The dominant influence in the causation of the ischemic heart disease syndromes is diminished coronary perfusion relative to myocardial demand, owing largely to a complex dynamic interaction among fixed atherosclerotic narrowing of the epicardial coronary arteries, intraluminal thrombosis overlying a ruptured or fissured atherosclerotic plaque, platelet aggregation, and vasospasm. [1 ] , [8 ] , [23 ] , [69 ] Increased myocardial demand or reduced oxygen carrying capacity of the blood may be contributory.
Under normal conditions, coronary arterial flow provides adequate myocardial perfusion at rest, and compensatory vasodilation provides flow reserve that is generally more than sufficient to accommodate the increased myocardial metabolic demands during vigorous exertion. When the luminal cross-sectional area is decreased by 75 percent or more, coronary blood flow generally becomes limited with exertion. With 90 percent or greater reduction, coronary flow may be inadequate at rest. Over 90 percent of patients with ischemic heart disease have advanced stenosing coronary atherosclerosis (fixed obstructions). [8 ] Among these, most have one or more lesions causing at least 75 percent reduction of the cross-sectional area in one or more of the major epicardial arteries. Thus, the clinical effects of advanced atherosclerotic plaques in most medium-sized arteries, including the coronary arteries, are in part owing to their encroachment on the lumen, leading to stenosis.
However, the onset and prognosis of ischemic heart disease and other complications of atherosclerosis are not well predicted by the arteriographically determined extent and severity of fixed anatomic disease. [7 ] , [13 ] , [16 ] – [20 ] , [23 ] , [69 ] – [75 ] Considerable evidence exists that dynamic vascular changes are largely responsible for the conversion of chronic stable angina or an asymptomatic state to acute ischemic heart disease (unstable angina, myocardial infarction, or sudden coronary death). Acute coronary occlusion can be caused by vasospasm, intravascular plugging by blood constituents, disruption of or hemorrhage into plaque, platelet aggregation, thrombosis, embolization, or a combination of these events.
The acute coronary syndromes—unstable angina, acute myocardial infarction, and sudden ischemic death—usually are precipitated by atherosclerotic plaque disruption with hemorrhage, fissuring, and/or ulceration. [8 ] , [18 ] , [19 ] , [69 ] , [71 ] , [72 ] Angiographically, disrupted plaque appears substantially different from that of chronic stable disease. Microscopically, injury spans a broad morphologic range, from minimal surface erosions, to lacerations that extend deep within the plaque. Regardless of the extent of injury, however, the result is flow disruption and exposure of the luminal blood to a thrombogenic surface (collagen or necrotic debris), thereby setting the stage for mural or total thrombosis (Fig. 4-10) .
Pathologic and clinical studies also show that plaques that undergo abrupt disruption leading to acute ischemic heart disease often are those that previously produced only mild to moderate luminal stenosis. [69 ] , [71 ] – [73 ] In one study, 70 percent of the vessels with thrombi over plaque tears and deeper intimal injury had pre-existing stenosis of <60 percent in diameter (or <85 percent in luminal area), correlating with the observation that, following thrombolytic therapy for acute myocardial infarction, the underlying lesion often has <75 percent diameter stenosis (or <95 percent in luminal area). [73 ] Plaque fissures without substantial thrombosis also are found in occasional patients without acute coronary syndromes. In a group of patients who died of non-cardiac disease, plaque fissures without thrombosis were found in 9 percent of patients without hypertension or diabetes and 17 percent of those with these atheroma-related diseases. [73 ]
Potential outcomes for unstable lesions include healing at the site of plaque erosion, atheroembolization, nonocclusive thrombosis, thromboembolization, organization of mural thrombus (plaque progression), acute thrombotic occlusion, and organization of the occlusive mass, with varying degrees of recanalization. Among these outcomes, the most common fate is plaque progression, owing either to resealing of the plaque fissure or to organization of a nonocclusive mural thrombus. Indeed, asymptomatic plaque rupture and its subsequent healing is likely an important mechanism of stenosis progression.
