pulmonary valvular stenosis) produce 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) and a shunt (right-to-left through a VSD) are both present.

The altered hemodynamics of congenital heart disease usually cause cardiac dilation or hypertrophy (or both). However, some defects induce a decrease in the volume and muscle mass of a cardiac chamber; this is called hypo-plasia if it occurs before birth and atrophy if it develops postnatally.

Clinical Features.

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 two to four times normal. A murmur is often present as a result of excessive flow through the pulmonary valve. Despite the right-sided volume overload, ASDs are generally well tolerated and usually do not become symptomatic before age 30; irreversible pulmonary hypertension is unusual. Surgical or catheter-based closure of an ASD reverses the hemodynamic abnormalities and prevents complications, including heart failure, paradoxical embolization, and irreversible pulmonary vascular disease.³⁶ Mortality is low, and long-term survival is comparable to that of a normal population.

Clinical Features.

The functional consequences of a VSD depend on the size of the defect and whether there are associated with right-sided malformations. Large VSDs cause difficulties virtually from birth; smaller lesions are generally well tolerated for years, and may not be recognized until much later in life. Approximately 50% of small muscular VSDs close spontaneously.³⁹ Large defects are usually membranous or infundibular, and they generally cause significant left-to-right shunting, leading to right ventricular hypertrophy and pulmonary hypertension virtually from birth. Over time, irreversible pulmonary vascular disease develops in essentially all persons with large unclosed VSDs, ultimately resulting in shunt reversal, cyanosis, and death. Surgical or catheter-based closure of asymptomatic VSDs is generally delayed beyond infancy, in hope of spontaneous closure. Early correction, however, must be performed in babies with large defects to prevent the development of irreversible obstructive pulmonary vascular disease.

Clinical Features.

Even untreated, some patients with TOF survive into adult life (in reports of untreated patients with this condition, 10% were alive at 20 years and 3% at 40 years).⁴⁹ The clinical consequences depend primarily on the severity of the subpulmonary stenosis, as this 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 right-sided pressures approach or exceed left-sided pressures, right-to-left shunting develops, producing cyanosis (classic TOF). With increasingly severe subpulmonic stenosis, the pulmonary arteries become progressively smaller and thinner walled (hypoplastic), and the aorta grows 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. Most infants with TOF 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 by the shunting of blood into the left ventricle and aorta. Complete surgical repair is possible for classic TOF but is more complicated for persons with pulmonary atresia and dilated bronchial arteries.

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. As troublesome as these numbers may be, they represent an improvement over those that prevailed 2 to 3 decades ago. Since its peak in 1963, the overall death rate from IHD has fallen in the United States by approximately 50%. This remarkable improvement has resulted primarily from (1) prevention, achieved by modification of important risk factors, such as smoking, elevated blood cholesterol, and hypertension, and (2) diagnostic and therapeutic advances, allowing earlier, more effective, and safer treatments. The latter include new medications, coronary care units, thrombolysis for MI, percutaneous transluminal coronary angioplasty, endovascular stents, coronary artery bypass graft (CABG) surgery, and improved control of heart failure and arrhythmias. Additional risk reduction may potentially be achieved by maintenance of normal blood glucose levels in diabetic patients, control of obesity, and prophylactic anticoagulation of middle-aged men with aspirin. Nevertheless, continuing this encouraging trend in the 21st century will be challenging, in view of the predicted doubling of the number of individuals over age 65 by 2050 and the increased longevity of “baby boomers,” the “obesity epidemic,” and other factors. Interestingly, the genetic determinants of coronary atherosclerosis and IHD may not be identical, since MI occurs in only a small fraction of individuals with coronary disease. For example, the risk of MI but not coronary atherosclerosis is associated with genetic variants that modify leukotriene B4 metabolism.⁴⁴

Pathogenesis.

The dominant cause of the IHD syndromes is insufficient coronary perfusion relative to myocardial demand, due to chronic, progressive atherosclerotic narrowing of the epicardial coronary arteries, and variable degrees of superimposed acute plaque change, thrombosis, and vasospasm. The individual elements and their interactions are discussed below.

Chronic Atherosclerosis.

More than 90% of patients with IHD have atherosclerosis of one or more of the epicardial coronary arteries. The clinical manifestations of coronary atherosclerosis are generally due to progressive narrowing of the lumen leading to stenosis (“fixed” obstructions) or to acute plaque disruption with thrombosis, both of which compromise blood flow. A fixed lesion obstructing 75% or greater of the lumen is generally required to cause symptomatic ischemia precipitated by exercise (most often manifested as chest pain, known as angina); with this degree of obstruction, compensatory coronary arterial vasodilation is no longer sufficient to meet even moderate increases in myocardial demand. Obstruction of 90% of the lumen can lead to inadequate coronary blood flow even at rest. The progressive myocardial ischemia induced by slowly developing occlusions may stimulate the formation of collateral vessels over time, which can protect against myocardial ischemia and infarction and mitigate the effects of high-grade stenoses.⁴⁵

Although only a single major coronary epicardial trunk may be affected, two or all three—the left anterior descending (LAD), the left circumflex (LCX), and the right coronary artery (RCA)—are often involved by atherosclerosis. 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 (penetrating) branches is rare.

