CHAPTER 37: PATHOLOGY OF MYOCARDIAL INFARCTION AND SUDDEN DEATH

The major cause of acute myocardial infarction (MI) is coronary atherosclerosis with superimposed luminal thrombus, which accounts for more than 80% of all infarcts. MIs resulting from nonatherosclerotic diseases of the coronary arteries are rare. In past decades, there have been several trends regarding the epidemiology and outcome of patients hospitalized with acute MI. Over the time span from 1975 to 2009, patients became significantly older, were more likely to be women, and were more likely to receive effective cardiac medications. Despite a greater prevalence of comorbidities, hospital survival rates have globally improved over time.¹ However, mortality has remained unchanged for patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment elevation MI,² mostly because of secular trends as a result of changing population.³ Reperfusion (blood flow restoration into the ischemic territory) is the only available treatment to stop the progression of ischemic damage during an MI, but comes at a price, inducing additional harm to the myocardium.⁴ Reperfusion injury, which accounts for up to 40% of total infarct size, is thus considered “a necessary evil.”⁵

Mechanisms of Myocardial Injury

The normal function of the heart muscle is supported by high rates of myocardial blood flow, oxygen consumption, and combustion of fat and carbohydrates (glucose and lactate). Under normal aerobic conditions, cardiac energy is derived from fatty acids, supplying 60% to 90% of the energy for adenosine triphosphate (ATP) synthesis (Fig. 37–1). The rest of the energy (10%-40%) comes from oxidation of pyruvate formed from glycolysis and lactate oxidation. Almost all of the ATP formed comes from oxidative phosphorylation in the mitochondria; only a small amount of ATP (< 2%) is synthesized by glycolysis. Approximately two-thirds of the ATP used by the heart goes to contractile shortening, and the remaining third is used by sarcoplasmic reticulum Ca²⁺ ATPase and other ion pumps.

Sudden occlusion of a major branch of a coronary artery shifts aerobic or mitochondrial metabolism to anaerobic glycolysis within seconds of reduced arterial flow. Myocardial ischemia primarily affects mitochondrial metabolism, resulting in a decrease in ATP formation by shutting off oxidative phosphorylation. The reduced aerobic ATP formation stimulates glycolysis and an increase in myocardial glucose uptake and glycogen breakdown (Fig. 37–2). Decreased ATP inhibits Na⁺/K⁺-ATPase, increasing intracellular Na⁺ and Cl, leading to cell swelling. Derangements in transport systems in the sarcolemma and sarcoplasmic reticulum increase cytosolic Ca²⁺, inducing activation of proteases and alterations in contractile proteins. Pyruvate is not readily oxidized in the mitochondria, leading to the production of lactate, a decrease in intracellular pH, and a reduction in contractile function. The decrease in pH also leads to greater ATP requirement to maintain Ca²⁺ homeostasis.^6,7

Electron microscopic alterations result from reversible and irreversible myocardial ischemic injury and are similar across animal species, with some variation in time course. Reversibly injured myocytes are edematous and swollen from the osmotic overload. The cell size is increased with a decrease in the glycogen content.^8,9,10 The myocyte fibrils are relaxed and thinned; I-bands are prominent secondary to noncontracting ischemic myocytes.⁷ The nuclei show mild condensation of chromatin at the nucleoplasm. The cell membrane (sarcolemma) is intact, and no breaks can be identified. The mitochondria are swollen, with loss of normal dense mitochondrial granules and incomplete clearing of the mitochondrial matrix but without amorphous or granular flocculent densities (Fig. 37–3). Irreversibly injured myocytes contain shrunken nuclei with marked chromatin margination. The two hallmarks of irreversible injury are cell membrane breaks and mitochondrial presence of small osmiophilic amorphous densities.¹¹ The densities are composed of lipid, denatured proteins, and calcium.¹² The cell membrane breaks are small and are associated with subsarcolemmal blebs of edema fluid (see Fig. 37–3B).