The events that trigger abrupt changes in plaque configuration and superimposed thrombosis are poorly understood. [13 ] , [18 ] – [20 ] , [71 ] – [75 ] Influences both extrinsic and intrinsic to the plaque likely are important. Surface erosions, fissures, and ruptures are more likely to involve soft and eccentric plaques than hard and concentric lesions, those that contain large areas of foam cells, and fibrous caps that are thin or contain clusters of inflammatory cells that can produce tissue metalloproteinases that degrade collagen. Fissures and ruptures most frequently occur at the junction of the fibrous cap with the adjacent normal arterial wall (plaque-free segment), a location associated with high circumferential stress. [16 ] , [17 ] Vasospasm, tachycardia, hypercholesterolemia, or intraplaque hemorrhage are likely contributors, as are stresses produced by abnormal blood flow and/or coronary intramural pressure or tone in areas of stenosis. Interestingly, there is a pronounced circadian periodicity for the time of onset of acute myocardial infarction and other acute coronary syndromes, with a peak incidence between 9–11 a.m., concurrent with a surge in blood pressure and immediately following heightened platelet reactivity. [74 ] , [75 ]
Revascularization by thrombolysis in early acute myocardial infarction limits infarct size and enhances function and survival. [1 ] , [23 ] , [25 ] , [76 ] – [78 ] The pathologic basis of thrombolytic therapy is as follows: (1) Untreated thrombotic occlusion of a coronary artery usually causes transmural infarction; (2) the extent of necrosis during an evolving myocardial infarction progresses as a wavefront and becomes complete only 6 hours or more following coronary occlusion (see Fig. 4-5 ); (3) both early- and long-term mortality following acute myocardial infarction correlate strongly with the amount of residual functioning myocardium; and (4) early reperfusion prevents necrosis of some jeopardized myocardium. The benefit of thrombolytic therapy depends on and is assessed by the amount of myocardium salvaged, recovery of left ventricular function, and resultant reduction in mortality. These important clinical endpoints largely are determined by the time interval between onset of symptoms and a successful intervention, adequacy of early coronary reflow, and the degree of residual stenosis of the infarct vessel.
Recanalization rates vary from 60–90 percent; the best efficacy relates to the earliest time of infusion of thrombolytic agents (streptokinase, urokinase, or tissue-derived plasminogen activator). [76 ] – [78 ] Most studies conclude that the critical time for substantial myocardial salvage is approximately within 4 hours for intracoronary and 3 hours for intravenous administration but studies also suggest that at least some benefit can occur following later reperfusion, usually within 12 hours of symptoms. Moreover, spontaneous recanalization, presumably owing to inherent thrombolysis, can be beneficial to left ventricular function, and has been well-documented within 24 hours of infarct initiation. However, spontaneous thrombolysis with reperfusion probably occurs in fewer than 10 percent of patients within the critical 3–4 hours after symptom onset.
Successful thrombolytic therapy re-establishes antegrade flow in the infarct-related coronary artery but does not reverse factors responsible for initiating the original thrombosis, such as advanced atherosclerotic plaque, intimal rupture, enhanced platelet adhesiveness, or coronary spasm. High-grade residual stenosis is likely to be associated with recurrent ischemic events, as evidenced by post-infarction angina or recurrent infarction. Thus, balloon angioplasty or surgical revascularization during infarct evolution constitutes a more effective management of the underlying disease process than thrombolysis alone. The most common complications of streptokinase or tPA-mediated reperfusion are myocardial and systemic hemorrhage and so-called reperfusion arrhythmias. [76 ] [78 ]
Percutaneous transluminal coronary angioplasty (PTCA) is used widely in patients with stable angina, unstable angina, or acute myocardial infarction. [7 ] , [18 ] , [23 ] , [79 ] In PTCA, the progressive and substantial expansile force induced by balloons inflated at 8–12 atm of pressure causes the essentially non-distensible plaque to split at its weakest point, a site not necessarily most severely involved with atherosclerosis. [7 ] , [18 ] , [23 ] , [81 ] , [82 ] The split extends at least to the intimal-medial border and often into the media, with consequent circumferential and longitudinal dissection of the media (Fig. 4-11) . [1 ] , [8 ] , [18 ] , [23 ] , [80 ] Dissimilar plaques respond differently to balloon dilation, and the composition