Acute Plaque Change.

The risk of an individual developing clinically important IHD depends in part on the number, distribution, structure, and degree of obstruction of atheromatous plaques. However, the varied clinical manifestations of IHD cannot be explained by the anatomic disease burden alone. This is particularly true for the so-called acute coronary syndromes, unstable angina, acute MI, and sudden death. The acute coronary syndromes are typically initiated by an unpredictable and abrupt conversion of a stable atherosclerotic plaque to an unstable and potentially life-threatening atherothrombotic lesion through rupture, superficial erosion, ulceration, fissuring, or deep hemorrhage (Chapter 11). In most instances, the plaque change causes the formation of a superimposed thrombus that partially or completely occludes the affected artery.^{46, 47} These acute events are often associated with intralesional inflammation, which you will remember mediates the initiation, progression, and acute complications of atherosclerosis (discussed in Chapter 11). For purposes of simplicity, the spectrum of acute alterations in atherosclerotic lesions will be termed either plaque disruption or plaque change.

Consequences of Myocardial Ischemia.

In each syndrome the critical consequence is downstream myocardial ischemia. Stable angina results from increases in myocardial oxygen demand that outstrip the ability of stenosed coronary arteries to increase oxygen delivery; it is usually not associated with plaque disruption. Unstable angina is caused by plaque rupture complicated by partially occlusive thrombosis and vasoconstriction, which lead to severe but transient reductions in coronary blood flow. In some cases, microinfarcts can occur distal to disrupted plaques due to thromboemboli. In MI, acute plaque change induces total thrombotic occlusion and the subsequent death of heart muscle. Finally, sudden cardiac death frequently involves an atherosclerotic lesion in which a disrupted plaque causes regional myocardial ischemia that induces a fatal ventricular arrhythmia. Each of these important syndromes is discussed in detail below, followed by an examination of the important myocardial consequences.

Incidence and Risk Factors.

MI can occur at virtually any age, but its frequency rises progressively with increasing age and when predispositions to atherosclerosis are present. 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 than women.⁴⁹ Indeed, except for those having some predisposing atherogenic condition, women are protected against MI and other heart diseases during the reproductive years. However, the decrease of estrogen following menopause is associated with rapid development of CAD, and IHD is the most common cause of death in elderly women. Postmenopausal hormonal replacement therapy is not currently felt to protect against atherosclerosis and IHD (Chapter 11).⁵⁰

Pathogenesis.

We now consider the basis for and consequences of myocardial ischemia.

Myocardial Response.

Coronary arterial obstruction compromises the blood supply to a region of myocardium (Fig. 12-10), causing ischemia, myocardial dysfunction, and potentially myocyte death. The anatomic region supplied by that artery is referred to as the area at risk. The outcome depends predominantly on the severity and duration of flow deprivation (Fig. 12-11).

FIGURE 12-10 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. The heart has been fixed by coronary arterial perfusion with glutaraldehyde and cleared with methyl salicylate, followed by intracoronary injection of silicone polymer (yellow). 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.)

FIGURE 12-11 Temporal sequence of early biochemical findings and progression of necrosis after onset of severe myocardial ischemia. A, Early changes include loss of adenosine triphosphate (ATP) and accumulation of lactate. B, 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, and are progressively lost when reperfusion is delayed.

(Modified with permission from Antman E: Acute myocardial infarction. In Braunwald E et al. (eds): Heart Disease: A Textbook of Cardiovascular Medicine, 6th ed. Philadelphia, WB Saunders, 2001, pp 1114–1231.)

The early biochemical consequence of myocardial ischemia is the cessation of aerobic metabolism within seconds, leading to inadequate production of high-energy phosphates (e.g., creatine phosphate and adenosine triphosphate) and accumulation of potentially noxious metabolites (such as lactic acid) (Fig. 12-11A). Because of the exquisite dependence of myocardial function on oxygen, severe ischemia induces loss of contractility within 60 seconds. This cessation of function 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 of the onset of ischemia. Nevertheless, these early changes are potentially reversible. As demonstrated both experimentally and in clinical studies, only severe ischemia lasting 20 to 30 minutes or longer leads to irreversible damage (necrosis) of cardiac myocytes. Ultrastructural evidence of irreversible myocyte injury (primary structural defects in the sarcolemmal membrane) develops only after prolonged, severe myocardial ischemia (such as occurs when blood flow is 10% or less of normal).

A key feature that marks the early phases of myocyte necrosis is the disruption of the integrity of the sarcolemmal membrane, which allows intracellular macromolecules to leak out of cells into the cardiac interstitium and ultimately into the microvasculature and lymphatics in the region of the infarct. Tests that measure the levels of myocardial proteins in the blood are important in the diagnosis and management of MI (see later). With prolonged severe ischemia, injury to the microvasculature then follows. The temporal progression of these events 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.

In most cases of acute MI, permanent damage to the heart occurs when the perfusion of the myocardium is severely reduced for an extended interval (usually at least 2 to 4 hours), (Fig. 12-11B). This delay in the onset of permanent myocardial injury provides the rationale for rapid diagnosis in acute MI—to permit early coronary intervention, the purpose of which is to establish reperfusion and salvage as much “at risk” myocardium as possible.