Irreversible ischemic injury is characterized by a variety of processes involving the sarcolemmal membrane and eventuating in its disruption and cell death. Increased cytosolic Ca²⁺ and mitochondrial impairment cause phospholipase activation and release of lysophospholipids and free fatty acids, which are incorporated within the cell and are damaged by peroxidation from free radicals and toxic oxygen species. Cleavage of anchoring cytoskeletal proteins and progressive increases in cell membrane permeability result in physical disruption and cell death.¹²

Different Types of Cardiomyocyte Death During Myocardial Infarction: Necrosis, Apoptosis, Autophagy, and Necroptosis

MI has traditionally been viewed as a manifestation of necrotic cell death, but recently, different forms of cardiomyocyte death have been identified during reperfused MI.⁴ Necrosis is morphologically characterized by myofibrillar contraction bands, swollen and ruptured mitochondria, destruction of cardiomyocyte membranes, microvascular destruction, hemorrhage, and inflammation. Most of these morphologic features are aggravated and made more manifest by reperfusion.^{13,14,15,16,17} Necrosis is thought to result from unregulated and uncoordinated pathophysiologic mechanisms. During ischemia, the developing acidosis from anaerobic glycolysis increases the influx of Na⁺ through the Na⁺/H⁺ exchanger, and intracellular Na⁺ accumulation is increased by the inhibition of Na⁺/K⁺-ATPase as a result of the lack of available ATP.^18,19 The subsequent exchange of Na⁺ for Ca²⁺ by reverse mode operation of the sarcolemmal Na⁺/Ca²⁺ exchanger induces intracellular Ca²⁺ overload. Upon reperfusion, the rapid normalization of pH and re-energization in the context of elevated cytosolic Ca²⁺ induces oscillatory release and re-uptake of Ca²⁺ into the sarcoplasmic reticulum, causing uncontrolled excess myofibrillar hypercontraction.^19,20,21 The normalization of the acidic pH also activates calpain, which digests the cytoskeleton and the sarcolemma.²² The high cytosolic concentrations of Na⁺ and Ca²⁺ result in intracellular edema when extracellular osmolarity is rapidly normalized by reperfusion. Finally, excess formation of reactive oxygen species contributes to sarcolemmal disruption.²³ Necrosis is typically followed by an inflammatory response.

Unlike necrosis, apoptosis, autophagy, and necroptosis are regulated processes with specific underlying signal transduction mechanisms.^24,25 Apoptosis is an energy-consuming form of cell death characterized by characteristic DNA strand breaks that are identified by DNA laddering and/or terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining.²⁶ Apoptosis can be initiated extrinsically by activation of sarcolemmal receptors, notably Fas and tumor necrosis factor-α receptors,²⁷ or intrinsically by mitochondrial release of cytochrome C, which initiates a cascade of caspase activation leading to intracellular proteolysis, typically without an inflammatory response.²⁵ A pivotal event in the initiation of apoptotic cell death is the opening of the mitochondrial permeability transition pore (MPTP).²⁸ The MPTP is a large-conductance megachannel that is closed under physiologic conditions but opens in response to increased concentrations of calcium, inorganic phosphate, or reactive oxygen species and to a decreased inner mitochondrial membrane potential, all of which are present in myocardial ischemia/reperfusion.^29,30 Formation and opening of the MPTP result in mitochondrial matrix swelling, ultimately leading to rupture of the outer membrane and release of cytochrome C to the cytosol, where it activates the caspase cascade. Pro- and antiapoptotic proteins of the Bcl family interact with the MPTP.³¹ Recently, the traditional view of the MPTP has been questioned because all of its purported constituents are dispensable under some conditions, and it is possible that the MPTP originates from F-ATP synthase.³² Autophagy is a regulated process of lysosomal degradation and re-cycling of proteins, including mitochondrial proteins (mitophagy).³³ Autophagy is characterized by the presence of double-membrane vesicles (autophagosomes) and increased expression of beclin-1, light chain 3, the autophagy-related gene 5-12 complex, p62, and parkin, with the last two being essential for mitophagy.³⁴ Somewhat paradoxically, cell death by autophagy is considered protective rather than detrimental.³⁵ For example, in pigs subjected to 45 minutes of coronary occlusion and reperfusion, the purported autophagy inducer chloramphenicol reduced infarct size.³⁶ However, the role of autophagy in myocardial ischemia/reperfusion injury in humans remains contentious.^37,38 Necroptosis shares features with necrosis and apoptosis but is distinctly regulated by activation of receptor-interacting protein kinases 1 and 3³⁹ and can be inhibited by substances such as necrostatin.⁴⁰