and configuration of the original atherosclerotic lesion play a key role in the outcome of angioplasty. [18 ] , [81 ] Immediate success probably is enhanced in dilated arteries having eccentric plaques with large lipid-rich necrotic cores and/or calcification, in contrast to concentric fibrotic lesions. For eccentric atheromas, balloon-induced splits most commonly involve the junction between the plaque and the disease-free portion of the arterial wall. Structural/stress analysis based on intravascular ultrasound imaging prior to balloon angioplasty can predict the location of plaque fracture that accompanies angioplasty. [82 ] Acute dissection may contribute to the propensity for acute closure that occurs in up to 5 percent of patients. For example, a dissection that involves a considerable portion of the circumference can generate a “flap” that may impinge on the lumen. Alternatively, a dissection that involves a substantial proximal-to-distal segment of the vessel, which traverses a large plaque-free wall segment, can induce compression of the vessel at a point of minimal disease. [23 ]
Thus, the key vascular consequences of angioplasty are plaque fracture, medial dissection, and stretching of the media beyond the dissection. These, in turn, are accompanied by local flow abnormalities and generation of new, thrombogenic blood-contacting surfaces. This supports the concept that an atherosclerotic plaque following angioplasty has many features of a spontaneously disrupted plaque, namely those associated with the acute coronary syndromes. [23 ] The immediate post-angioplasty healing process in either arteries or bypass grafts is not well understood, but dissolution of soft atheromatous material, retraction of the split plaque, thrombus formation, and intimal healing with re-endothelialization likely occur.
The long-term success of angioplasty is limited by the development of progressive, proliferative restenosis over a period of months to years (Fig. 4-12) . [23 ] , [79 ] , [80 ] , [83 ] – [86 ] Clinically significant restenosis occurs in approximately 30–40 percent of patients following coronary balloon angioplasty, most frequently within the first 4–6 months. Restenosis probably represents a fundamental vascular healing response that achieves clinical significance only in some patients.
The factors causing restenosis are complex. [79 ] , [84 ] , [86 ] Although vessel wall recoil and organization of thrombus likely contribute, the major process leading to restenosis is excessive medial and plaque smooth muscle proliferation as an exaggerated response to angioplasty-induced injury. Medial smooth muscle cells migrate to the intima where, along with existing plaque smooth muscle cells, they proliferate and secrete abundant extracellular matrix, consisting predominantly of collagen and glycosaminoglycans. Early lesions have a loose myxoid matrix in which numerous stellate smooth muscle cells are haphazardly arranged. Over weeks to months, the extracellular matrix becomes more densely collagenous, and the neointima becomes less cellular, with scattered spindle-shaped cells in a more laminar arrangement. The restenosis process has mechanistic similarities to both atherosclerosis and vascular graft healing previously described (see the preceding). [23 ] Moreover, following prominent thrombus formation, or in a hyperlipidemic patient, the site of healing also may contain foam cells and cholesterol crystals, resembling a mature fibrofatty atheroma. There is considerable interest in locally delivered pharmacologic and molecular therapies to mitigate restenosis; regrettably, success is limited. [87 ] – [90 ]
The general goals with the newer techniques of plaque ablation and stent devices are to enhance the acute success rate and lumen size, decrease disease complications, reduce late proliferative stenosis, extend the range of treatable lesions, and increase cost-effectiveness. In general, the largest acute luminal diameter safely possible provides better tolerance of subsequent intimal hyperplasia before hemodynamically significant renarrowing results at the treatment site. [83 ] , [91 ]
The morphology of arterial vessel healing after transluminal procedures that remove obstructive tissue by excision, such as directional or rotational atherectomy, is similar to that following angioplasty. [80 ] , [92 ] , [93 ] However, atherectomy techniques may permit a larger acute lumen than angioplasty, with potential benefit. [94 ] Moreover, beyond therapeutic objectives, directional atherectomy obtains human restenosis tissue for tissue culture, and molecular or other studies, and aids in evaluating differences in the pathobiology of restenosis following various pharmacological or mechanical therapies or plaque ablation procedures.