The progression of ischemic necrosis in the myocardium is summarized in Figure 12-12. Ischemia is most pronounced in the subendocardium; thus, 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 and breadth of the ischemic zone. The precise location, size, and specific morphologic features of an acute MI depend on:

• The location, severity, and rate of development of coronary obstructions due to atherosclerosis and thromboses

• 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 heart rate, cardiac rhythm, and blood oxygenation

FIGURE 12-12 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. The area that depends on the occluded vessel for perfusion is the “at risk” myocardium (shaded). 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.

Necrosis is usually complete within 6 hours of the onset of severe myocardial ischemia. However, in instances where the coronary arterial collateral system, stimulated by chronic is-chemia, is better developed and thereby more effective, the progression of necrosis may follow a more protracted course (possibly over 12 hours or longer).

Knowledge of the areas of myocardium perfused by the three major coronary arteries helps correlate sites of vascular obstruction with regions of myocardial infarction. Typically, the left anterior descending branch of the left coronary artery (LAD) supplies most of the apex of the heart (distal end of the ventricles), the anterior wall of the left ventricle, and the anterior two thirds of the ventricular septum. By convention, the coronary artery (either the right coronary artery [RCA] or the left circumflex artery [LCX]) that perfuses the posterior third of the septum is called “dominant” (even though the LAD and LCX collectively perfuse the majority of the left ventricular myocardium). In a right dominant circulation, present in approximately four fifths of individuals, the LCX generally perfuses only the lateral wall of the left ventricle, and the RCA supplies the entire right ventricular free wall, the posterobasal wall of the left ventricle, and the posterior third of the ventricular septum. Thus, occlusions of the RCA (as well as the left coronary artery) can cause left ventricular damage. The right and left coronary arteries function as end arteries, although anatomically most hearts have numerous intercoronary anastomoses (connections called the collateral circulation). Little blood courses through the collateral circulation in the normal heart. However, when one artery is severely narrowed, blood flows via collaterals from the high- to the low-pressure system, and causes the channels to enlarge. Thus, progressive dilation and growth of collaterals, stimulated by ischemia, may play a role in providing blood flow to areas of the myocardium otherwise deprived of adequate perfusion.

Transmural Versus Subendocardial Infarction.

The distribution of myocardial necrosis correlates with the location and cause of the decreased perfusion (Fig. 12-16). 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 a combination of chronic 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 to one half of the ventricular wall. As the subendocardial zone is normally the least perfused region of myocardium, this area is most vulnerable to any reduction in coronary flow. A subendocardial infarct can occur as a result of a plaque disruption followed by a coronary thrombus that becomes lysed before myocardial necrosis extends across the full thickness of the wall; in this case the infarct will be limited to the distribution of the coronary artery that suffered plaque change. However, subendocardial infarcts can also result from prolonged, severe reduction in systemic blood pressure, as in shock superimposed on chronic, otherwise noncritical, coronary stenoses. In the subendocardial infarcts that occur as a result of global hypotension, myocardial damage is usually circumferential, rather than being limited to the distribution of a single major coronary artery. Owing to the characteristic electrocardiographic changes resulting from myocardial ischemia/necrosis in various distributions, transmural infarcts are often referred to as “ST elevation infarcts” and subendocardial infarcts are known as “non-ST elevation infarcts.”

FIGURE 12-16 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 longer than 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 also demonstrate stunning. Reperfusion beyond 6 hours does not appreciably reduce myocardial infarct size. B, Gross and C, microscopic appearance of myocardium modified by reperfusion. B, Large, densely hemorrhagic, anterior wall acute myocardial infarction in a patient with left anterior descending artery thrombus treated with streptokinase, a fibrinolytic agent (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.

Morphology. The temporal evolution of the morphologic changes in acute MI and subsequent healing are summarized in Table 12-5.

TABLE 12-5 Evolution of Morphologic Changes in Myocardial Infarction

Nearly all transmural infarcts involve at least a portion of the left ventricle (comprising the free wall and ventricular septum) and encompass nearly the entire perfusion zone of the occluded coronary artery save for a narrow rim (∼0.1 mm) of preserved subendocardial myocardium that is sustained by the diffusion of oxygen and nutrients from the ventricular lumen.

Of MIs caused by a right coronary obstruction, 15% to 30% extend from the posterior free wall of the septal portion of the left ventricle into the adjacent right ventricular wall. Isolated infarction of the right ventricle is unusual (1% to 3% of cases), as is infarction of the atria.

The frequencies of involvement 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 (Fig. 12-13A):

• Left anterior descending coronary artery (40% to 50%): infarcts involving the anterior wall of left ventricle near the apex; the anterior portion of ventricular septum; and the apex circumferentially

• Right coronary artery (30% to 40%): infarcts involving the inferior/posterior wall of left ventricle; posterior portion of ventricular septum; and the inferior/posterior right ventricular free wall in some cases

• Left circumflex coronary artery (15% to 20%): infarcts involving the lateral wall of left ventricle except at the apex

FIGURE 12-13 Distribution of myocardial ischemic necrosis correlated with the location and nature of decreased perfusion. Left, The positions of transmural acute infarcts resulting from occlusions of the major coronary arteries; top to bottom, left anterior descending, left circumflex, and right coronary arteries. Right, The types of infarcts that result from a partial or transient occlusion, global hypotension, or intramural small vessel occlusions.