It is currently unclear to what extent necrosis, apoptosis, autophagy, and necroptosis are mutually exclusive processes and to what extent each contributes to infarct size. Typical features of apoptosis (TUNEL staining) and autophagy (characteristic protein expression) are both found in the triphenyltetrazolium chloride staining–defined infarct zone, which has traditionally been considered necrotic. The opening of the MPTP appears to be decisive for necrosis, apoptosis, and necroptosis, and mitochondria are also decisive in mitophagy/autophagy. The importance of regulated forms of cardiomyocyte cell death in ischemia/reperfusion injury is probably related more to their specific signal transduction mechanisms. Recognition of the different modes of cardiomyocyte death during infarction suggests the possibility of identifying therapeutic targets that can modulate these processes. From the clinical perspective, cardiomyocyte death is equally relevant whatever the mechanism.

Evolution of Myocardial Infarction, Determinants of Infarct Size, and Ventricular Remodeling

Myocardial ischemia occurs when oxygen and nutrient supply does not meet myocardial demand, and necrosis or infarction occurs when ischemia is severe and prolonged. Although biochemical and functional abnormalities begin almost immediately at onset of ischemia, severe loss of myocardial contractility occurs within 60 seconds, and other changes take a more protracted course; for example, the loss of viability (irreversible injury) takes at least 20 to 40 minutes after total occlusion of blood flow.⁴¹

Two zones of myocardial damage occur: a central zone with no flow or very low flow, and a zone of collateral vessels in a surrounding marginal zone. The survival of the marginal zone depends on the level of ischemia and the duration of ischemia. In autopsy hearts, the size of the ischemic zone surrounding an acute MI is associated with increased apoptosis and degree of occlusion of the infarct-related artery.⁴² The extent of coronary collateral flow is one of the principal determinants of infarct size. Indeed, at autopsy, it is common to see chronic total coronary occlusion and an absence of MI in the distribution of that artery. Absence of myocardial ischemia (revealed by electrocardiographic changes or angina during transient coronary balloon occlusion) is associated with presence of well-developed collateral vessels, suggesting that patients with well-developed collateral vessels have a low risk of developing acute MI upon abrupt closure of the culprit coronary artery.⁴³ Collaterals are better developed in patients with angina and in younger individuals than in older patients with acute infarcts.^44,45 Because infarct size is an important determinant of survival as well as development of congestive heart failure, efforts have been directed to limit infarct size by early reperfusion, reduction of myocardial oxygen demand, and prevention of reperfusion injury.

Reimer and Jennings, initially in 1979, showed that if a canine coronary artery was occluded for 15 minutes, for 40 minutes, for 3 hours, or permanently for 4 days, myocardial necrosis progressed as a “wave front phenomenon” (Fig. 37–4A).^13,46 The extent of myocardial necrosis therefore depended on the duration of coronary occlusion. After only 15 minutes of occlusion, no infarct occurred. At 40 minutes, the infarct was subendocardial, involving only the papillary muscle, resulting in 28% of the myocardium at risk. At 3 hours after coronary artery occlusion and reperfusion, the infarct was significantly smaller compared with nonreperfused permanently occluded infarct (62% of area at risk). The infarct size was the greatest in permanent occlusion, becoming transmural and involving 75% of the area at risk (Fig. 37–4B).¹³ In the dog model, it is impossible to achieve 100% infarction of the area at risk because of species-related native collaterals. In humans, it has been shown that approximately 40% of patients with acute MI have well-developed collateral circulation.^44,45

Other than the presence of collateral circulation, factors that influence infarct size include preconditioning, which may greatly reduce infarct size, and reperfusion.⁴¹ However, there is a balance between benefits of reperfusion in reducing infarct size and reperfusion injury, which is dependent on the time of onset. In general, if ischemic myocardium is reperfused early, the degree of myocardial salvage greatly exceeds damage from free radicals and calcium loading caused by reperfusion. These positive functional consequences of reperfusion are most beneficial within the initial 12 hours after occlusion in humans.