Recent studies suggest that as an adjunct to interventional procedures that manipulate plaque, metallic balloon-expandable and self-expanding intravascular stents may reverse the untoward effects of PTCA. Such devices could provide a larger and more regular lumen initially acting as a scaffold to support the intimal dissections that occur in PTCA, mechanically prevent vascular spasm, and increase blood flow, all of which could minimize thrombus formation, and reduce the impact of postangioplasty restenosis. [95 ] – [97 ] Stent wires initially are covered with a variable platelet-fibrin coating, and may eventually become covered by neointima (Fig. 4-13) . [98 ] – [100 ] Nevertheless, the neointima may thicken, and proliferative restenosis currently is not prevented by stenting. Important questions remain relative to determinants of healing and the potential for late complications of endovascular stents, such as migration, perforation, or infection.
Now widely done, coronary artery bypass graft surgery is widely acknowledged to improve survival in patients with significant left main coronary artery disease, improve survival in patients with three-vessel disease and reduced ventricular function, and prolong and improve the quality of life in patients with “left main equivalent” disease (proximal left anterior descending and proximal left circumflex), but not protect from the risk of subsequent myocardial infarction. [101 ] Moreover, graft patency deteriorates with time and accelerated changes of atherosclerosis develop in bypassed vessels. [23 ] , [102 ]
Early cardiac failure with low output or arrhythmias following uncomplicated coronary artery bypass surgery occurs infrequently; the causes are unclear in many cases. Many such patients have no detectable myocardial necrosis, either clinically or at autopsy. In others, the extent of necrosis noted at autopsy seems insufficient to account for the profound ventricular dysfunction encountered clinically; possible explanations include (1) evolving myocardial necrosis either undetectable clinically or too recent to detect at autopsy; (2) postischemic dysfunction of viable myocardium, for which no morphologic markers of the dysfunctional state are known; or (3) a metabolic cause, such as hypokalemia, for which there is no morphologic counterpart. Thus, although established myocardial necrosis causes cardiac dysfunction in many patients with postoperative failure; it may not be the predominant lesion or the cause of death. However, when such necrosis is detected at autopsy, it may indicate that a potentially larger volume of adjacent myocardium was biochemically and functionally (but not morphologically) deranged. [23 ]
Early thrombotic occlusion occurs in approximately 15 percent of grafts, and the clinical and autopsy incidences of early graft occlusion are not widely different. [23 ] , [102 ] Factors in the acute occlusion of aortocoronary bypass grafts (with or without superimposed thrombus) include anastomotic compression by atherosclerosis, suboptimal insertion site, poor distal run-off, graft or native vessel mural dissection at the anastomotic site, and distortion of a graft that is too short or too long for the intended bypass. In some cases, thrombosis occurring early postoperatively involves only the distal portion of the graft, suggesting that early graft thrombosis is most frequently initiated at the distal anastomosis. Inadequate distal run-off from extremely small distal native coronaries, frequently further compromised by partial atherosclerotic occlusions, comprises the major cause of early graft thrombosis.
Graft thromboses account for only a minority of early cardiac deaths; most patients who die early have patent grafts. Moreover, graft occlusions frequently do not account for early postoperative myocardial necrosis, which occurs most often in regions perfused by patent grafts. Perioperative infarction usually is caused by either hypotensive episodes during anesthesia induction or inadequate intraoperative regional preservation owing to severe obstruction of the feeding artery and poor collaterals. Such necrosis usually predominates in the subendocardium and often has the morphology of necrosis with contraction bands. As in cardiac surgery in general, perioperative myocardial infarction is more likely to occur in patients with cardiomegaly than in those with normal-sized hearts.
In contrast, both progression of obstructive atherosclerosis in non-bypassed coronary artery segments and graft obstruction are major factors in late symptom recurrence . [23 ] , [101 ] , [102 ] As in the coronary arteries, atherosclerosis in aortocoronary bypass grafts can cause myocardial ischemia through progressive luminal stenosis or plaque rupture with secondary thrombotic obstruction. The potential for disruption and embolization of atherosclerotic lesions in vein grafts exceeds that for native coronary atherosclerotic lesions. Plaques in grafts generally involve dilated segments, often have poorly developed fibrous caps, have large necrotic cores, and develop secondary dystrophic calcific deposits that may be adjacent to the lumen rather than deep to the surface as in typical native arterial atherosclerosis (Fig. 4-14) . Finally, because of the large size of the affected graft relative to the coronary artery to which it is anastomosed, atheroembolization is likely to be widespread or occlusive, often with catastrophic results; balloon angioplasty or intraoperative manipulation of grafts may stimulate atheroembolism. [103 ]
The long-term patency of saphenous vein grafts is 60 percent or less at 10 years, owing to pathologic changes, including thrombosis (early), intimal thickening (several months to several years postoperatively), and graft atherosclerosis (years). [23 ] , [101 ] , [102 ] , [104 ] , [105 ] These may be associated with superimposed plaque rupture, thrombi, or aneurysms (usually more than 2–3 years postoperatively).