Other locations of critical coronary arterial lesions causing infarcts are sometimes encountered, such as the left main coronary artery, the secondary branches of the left anterior descending coronary artery, or the marginal branches of the left circumflex coronary artery.

The gross and microscopic appearance of an infarct 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 (the predominant mechanism of cell death in MI, although apoptosis may also occur), followed by inflammation and repair that closely parallels tissue responses to injury at other sites.

Early recognition of acute MI can be difficult, particularly when death has occurred within a few hours after the onset of symptoms. MIs less than 12 hours old are usually not apparent on gross examination. If the patient died at least 2 to 3 hours after the infarct, however, it is possible to highlight the area of necrosis by immersion of tissue slices in a solution of triphenyltetrazolium chloride. This histochemical stain imparts a brick-red color to intact, noninfarcted myocardium where dehydrogenase (e.g., lactate dehydrogenase) activity is preserved. Because dehydrogenases leak out through the damaged membranes of dead cell, an infarct appears as an unstained pale zone (Fig. 12-14). By 12 to 24 hours an infarct can be identified grossly in transverse slices as a reddish-blue area of discoloration caused by stagnated, trapped blood. Thereafter, the infarct becomes progressively more sharply defined, yellow-tan, and soft. By 10 days to 2 weeks, it is rimmed by a hyperemic zone of highly vascularized granulation tissue. Over the succeeding weeks, the injured region evolves to a fibrous scar.

FIGURE 12-14 Acute myocardial infarct, predominantly of the posterolateral left ventricle, demonstrated histochemically by a lack of staining by triphenyltetrazolium chloride 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 is oriented with the posterior wall at the top.

The histopathologic changes also proceed in a fairly predictable sequence (summarized in Fig. 12-15). The typical changes of coagulative necrosis become detectable in the first 6 to 12 hours. “Wavy fibers” may be present at the periphery of the infarct; these changes probably result from the forceful systolic tugs of the viable fibers on immediately adjacent, noncontractile dead fibers, which stretches and folds them. An additional sublethal ischemic change may be seen in the margins of infarcts: so-called vacuolar degeneration or myocytolysis, which takes the form of large vacuolar spaces within cells that probably contain water. The necrotic muscle elicits acute inflammation (most prominent between 1 and 3 days). Thereafter macrophages remove the necrotic myocytes (most pronounced at 3 to 7 days), and the damaged zone is progressively replaced by the ingrowth of highly vascularized granulation tissue (most prominent at 1 to 2 weeks); as healing progresses, this is replaced by fibrous tissue. 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.

FIGURE 12-15 Microscopic features of myocardial infarction and its repair. A, One-day-old infarct showing coagulative necrosis and wavy fibers (elongated and narrow, as 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.

Since 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 margins toward its center. Thus, a large infarct may not heal as quickly or 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 determine its age (i.e., the dense fibrous scar of 8-week-old and 10-year-old infarcts may look identical).

Infarcts may expand beyond their original borders over a period of days to weeks via a process of repetitive necrosis of adjacent regions (extension). In such cases, there is a central zone in which healing is more advanced than the periphery of the infarct. This contrasts with the appearance of a simple infarct described above, in which the most advanced repair is peripheral. Infarct extension may occur because of retrograde propagation of a thrombus, proximal vasospasm, progressively impaired cardiac contractility that renders flow through moderate stenoses insufficient, the deposition of platelet-fibrin microemboli, or an arrhythmia that impairs cardiac function.

We now consider interventions that seek to limit infarct size by salvaging myocardium that is not yet necrotic.

Infarct Modification by Reperfusion.

The most effective way to “rescue” ischemic myocardium threatened by infarction is to restore myocardial blood flow as rapidly as possible, a process referred to as reperfusion.⁵¹ Although this can often be accomplished, reperfusion may also trigger deleterious complications, including arrhythmias, myocardial hemorrhage with contraction bands, irreversible cell damage superimposed on the original ischemic injury (reperfusion injury), microvascular injury, and prolonged ischemic dysfunction (myocardial stunning); these are discussed below and summarized in Figures 12-16 and 12-17. Coronary intervention (i.e., thrombolysis, angioplasty, stent placement, or coronary artery bypass graft [CABG] surgery) is often used in an attempt to dissolve, mechanically alter, or bypass the lesion that initiated the acute MI. The purpose of these treatments is to restore blood flow to the area at risk for infarction and rescue the ischemic (but not yet necrotic) heart muscle. Because loss of myocardial viability in infarction is progressive, occurring over a period of at least several hours (see Fig. 12-11B and Fig. 12-17A), early reperfusion can salvage myocardium and thereby limit infarct size, with consequent improvement in both short- and long-term function and survival. The potential benefit of reperfusion is related to (1) the rapidity with which the coronary obstruction is alleviated (the first 3 to 4 hours following onset are critical) and (2) the extent of correction of the vascular occlusion and the underlying causal lesion. For example, thrombolysis can remove a thrombus occluding a coronary artery, but does not alter the underlying atherosclerotic plaque that initiated it. In contrast, percutaneous transluminal coronary angioplasty (PTCA) with stent placement not only eliminates a thrombotic occlusion but also can relieve some of the original obstruction and instability caused by the underlying disrupted plaque. CABG provides flow around a blocked vessel.