It was documented in the late 1970s that transmural infarcts may increase in size for weeks after the initial event, and the degree of this expansion is associated with a decrease in survival rate.⁴⁷ The processes involved in postinfarction ventricular dilatation are known as ventricular remodeling. In general, transmural extent of necrosis is a major determinant of infarct expansion (remodeling) based on large infarct size and the persistence of the occlusion. The preservation of islands of viable myocardium in the subepicardial regions is associated with decreased remodeling or infarct expansion. Other factors that are implicated in reduced ventricular remodeling include microvascular integrity⁴⁸ and initial ventricular compliance.⁴⁹ The effect of reperfusion on ventricular remodeling is clear as far as early reperfusion is concerned because there are definite benefits in reducing infarct size and expansion. The benefits of late reperfusion beyond myocardial salvage are unclear. It has been demonstrated that remodeling is affected by the presence of viable zones after successful late PCI.⁵⁰ In general, the mechanisms of ventricular remodeling are poorly understood because different techniques have been used to assess myocardial viability in human subjects, animal studies, and postmortem specimens. The immune system and the release of matrix metalloproteinases are now being linked to remodeling.^51,52,53,54

The No-Reflow Phenomenon and Reperfusion Injury

The no-reflow phenomenon (also termed microvascular obstruction) was originally described by Kloner et al⁵⁵ in 1974 in an experimental canine model of MI. They demonstrated homogenous distribution of thioflavin S dye after 40 minutes of ischemia and reperfusion. However, after 90 minutes of ischemia, areas of no-reflow were identified mainly in the subendocardial regions as zones not staining with thioflavin S. By electron microscopy, they showed swollen endothelial protrusions and membrane-bound intraluminal bodies, which obstructed the capillary lumen and resulted in plugging of the capillaries by red blood cells, neutrophils, platelets, and fibrin thrombi. The areas not stained by thioflavin S were characterized by low regional myocardial blood flow. It is now well-known that angiographic no-reflow is also a strong predictor of major cardiac events, similar to congestive heart failure, malignant arrhythmias, and cardiac death, after acute MI.⁴

The process of restoring blood flow to ischemic myocardium has shown utility in limiting cell death in the presence of severe ischemia. Reperfusion, however, has paradoxical effects on myocardium that can result in adverse reactions, thereby reducing its beneficial actions. During reperfusion, the myocardium is subject to abrupt biochemical and metabolic changes governed by several mediators that interact with each other in complex ways.^4,56 The term reperfusion injury was coined to describe reperfusion-related expansion or worsening of the ischemic cardiac injury as assessed by contractile performance, the arrhythmogenic threshold, conversion of reversible to irreversible myocyte injury, and microvessel dysfunction.

The coronary microcirculation, the interface between the epicardial vessel and the cardiomyocytes, plays a critical role in the complex phenomenon of no-reflow and reperfusion injury. No matter how efficiently and rapidly the blood flow is restored to the epicardial artery, if there is a microvascular obstruction, the myocardial tissue will remain without efficient perfusion.⁴ Potential mediators of reperfusion injury include oxidative stress (oxygen paradox), sudden increases in intracellular Ca²⁺ (calcium paradox), rapid restoration of physiologic pH (pH paradox), and inflammation.^4,56 Neutrophils are activated early during myocardial ischemia and precede the appearance of histologic tissue injury. Reperfusion markedly enhances the infiltration of neutrophils into the ischemic region. The essential initiating step involves interaction of neutrophils with vascular endothelial cells (adhesion). This is followed by activation, diapedesis, and extravascular migration into surrounding myocytes. Production of additional chemoattractants by activated neutrophils amplifies the initial inflammatory response. Neutrophil activation causes a greatly enhanced oxygen uptake by the cell, resulting in the production of large quantities of reactive oxygen species that may lead to disruption of excitation-contraction coupling and inactivate antiproteases present in the plasma.⁵⁷

At the time of myocardial reperfusion, there is an abrupt increase in intracellular Ca²⁺, leading to a disturbance in the normal mechanisms that regulate Ca²⁺ within the cardiomyocyte, known as the calcium paradox.⁵⁶ This intracellular Ca²⁺ overload induces death by causing hypercontracture of myofibrils and MPTP opening.^4,56 MPTP is a nonselective channel located on the inner mitochondrial membrane and is a critical determinant of lethal reperfusion injury. Opening the channel, as occurs within the first few minutes after reperfusion, uncouples oxidative phosphorylation, resulting in ATP depletion and cell death.