In contrast, the internal mammary (internal thoracic) artery has a greater than 90 percent patency rate at 10 years (Fig. 4-15) . [23 ] , [101 ] , [102 ] , [106 ] Multiple factors likely contribute to the remarkably higher long-term patency of IMA grafts compared to vein grafts. [23 ] , [101 ] , [102 ] Free saphenous vein grafts, during autotransplantation, sustain not only disruption of their vasa vasora but also endothelial damage, medial ischemia, and acutely increased internal pressure. In contrast, the internal mammary artery generally has minimal pre-existing atherosclerosis, requires minimal surgical manipulation, maintains its nutrient blood supply, is accustomed to arterial pressures, needs no proximal anastomosis, and has an artery-to-artery distal anastomosis. The sizes of graft and recipient vessel are comparable with the internal mammary artery but disparate (graft substantially larger) with saphenous vein. As another distinguishing feature, the IMA is an elastic artery, whereas coronary arteries are muscular.
Transmyocardial laser revascularization is being tested in selected patients with chronic obstructive coronary artery disease that is refractory to conventional revascularization techniques and to maximal medical therapy. Performed on a beating heart through a left thoracotomy, the operation employs a high-energy laser to bore transmural channels (1 mm in diameter) into the left ventricle. The rationale for this procedure is the hypothesis that blood will flow directly from the left ventricular chamber into the channels and then into the intramyocardial vascular plexus, thereby restoring perfusion to potentially viable myocardium and improving ventricular function. Although experimental and clinical reports suggest benefit, the morphological basis for success is yet uncertain. [107 ] – [111 ] Our examinations of hearts from patients who have died at various post-mortem intervals fail to reveal patent channels (Fig. 4-16) . [112 ]
Although an electrocardiogram cannot reliably distinguish transmural from subendocardial infarcts, patients who develop Q-waves usually have transmural infarcts and those with subendocardial infarcts usually do not (Q-wave and non-Q-wave infarcts, respectively). [78 ] The two types of myocardial infarction have differing morphology and clinical significance. In the more common transmural infarct, ischemic necrosis involves at least one-half and usually the full or nearly full thickness of the ventricular wall in the distribution of a single coronary artery. [1 ] It usually is associated with chronic coronary atherosclerosis, and with acute plaque rupture and superimposed thrombosis. 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. It often extends laterally beyond the perfusion territory of a single coronary artery and can be multifocal. It is commonly associated with diffuse stenosing coronary atherosclerosis without acute plaque rupture or superimposed thrombosis, in the setting of episodic hypotension, global ischemia, or hypoxemia. However, a subendocardial infarct also can result from a coronary thrombus that is nonocclusive or becomes lysed before myocardial necrosis becomes transmural.
Important and frequent complications of myocardial infarction include ventricular dysfunction, cardiogenic shock, arrhythmias, infarct rupture, infarct extension and expansion, papillary muscle dysfunction, right ventricular involvement, ventricular aneurysm, pericarditis, and systemic arterial embolism. [1 ] , [78 ] Of the many patients who have conduction disturbances or myocardial irritability following myocardial infarction, histologic evidence of direct conduction system involvement is present only in a minority. Heart block following myocardial infarction usually is transient, and owing to efflux of extracellular necrotic debris and electrolytes, from a nearby infarct, that gain entry to venules and lymphatics that drain directly through the AV node and AV (His) bundle. Nevertheless, conduction block in the proximal atrioventricular conduction system may necessitate pacemaker implantation. In contrast, tachyarrhythmias usually originate in areas of severely ischemic or necrotic myocardium.