FIGURE 12-17 Effects of reperfusion on myocardial viability and function. Following coronary occlusion, contractile function is lost within 2 minutes and viability begins to diminish after approximately 20 minutes. If perfusion is not restored (A), then nearly all myocardium in the affected region will die. B, If flow is restored, then some necrosis is prevented, myocardium is salvaged, and at least some function will return. The earlier reperfusion occurs, the greater the degree of salvage. However, the process of reperfusion itself may induce some damage (reperfusion injury), and return of function of salvaged myocardium may be delayed for hours to days (post-ischemic ventricular dysfunction).

Recall that (1) severe ischemia does not cause immediate cell death even in the most severely affected regions of myocardium, and (2) not all regions of myocardium are equally ischemic. Therefore, the outcome following the restoration of blood flow may vary from region to region. As indicated in Figure 12-16A, reperfusion of myocardium within 20 minutes of the onset of ischemia may completely prevent necrosis. Reperfusion after a longer interval may not prevent all necrosis but can salvage at least some myocytes that would have otherwise died.

The typical appearance of reperfused myocardium is illustrated in Figure 12-16B and C. A reperfused infarct is usually hemorrhagic because the vasculature is injured during the period of ischemia and leaks when flow is restored. Microscopic examination reveals that myocytes that were irreversibly injured at the time of reperfusion often contain contraction bands, intensely eosinophilic intracellular “stripes” composed of closely packed sarcomeres. These result from the exaggerated contraction of myofibrils when perfusion is reestablished, at which time the interior of dead cells with damaged plasma membranes 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 lethally injured cells.

In addition to its benefits, reperfusion may also have some deleterious effects on the vulnerable ischemic myocardium (reperfusion injury; see Fig. 12-17B).⁵² The clinical significance of myocardial reperfusion injury is uncertain. As discussed in Chapter 1, reperfusion injury may be mediated by oxidative stress, calcium overload, and potentially inflammation initiated during reperfusion. Reperfusion-induced microvascular injury causes not only hemorrhage but also endothelial swelling that occludes capillaries and may limit the reperfusion of critically injured myocardium (called no-reflow).

Biochemical abnormalities may also persist for a period of days to several weeks in myocytes that are rescued from ischemia by reperfusion. These are thought to underlie a phenomenon referred to as stunned myocardium, a state of reversible cardiac failure that usually recovers after several days.⁵³ Reperfusion also frequently induces arrhythmias. Myocardium that is subjected to chronic, sublethal ischemia may also enter into a state of lowered metabolism and function that is referred to as hibernation.⁵⁴ The function of hibernating myocardium may be restored by revascularization (e.g., by CABG surgery, angioplasty, or stenting). Paradoxically, repetitive short-lived transient severe ischemia may protect the myocardium against infarction (a phenomenon known as preconditioning) by mechanisms that are not understood.⁵⁵

Clinical Features.

MI is diagnosed by clinical symptoms, laboratory tests for the presence of myocardial proteins in the plasma, and characteristic electrocardiographic changes. Patients with MI often present with a rapid, weak pulse and profuse sweating (diaphoresis). Dyspnea due to impaired contractility of the ischemic myocardium and the resultant pulmonary congestion and edema is common. However, in about 10% to 15% of patients the onset is entirely asymptomatic and the disease is discovered only by electrocardiographic changes or laboratory tests that show evidence of myocardial damage (see below). Such “silent” MIs are particularly common in elderly patients and in the setting of diabetes mellitus.

The laboratory evaluation of MI is based on measuring the blood levels of proteins that leak out of fatally injured myocytes; these molecules include myoglobin, cardiac troponins T and I, the MB fraction of creatine kinase (CK-MB), lactate dehydrogenase, and many others (Fig. 12-18).⁵⁶ The diagnosis of myocardial injury is established when blood levels of these cardiac biomarkers are increased in the clinical setting of acute ischemia. The rate of appearance of these markers in the peripheral circulation depends on several factors, including their intracellular location and molecular weight, the blood flow and lymphatic drainage in the area of the infarct, and the rate of elimination of the marker from the blood.

FIGURE 12-18 Release of myocyte proteins in myocardial infarction. Some of these proteins (e.g., troponin I, C, or T and creatine phosphokinase, MB fraction [CK-MB]) are used as diagnostic biomarkers.