In addition, experimental studies have shown that reperfusion of ischemic myocardium generates reactive oxygen species (oxygen paradox). This oxidative stress results in extension of the myocardial injury beyond that induced by ischemia alone. A key mechanism involves the reduction of the bioavailability of the nitric oxide, a cardioprotective signaling molecule. Nitric oxide inhibits neutrophil accumulation, inactivates superoxide radicals, and improves coronary blood flow.⁵⁶ Further contributing to reperfusion injury is the rapid restoration of physiologic pH that occurs after washout of lactic acid and the activation of the sodium-hydrogen exchanger and the sodium-bicarbonate symporter.⁶

The understanding of mechanisms leading to myocardial death during ischemia/reperfusion injury has led to several potential strategies to limit infarct size. These are beyond the scope of this chapter and are described in Chap. 38.

Microembolization

Acute coronary thrombosis with or without percutaneous intervention results in the embolization of microparticles, including fragments of fibrin-platelet thrombus and necrotic core. Coronary microembolization is associated with arrhythmias, contractile dysfunction, microinfarcts, and reduced coronary reserve.⁵⁸ Early autopsy studies showed a 30% rate of microembolization in cardiac disease, often associated with focal myocyte necrosis; however, more recent studies show a significantly higher rate of distal embolization 54%.^59,60 The rate of coronary microembolization is highest in patients with documented epicardial coronary thrombosis, especially in those with acute MI. Few data are available that compare acute plaque rupture with acute plaque erosion and the rate of embolization, but it has been suggested that distal embolization is more frequent in erosions (70%) than ruptures (42%).⁶⁰ These emboli and microvessel obstructions have a prominent clinical role because myonecrosis is often associated with these findings.

Other potential sources of distal embolization include primary PCI, PCI of atherosclerotic plaque in native and saphenous vein grafts, and thrombolysis. Thus, angiographic evidence of distal embolization in patients presenting with acute MI undergoing primary PCI ranges from 15% to 70% (Fig. 37–5).^61,62,63 A detailed description of the mechanisms leading to microvascular obstruction during MI (ischemia/reperfusion) can be found in Chap. 38.

Hibernating Myocardium

Left ventricular systolic dysfunction caused by ischemia may arise in dead myocardium or from hypocontractile areas of viable myocardium. In the early 1980s, Rahimtoola et al⁶⁴ found significant improvement in left ventricular function after coronary revascularization in a subset of patients with depressed ventricular performance. They postulated that the mechanism of poor myocardial contractility was chronic ischemia, which could be improved by revascularization. The premise behind this rationale was dependent on the surviving myocardium being in a functional, albeit depressed, state, suggesting that the myocardium may adapt to chronic ischemia by decreasing its contractility but preserving viability.^65,66 Reversibly, dysfunctional tissue is commonly referred to as hibernating myocardium. Sheiban et al⁶⁷ demonstrated that 5 to 7 minutes of angioplasty balloon inflations in the coronary arteries of patients undergoing interventional procedures, followed by tracking of the resolution of the regional wall motion abnormalities over the next 5 days, showed persistence of regional wall motion abnormalities for up to 36 hours. Similarly, return of left ventricular function has been studied after acute MI. Delayed recovery of wall motion was observed in the infarct region, with a positive change in wall motion from 0.2 at 3 days to 1.0 at 6 months in patients with reperfusion but not in those without reperfusion, as measured by the centerline method.⁶⁸