Myocardial infarcts produce functional abnormalities approximately proportional to their size. [78 ] Cardiogenic shock occurs in 10–15 percent of patients following myocardial infarction and is generally indicative of a large infarct (often >40 percent of the left ventricle). The previously high mortality of cardiogenic shock has been alleviated somewhat in recent years by the use of intra-aortic balloon pumps (IAPB) and ventricular assist devices.
Frequently catastrophic, cardiac rupture syndromes include three entities: (1) rupture of the ventricular free wall (most commonly), usually with hemopericardium and cardiac tamponade; (2) rupture of the ventricular septum (less commonly), leading to an acquired ventricular septal defect with a left-to-right shunt; and (3) papillary muscle rupture (least commonly), resulting in the acute onset of severe mitral or, very rarely, tricuspid regurgitation. Cardiac rupture is the cause of death noted at autopsy in 8–10 percent of patients with fatal acute transmural myocardial infarcts. Ruptures tend to occur relatively early following infarction, with a mean interval of approximately 4–5 days, and a range of 1–10 days. Even though they can be associated with large or small infarcts, all free wall and septal ruptures involve transmural infarcts. [113 ] Although the lateral wall is the least common site for left ventricular infarction, it is the most common site for postinfarction free-wall rupture. Acute free-wall ruptures usually are rapidly fatal, but repair may be possible in some cases. [114 ]
A strategically located pericardial adhesion that arrests the rapidly moving blood front and aborts a rupture may result in the formation of a false aneurysm (that is, a contained rupture with a hematoma communicating with the ventricular cavity). [115 ] False aneurysms contain no myocardial elements in their walls, and consist only of epicardium and adherent parietal pericardium. Many are filled with mural thrombus. Half of postinfarction false aneurysms ultimately rupture.
Acute ventricular septal defect complicates only 1–2 percent of infarcts. Grossly, infarct-related septal defects are of two types: (1) single or multiple, sharply localized, jagged, linear passageways that connect the ventricular chambers (simple type); and (2) defects that tunnel serpiginously through the septum to a somewhat distant opening on the right side (complex type). [116 ] In simple lesions, neither gross hemorrhage nor peripheral laceration usually is present. In complex lesions, the tract may extend into regions remote from the site of the infarct. Complex ruptures most frequently involve the inferoseptal wall, especially basally. Without surgery, the prognosis following infarct-related septal rupture is poor; 50 percent of patients die within the first week (half of these within 24 hours), and only 15–20 percent survive beyond 2 months.
Mitral regurgitation secondary to myocardial infarction reflects loss of the structural or functional integrity of the mitral valve apparatus, usually at the level of the papillary muscle-left ventricular wall. Since chordae tendineae arise from the heads of the papillary muscles and provide continuity with each of the valve leaflets, interference with the structure or function of either papillary muscle can result in dysfunction of both mitral valve leaflets. Papillary muscles are perfused with blood that has traversed the entire transmural extent of the myocardium, and thus are particularly vulnerable to ischemic injury. Since the collateral circulation of the posterior myocardium is not as extensive as it is in the anterolateral segments, the posterior medial papillary muscle is susceptible to widespread necrosis and rupture. [117 ] Papillary muscle ruptures can occur with either subendocardial or transmural infarcts. They also can occur later than other rupture syndromes (i.e., as late as 1 month), since healing in this area can be particularly retarded because of the limited vasculature and resultant inaccessibility of inflammatory cells.
Other mechanisms can produce mitral regurgitation in the setting of chronic rather than acute ischemic heart disease. A papillary muscle can fail to tighten the chordae during systole, thereby allowing the mitral leaflets to prolapse into the left atrium. Additionally, a previously infarcted papillary muscle that ultimately undergoes fibrosis and shortening can fix the chordae deeply within the ventricle, maintaining an opened valve orifice. Moreover, left ventricular failure can cause ventricular dilation with distortion and malalignment of the papillary muscle axes. Left ventricular failure with subsequent dilation can produce mild stretching of the mitral annulus and contribute to valvular incompetence.
Isolated right ventricular infarction is rare. In contrast, involvement of the right ventricular myocardium by extension of an inferoseptal infarct occurs in approximately 10 percent of transmural infarcts and can have important functional consequences. [118 ] , [119 ] These include right ventricular failure with or without tricuspid regurgitation and arrhythmias, among others.