The most sensitive and specific biomarkers of myocardial damage are cardiac-specific proteins, particularly Troponins I and T (proteins that regulate calcium-mediated contraction of cardiac and skeletal muscle). Troponins I and T are not normally detectable in the circulation. Following an MI, levels of both begin to rise at 2 to 4 hours and peak at 48 hours. Formerly the “gold standard,” cardiac creatine kinase remains useful. Creatine kinase, an enzyme that is present in brain, myocardium, and skeletal muscle, is a dimer composed of two isoforms designated “M” and “B.” MM homodimers are found predominantly in cardiac and skeletal muscle; BB homodimers in brain, lung, and many other tissues; and MB heterodimers principally in cardiac muscle, with lesser amounts also being found in skeletal muscle. As a result, the MB form of creatine kinase (CK-MB) is sensitive but not specific, since it is also elevated when skeletal muscle is injured. CK-MB begins to rise within 2 to 4 hours of the 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, elevated troponin levels persist for approximately 7 to 10 days after acute MI, well after CK-MB levels have returned to normal. Troponin and CK-MB levels peak earlier in patients whose hearts are successfully reperfused, because proteins are washed out of the necrotic tissue more rapidly. Unchanged levels of CK-MB and troponin over a period of 2 days essentially excludes the diagnosis of MI.

Consequences and Complications of MI.

Extraordinary progress has been made in the treatment of patients with acute MI. Concurrent with the decrease in the overall mortality of IHD since the 1960s, the in-hospital death rate has declined from around 30% to approximately 7% in patients receiving timely therapy. Half of the deaths associated with acute MI occur within 1 hour of onset; most of these individuals never reach the hospital. Therapies given routinely in the setting of acute MI include aspirin and heparin (to prevent further thrombosis); oxygen (to minimize ischemia); nitrates (to induce vasodilation and reverse vasospasm); beta-adrenergic inhibitors (beta-blockers, to diminish cardiac oxygen demand and decrease the risk of arrythmias); angiotensinogen converting enzyme (ACE) inhibitors (to limit venticular dilation); and maneuvers that aim to open up blocked vessels, including the administration of fibrinolytic agents, coronary angioplasty with or without stenting, and emergent CABG surgery. The choice of therapy depends on the clinical picture and the expertise of the treating institution. Angioplasty is highly effective in skilled hands, while fibinolytic therapy can be given with almost equivalent efficacy by simple infusion. In general, factors associated with a poor prognosis include advanced age, female gender, diabetes mellitus, and, as a result of the cumulative loss of functional myocardium, previous MI.

Despite these interventions, many patients have one or more complications following acute MI, including the following (some of which are illustrated in Fig. 12-19):

FIGURE 12-19 Complications of myocardial infarction. Cardiac rupture syndromes (A–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, MD, Mayo Clinic, Rochester, MN.)

The risk of specific postinfarct complications and the prognosis depend primarily on the infarct size, location, and thickness (subendocardial or transmural). 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 conduction blocks, right ventricular involvement, or both; when acute VSDs occur in this area they are more difficult to manage. Overall, however, patients with anterior infarcts have a worse clinical course than those with inferior (posterior) infarcts. With subendocardial infarcts, only rarely do pericarditis, rupture, and aneurysms occur.

In addition to the sequence of repair in the infarcted tissues described above, the noninfarcted segments of the ventricle undergo hypertrophy and dilation; collectively, these changes are termed ventricular remodeling. The compensatory hypertrophy of noninfarcted myocardium is initially hemodynamically beneficial. However, this adaptive effect may be overwhelmed by ventricular dilation (with or without ventricular aneurysm) and increased oxygen demand, which can exacerbate ischemia and depress cardiac function. There may also be changes in ventricular shape and stiffening of the ventricle due to scar formation and hypertrophy that further diminish cardiac output. Some of these deleterious effects appear to be reduced by ACE inhibitors, which lessen the ventricular dilation that occurs after MI.

Long-term prognosis after MI depends on many factors, the most important of which are the quality of residual left ventricular function and the extent of vascular obstructions in vessels that perfuse the viable myocardium. The overall total mortality within the first year is about 30%. 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 achieved considerable success.

The relationship of the causes, pathophysiology, and consequences of MI are summarized in Figure 12-20, including the possible outcomes of chronic IHD and sudden death, to be discussed next.

FIGURE 12-20 Schematic of the various pathways in the progression of ischemic heart disease (IHD), showing the interrelationships among coronary artery disease, acute plaque change, myocardial ischemia, myocardial infarction, chronic IHD, congestive heart failure, and sudden cardiac death.

Clinical Features.

In calcific aortic stenosis (superimposed on a previously normal or bicuspid aortic valve), the obstruction to left ventricular outflow leads to gradual narrowing of the valve orifice (valve area approximately 0.5 to 1 cm² in severe aortic stenosis; normal, ∼4 cm²) and an increasing pressure gradient across the calcified valve, reaching 75 to 100 mm Hg in severe cases. Left ventricular pressures rise to 200 mm Hg or more in such instances, producing concentric left ventricular (pressure overload) hypertrophy. The hypertrophied myocardium tends to be ischemic (as a result of diminished microcirculatory perfusion, often complicated by coronary atherosclerosis), and angina pectoris may appear. Both systolic and diastolic myocardial function may be impaired; eventually, cardiac decompensation and CHF may ensue. The onset of symptoms (angina, CHF, or syncope, for which the pathophysiologic basis is poorly understood) in aortic stenosis heralds cardiac decompensation and carries a poor prognosis; ∼50% with angina will die within 5 years, and 50% with CHF will die within 2 years, if the obstruction is not alleviated by surgical valve replacement. Medical therapy is ineffective in severe symptomatic aortic stenosis. In contrast, asymptomatic patients with aortic stenosis generally have an excellent prognosis.