The concept of myocardial hibernation was initially based on clinical observation. Subsequently, there have been a number of experimental studies to support the concept that ischemia is not the result of simple inadequacy of blood flow for myocardial contraction but that there is a stepwise decrease in function based on incremental decrease in oxygen-supplying perfusion (so-called perfusion-contraction matching). Evidence suggests that repeated episodes of ischemia-reperfusion may result in a state of chronic hibernation, with alterations in the flow-function relationship and decreased oxygen demand. Chronically hibernating myocardium demonstrates alterations in adrenergic control and calcium responsiveness. Substances that are upregulated in chronic hibernating myocardium include heat shock protein, hypoxia-inducible factor, inducible nitric oxide synthase, cyclooxygenase-2, and monocyte chemotactic protein. Because some of these pathways are involved in preconditioning, a relationship between cardiac hibernation and preconditioning is postulated.

Morphologically, hibernating myocytes show loss of contractile elements, especially in the perinuclear region and occasionally throughout the cytoplasm. The space left by the dissolution of the myofibrils is occupied by glycogen, as evidenced by the strong positivity for the periodic acid–Schiff reagent. Ultrastructurally, there is depletion of sarcomeres, most pronounced in the perinuclear region, with increased glycogen. The nuclei are enlarged, with a tortuous nuclear membrane and evenly distributed heterochromatin. The mitochondria are elongated, shrunken, and osmiophilic.⁶⁹ The interstitium shows an increase in connective tissue. Increased numbers of apoptotic myocytes, using the technique of DNA nick-end labeling,⁷⁰ as well as an increase in autophagic and oncotic cell death, have been demonstrated.^71,72

The composition and distribution of sarcomeric, cytoskeletal, and membrane-associated proteins is significantly altered in chronic myocardial hibernation.⁷³ There is a disorderly increase in cytoskeletal desmin, tubulin, and vinculin, with a decrease in contractile proteins myosin, titin, and actinin. More recently, decreased connexin 43, a membrane transport protein, has been associated with reduced gap junction size and a proposed propensity for arrhythmias in the hibernating state.⁷⁴

Advances in noninvasive imaging techniques have helped in the characterization of the hibernated myocardium in patients. Clinical functional techniques such as stress echocardiography and cardiac magnetic resonance are more specific but less sensitive than nuclear modalities, which assess perfusion and metabolic activity, in the detection of hibernating myocardium.⁶⁵ Radionuclide imaging with positron emission tomography (PET) seems to be especially suitable in assessing cardiac metabolism.⁷⁵ However, recent advances in magnetic resonance make this method a comprehensive modality that can accurately determine the amount of hibernating myocardium as well as the presence and degree of myocardial ischemia and the extent of the scar.^75,76

The vast majority of MIs occur in patients with coronary atherosclerosis, with more than 90% associated with superimposed luminal thrombi. Arbustini et al⁷⁷ found coronary thrombi in 98% of patients dying with clinically documented acute MI, and of those thrombi, 75% were caused by plaque rupture and 25% by plaque erosion. There are gender differences in the causation of coronary thrombi leading to acute MI: Arbustini et al⁷⁷ showed that 37% of thrombi in women were erosion compared with only 18% in men. The thrombus age also varies; the majority of acute thrombi (< 1 day) have been observed in plaque rupture, whereas the majority of thrombi in plaque erosion are organizing (> 1 day)⁷⁸ (Fig. 37–6). Kramer et al⁷⁹ have reported their findings in thrombi retrieved from patients presenting with ST-segment elevation MI during percutaneous coronary angioplasty intervention and demonstrate that more than 50% of thrombi show organization of more than 1 day in duration. Furthermore, the age of the thrombus, in addition to other risk factors, was an independent predictor of long-term mortality, especially within the first 2 weeks as well as at 4 years after PCI.