Following myocardial infarction, ventricular function and prognosis are influenced by changes in left ventricular size, shape, and thickness, involving both the infarcted and the noninfarcted segments of the ventricle. [78 ] The composite process, called ventricular remodeling, occurs by a combination of changes in left ventricular dimension (dilation) and regional compensatory hypertrophy of residual non-infarcted myocardium (determined by the metabolic state of the adjacent and remote myocardium). [120 ] , [121 ] The extent of architectural reorganization is determined by the patency of the infarct-related artery, ventricular loading conditions, size and distensibility of the infarct, and activation of tissue hormonal systems. Ventricular remodeling likely begins at the time of acute infarction and probably continues for months to years, until either a stable hemodynamic state is achieved or progressively severe cardiac decompensation occurs.
Intuitively, compensatory hypertrophy of noninfarcted myocardium should be hemodynamically beneficial. However, late decreases in ventricular performance with depression of regional and global contractile function may reflect degenerative changes in viable myocardium, as may occur in other states of hypertrophy in which pathologic changes follow those that are initially physiologic.
Congestive heart failure secondary to the myocardial consequences of coronary artery disease, often referred to as ischemic cardiomyopathy, may occur when the overall function of non-scarred myocardium can no longer maintain an adequate cardiac output. Moreover, the vulnerability of regions of hyperfunctioning but failing residual myocardium to additional ischemic episodes may be increased. [122 ]
Infarct extension is characterized by new necrosis in the same distribution as the existing recent infarct, but following its completion. [123 ] , [124 ] In contrast, infarct expansion is defined as disproportionate thinning and dilation of the infarcted region. [124 ] , [125 ] Infarct expansion increases the size of the infarcted segment by a combination of (1) slippage between muscle bundles, reducing the number of myocytes across the infarct wall; (2) disruption of the normal myocardial cells; and (3) tissue loss within the necrotic zone.
Expansion can be detected by two-dimensional echocardiography in up to 30 percent of transmural infarcts. More than 25 percent of hearts with infarcts studied at autopsy have marked expansion of the infarcted zone, frequently with superimposed mural thrombus. Patients with infarct expansion have increased morbidity and mortality. Regional dilation contributes to a significant increase in ventricular volume, thereby increasing the wall stress and workload of noninfarcted myocardium. Moreover, a combination of local myocardial contractility abnormality (causing stasis), endocardial damage (causing thrombogenicity), and systemic hypercoagulability can potentiate intracardiac mural thrombosis.
Ventricular aneurysms may develop in areas of infarct expansion. They most commonly result from a large transmural infarct that heals as a large area of thin scar tissue that paradoxically bulges during ventricular systole. [126 ] In contrast to false aneurysms, true ventricular aneurysms rarely rupture. Markedly hypertrophied myocardial remnants often are present in aneurysm walls. In addition, foci of mummified myocardium (necrotic but inadequately healed) may be present, indicating incomplete healing of an infarct. Although 50 percent of patients with chronic fibrous aneurysms have mural thrombus contained within the ventricle, systemic embolization occurs only rarely. Aneurysm formation historically was considered to be caused by stretching of maturing scars, but recent evidence suggests that early expansion of myocardial infarcts provides the substrate for scar thinning and late aneurysm formation. [23 ] Interestingly, some pharmacologic approaches to limiting infarct size, such as steroids and other anti-inflammatory agents, could exacerbate infarct expansion and aneurysm formation. [30 ] , [78 ] Whether the hemorrhage that frequently accompanies reperfusion facilitates or hinders infarct healing is yet unsettled. [33 ]
The specific anticipated complications and prognosis of myocardial infarction depend on myocardial infarct size, site, and transmurality. [78 ] Large infarcts have a higher probability of cardiogenic shock, arrhythmias, and late congestive heart failure. Patients with anterior infarcts are at greatest risk for regional dilatation and mural thrombi and have a substantially worse clinical course than those with inferior infarcts. In contrast, posterior infarcts are more likely to have serious conduction blocks and right ventricular involvement. Although the relative prognosis of patients with subendocardial versus transmural infarcts is controversial, mechanical complications clearly are more frequent and significant in patients with transmural lesions.