Pathogenesis.

The basis for the changes that weaken the valve leaflets and associated structures is unknown in most cases. Uncommonly, MVP is associated with heritable disorders of connective tissue including Marfan syndrome, which is usually caused by mutations in fibrillin-1 (FBN-1) (Chapter 5). As you will recall, defects in FBN-1 alter cell-matrix interactions and also dysregulate TGF-β signaling.⁷⁵ Of interest, mice engineered to express mutated FBN-1 develop a form of mitral valve prolapse that can be prevented by inhibitors of TGF-β,⁷⁶ indicating that excess TGF-β can cause the characteristic structural laxity and myxomatous change. Whether similar mechanisms contribute to sporadic MVP is unknown. Studies utilizing genetic linkage analysis have also mapped autosomal-dominant forms of MVP to several other genetic loci that may be involved in remodeling of the valvular extracellular matrix.⁷⁷

Clinical Features.

Most individuals diagnosed with MVP are asymptomatic, and the condition is discovered incidentally by detection of a midsystolic click on physical examination. The diagnosis can be confirmed by echocardiography. Those cases with mitral regurgitation are also associated with a systolic murmur. A minority of patients have chest pain mimicking angina, dyspnea, and fatigue. Although the great majority of persons with MVP have no untoward effects, approximately 3% develop one of four serious complications: (1) infective endocarditis; (2) mitral insufficiency, sometimes with chordal rupture; (3) stroke or other systemic infarct, resulting from embolism of leaflet thrombi; or (4) arrhythmias, both ventricular and atrial.

The risk of complications is very low when MVP is discovered incidentally in young asymptomatic patients, and higher in men, older patients, and those with arrhythmias or mitral regurgitation. For patients with symptoms or at high risk for serious complications, valve surgery is often done; indeed, MVP is presently the most common cause for surgical repair or replacement of the mitral valve.

Pathogenesis.

Acute rheumatic fever results from immune responses to group A streptococci, which happen to cross-react with host tissues. Antibodies directed against the M proteins of streptococci have been shown to cross-react with self antigens in the heart. In addition, CD4+ T cells specific for streptococcal peptides also react with self proteins in the heart, and produce cytokines that activate macrophages (such as those found in Aschoff bodies). Damage to heart tissue may thus be caused by a combination of antibody- and T cell–mediated reactions (Chapter 6).

Clinical Features.

RF is characterized by a constellation of findings that includes as major manifestations: (1) migratory polyarthritis of the large joints, (2) pancarditis, (3) subcutaneous nodules, (4) erythema marginatum of the skin, and (5) Sydenham chorea, a neurologic disorder with involuntary rapid, purposeless movements. The diagnosis is established by the so-called Jones criteria: evidence of a preceding group A streptococcal infection, with the presence of two of the major manifestations listed above or one major and two minor manifestations (nonspecific signs and symptoms that include fever, arthralgia, or elevated blood levels of acute-phase reactants).⁸⁰

Acute RF typically appears 10 days to 6 weeks after an episode of pharyngitis caused by group A streptococci in about 3% of infected patients. It occurs most often in children between ages 5 and 15, but first attacks can occur in middle to later life. Although pharyngeal cultures for streptococci are negative by the time the illness begins, antibodies to one or more streptococcal enzymes, such as streptolysin O and DNase B, can be detected in the sera of most patients with RF. The predominant clinical manifestations are carditis and arthritis, the latter more common in adults than in children. Clinical features related to acute carditis include pericardial friction rubs, weak heart sounds, tachycardia, and arrhythmias. Myocarditis may cause cardiac dilation that can evolve to functional mitral valve insufficiency or even heart failure. Approximately 1% of patients die from fulminant RF. Arthritis typically begins with migratory polyarthritis (accompanied by fever) in which one large joint after another becomes painful and swollen for a period of days and then subsides spontaneously, leaving no residual disability.

After an initial attack there is increased vulnerability to reactivation of the disease with subsequent pharyngeal infections, and the same manifestations are likely to appear with each recurrent attack. Damage to the valves is cumulative. Turbulence induced by ongoing valvular deformities begets additional fibrosis. Clinical manifestations appear years or even decades after the initial episode of RF and depend on which cardiac valves are involved. In addition to various cardiac murmurs, cardiac hypertrophy and dilation, and heart failure, individuals with chronic RHD may suffer from arrhythmias (particularly atrial fibrillation in the setting of mitral stenosis), thromboembolic complications, and infective endocarditis (see below). The long-term prognosis is highly variable. Surgical repair or prosthetic replacement of diseased valves has greatly improved the outlook for persons with RHD.

Etiology and Pathogenesis.