Although an individual severe stenosis is more likely to become occluded by a thrombus than a lesion with less severe stenosis, the less severely narrowed plaques give rise to more occlusions because there are many more sites that are mild-to-moderately narrowed.⁸⁰ We have observed that the mean percent stenosis underlying coronary plaque erosion is 70% versus 80% at the site of plaque rupture; however, 82% of fatal plaque erosions result in total occlusions compared with only 57% of plaque ruptures.⁸¹ The majority of thin cap fibroatheromas, acute and healed ruptures, and lesions with fibroatheromas occur predominantly in the proximal portion of the three major coronary arteries, and about 50% arise in the midportion of these arteries. By far, the proximal portion of the left anterior descending coronary artery (LAD) is the most frequent location, with sites in the proximal right and left circumflex contrary arteries about half as common. The culprit coronary artery of infarction at autopsy is most frequently the LAD (~ 50%), followed by the right coronary artery (30%-45%) and then the left circumflex artery (15%-20%).⁷⁸ No thrombi are found in fewer than 5% of acute MIs.

Gross Pathologic Findings

The earliest change that can be grossly discerned in the evolution of acute MI—pallor of the myocardium—occurs 12 hours or later after the onset of irreversible ischemia. The gross detection of infarction can be enhanced by the use of tetrazolium salt solutions, which form a colored precipitate on gross section of fresh heart tissue in the presence of dehydrogenase-mediated activity. The tetrazolium salts (nitroblue tetrazolium [NBT] and 2,3,5-triphenyltetrazolium chloride [TTC]) are dyes that are sensitive to the presence of tissue dehydrogenase enzyme activity, which is depleted in the infarcted myocardium. It has been shown that myocardial infarct can be detected by NBT as early as 2 to 3 hours in dogs and in a little less time in pigs because of poor collaterals.⁸² Red color (TTC) or blue color (NBT) only forms in the normal noninfarcted myocardium, thus revealing the pale, nonstained, infarcted region (Fig. 37–7). In humans, the necrotic myocardium can be detected within 2 to 3 hours after infarct by immersion of the fresh heart slices in a solution of TTC or NBT. TTC staining has a diagnostic sensitivity of 77% and a specificity of 93% compared with routine histology, with predictive values of positive and negative test of 81% and 91%, respectively.⁸³

At approximately 24 hours after the onset of irreversible ischemia, the pallor is enhanced (Fig. 37–8). However, in the present era, most patients receive primary PCI or thrombolytic therapy with percutaneous intervention as reperfusion strategy; therefore, most in-hospital patients will have received tissue plasminogen activator, streptokinase, or glycoprotein IIb/IIIa inhibitors with balloon angioplasty and stenting, which lyse the thrombus and restore blood flow into the area of infarction. Consequently, in a reperfused infarct, the infarcted region will appear red from trapping of the red blood cells and hemorrhage from the rupture of the necrotic capillaries (Fig. 37–9). However, if there has been no reperfusion, the area of the infarct is better defined at 2 to 3 days with a central area of yellow discoloration that is surrounded by a thin rim of highly vascularized hyperemia (see Fig. 37–8). At 5 to 7 days, the regions are much more distinct, with a central soft area and a depressed hyperemic border. At 1 to 2 weeks, the infarct begins to heal, with infiltration by macrophages as well as early fibroblasts at the margins. At the same time, the infarct begins to be more depressed, especially at the margins where organization takes place, and there is a white hue to the borders (Table 37–1; see also Fig. 37–8). Healing may be complete as early as 4 to 6 weeks in small infarcts or may take as long as 2 to 3 months when the area of infarction is large. Healed infarcts are white from the scarring, and the ventricular wall may or may not be thinned (aneurysmal). In general, infarcts that are transmural and confluent are likely to result in thinning, but subendocardial and nonconfluent infarcts are not.

Light Microscopic Findings in Nonreperfused Infarction

The earliest morphologic characteristic of MI that can be discerned and observed between 12 and 24 hours after onset of chest pain is the hypereosinophilic myocyte (Fig. 37–10). Despite the hypereosinophilia of the cytoplasm, which is seen best on routine hematoxylin and eosin staining, the myocyte striations appear normal, and some chromatin condensation may be seen in the nucleus. The area of infarction may show interstitial edema; however, this change is difficult to appreciate in human autopsy hearts and better appreciated in animal experiments. It has been suggested in experimentally induced infarction that the appearance of “wavy fibers” may be the earliest change and is thought to be the result of stretching of the ischemic noncontractile fibers by the adjoining viable contracting myocytes. Wavy fiber change is, however, nonspecific and occurs in the absence of ischemia, especially in the right ventricle. Neutrophil infiltration is present by 24 hours at the border areas. As the infarct progresses between 24 and 48 hours, coagulation necrosis is established with various degrees of nuclear pyknosis, early karyorrhexis, and karyolysis. The myocyte striations are preserved, and the sarcomeres elongate. The border areas show prominent neutrophil infiltration by 48 hours (see Fig. 37–10).