As mentioned above, IE can develop on previously normal valves, especially with highly virulent organisms, but a variety of cardiac and vascular abnormalities predispose to this form of infection. In years past, rheumatic heart disease was the major antecedent disorder, but more common now are mitral valve prolapse, degenerative calcific valvular stenosis, bicuspid aortic valve (whether calcified or not), artificial (prosthetic) valves, and unrepaired and repaired congenital defects.⁸² The causative organisms differ somewhat in the major high-risk groups. Endocarditis of native but previously damaged or otherwise abnormal valves is caused most commonly (50% to 60% of cases) by Streptococcus viridans, which is part of the normal flora of the oral cavity. In contrast, more virulent S. aureus organisms commonly found on the skin can infect either healthy or deformed valves and are responsible for 10% to 20% of cases overall; S. aureus is the major offender in intravenous drug abusers with IE. The roster of the remaining bacteria includes enterococci and the so-called HACEK group (Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, and Kingella), all commensals in the oral cavity. Prosthetic valve endocarditis is caused most commonly by coagulase-negative staphylococci (e.g., S. epidermidis). Other agents causing endocarditis include gram-negative bacilli and fungi. In about 10% to 15% of all cases of endocarditis, no organism can be isolated from the blood (“culture-negative” endocarditis).

Foremost among the factors predisposing to the development of endocarditis are those that lead to bacteremia. The source of the organism may be an obvious infection elsewhere, a dental or surgical procedure, a contaminated needle shared by intravenous drug users, or seemingly trivial breaks in the epithelial barriers of the gut, oral cavity, or skin. The risk can be lowered in those with predisposing factors (e.g., valve abnormalities, conditions causing bacteremia) by prophylaxis with antibiotics.

Morphology. The hallmark of IE is the presence of friable, bulky, potentially destructive vegetations containing fibrin, inflammatory cells, and bacteria or other organisms on the heart valves (Figs. 12-25B and 12-26). The aortic and mitral valves are the most common sites of infection, although the valves of the right heart may also be involved, particularly in intravenous drug abusers. The vegetations may be single or multiple and may involve more than one valve. Vegetations sometimes erode into the underlying myocardium and produce an abscess (ring abscess). Emboli may be shed from the vegetations at any time; because the embolic fragments may contain large numbers of virulent organisms, abscesses often develop at the sites where the emboli lodge, leading to sequelae such as septic infarcts or mycotic aneurysms.

FIGURE 12-26 Infective (bacterial) endocarditis. A, Endocarditis of mitral valve (subacute, caused by Streptococcus viridans). The large, friable vegetations are denoted by arrows. B, Acute endocarditis of congenitally bicuspid aortic valve (caused by Staphylococcus aureus) with extensive cuspal destruction and ring abscess (arrow). C, Histologic appearance of vegetation of endocarditis with extensive acute inflammatory cells and fibrin. Bacterial organisms were demonstrated by tissue Gram stain. D, Healed endocarditis, demonstrating mitral valvular destruction but no active vegetations.

(C, Reproduced from Schoen FJ: Surgical pathology of removed natural and prosthetic heart valves. Hum Pathol 18:558, 1987.)

The vegetations of subacute endocarditis are associated with less valvular destruction than those of acute endocarditis, although the distinction between the two forms may blur. Microscopically, the vegetations of typical subacute IE often have granulation tissue indicative of healing at their bases. With time, fibrosis, calcification, and a chronic inflammatory infiltrate can develop.

Clinical Features.

Fever is the most consistent sign of IE. Acute endocarditis has a stormy onset with rapidly developing fever, chills, weakness, and lassitude. However, fever may be slight or absent, particularly in the elderly, and the only manifestations may be nonspecific fatigue, loss of weight, and a flu-like syndrome. Complications of IE generally begin within the first few weeks of onset. They may be immunologically mediated, as exemplified by glomerulonephritis caused by the deposition of antigen-antibody complexes (Chapter 20). Murmurs are present in 90% of patients with left-sided IE and may stem from a new valvular defect or represent a preexisting abnormality. The so-called Duke criteria (Table 12-8) provide a standardized assessment of individuals with suspected IE that takes into account predisposing factors, physical findings, blood culture results, echocardiographic findings, and laboratory information.⁸³ Earlier diagnosis and effective treatment has nearly eliminated some previously common clinical manifestations of long-standing IE—for example, micro-thromboemboli (manifest as splinter or subungual hemorrhages), erythematous or hemorrhagic nontender lesions on the palms or soles (Janeway lesions), subcutaneous nodules in the pulp of the digits (Osler nodes), and retinal hemorrhages in the eyes (Roth spots).

TABLE 12-8 Diagnostic Criteria for Infective Endocarditis^*

* Diagnosis by these guidelines, often called the Duke Criteria, requires either pathologic or clinical criteria; if clinical criteria are used, 2 major, 1 major + 3 minor, or 5 minor criteria are required for diagnosis.

† Janeway lesions are small erythematous or hemorrhagic, macular, nontender lesions on the palms and soles and are the consequence of septic embolic events.

‡ Osler nodes are small, tender subcutaneous nodules that develop in the pulp of the digits or occasionally more proximally in the fingers and persist for hours to several days.

§ Roth spots are oval retinal hemorrhages with pale centers.

Modified from Durack DT et al: Am J Med, 96:200, 1994 and Karchmer AW: In Braunwald E, Zipes DP, Libby P (eds): Heart Disease. A Textbook of Cardiovascular Medicine, 6th ed. Philadelphia, WB Saunders, 2001, p 1723.