At 3 to 5 days, the central portion of the infarct shows loss of myocyte nuclei and striations; in smaller infarcts, neutrophils invade within the infarct and fragment, resulting in more severe karyorrhexis (nuclear dust). Loss of myocyte striations is best appreciated by using the Mallory trichrome stain. Markers of ischemia include hypoxia-inducible factor-1 and cyclooxygenase-2, which can be demonstrated immunohistochemically.⁴² The influx of inflammatory cells, including mast cells, induces a cascade of chemokines, which suppress further inflammation and result in scar tissue.^84,85 Macrophages and fibroblasts begin to appear in the border areas. By 1 week, neutrophils decline, and granulation tissue is established with neocapillary invasion and lymphocytic and plasma cell infiltration. Although lymphocytes may be seen as early as 2 to 3 days, they are not prominent in any stage of infarct evolution. Eosinophils may be seen within the inflammatory infiltrate but are only present in 24% of infarcts.⁸⁶ There is phagocytic removal of the necrotic myocytes by macrophages, and pigment is seen within macrophages.

By the second week, fibroblasts are prominent, but their appearance may be seen as early as day 4 at the periphery of the infarct. There is continued removal of the necrotic myocytes as the fibroblasts are actively producing collagen and angiogenesis occurs in the area of healing. The healing continues, and depending on the extent of necrosis, the healing may be complete as early as 4 weeks or may require 8 weeks or longer to complete (see Fig. 37–10). The central area of infarction may remain unhealed, showing mummified myocytes for extended periods even though the infarct borders are completely healed. For this reason, it is important to evaluate the age of the infarct by examining the border areas that adjoin the noninfarcted muscle.

The magnitude of repair and healing depends not only on the infarct size but also on local and systemic factors. If there is good collateral blood flow locally, healing will be relatively rapid, especially at the lateral borders where viable myocardium interdigitates with necrotic myocardium. There may be various levels of healing within an infarct, because of differences in blood flow in adjoining vascular beds caused by variable extent of coronary narrowing. The border areas may show hemorrhage and contraction band necrosis, depending on regional variations in blood flow. Systemic factors that influence repair of myocardium are the systemic blood pressure and cardiac output, which are severely decreased in the hearts of patients with multisystem failure.

Light Microscopic Appearance of Reperfused Acute Myocardial Infarction

In dogs, the amount of myocardium that can be salvaged depends on the duration of total occlusion of the artery supplying the area of infarction. The maximal salvage is possible, both in dogs and humans, if the artery is opened within 6 hours. The myocardium in dogs after 90 minutes of occlusion followed by reperfusion and sacrifice at 24 hours shows a hemorrhagic infarct limited to the area of occlusion, which is subendocardial in extent. Hemorrhage occurs when the myocardial blood flow during the occlusion period is less than one-fifth of normal. The myocytes are thin, hypereosinophilic, and devoid of nuclei or showing karyorrhexis, with ill-defined borders and interspersed areas of interstitial hemorrhage. There is a diffuse, but mild, neutrophil infiltration. Within 2 to 3 days, macrophage infiltration is obvious, and there is phagocytosis of necrotic myocytes and early stages of granulation tissue. The infarct healing in dogs is more rapid than that in humans, most likely a result of nondiseased adjoining coronary arteries (collaterals) and a lack of underlying myocardial disease. In humans with acute MI, there is often chronic ischemia secondary to extensive atherosclerotic disease.

In man, if reperfusion occurs within 4 to 6 hours after onset of chest pain or electrocardiographic (ECG) changes, there is myocardial salvage, and the infarct is likely to be subendocardial without transmural extension. There will be a nearly confluent area of hemorrhage within the infarcted myocardium, with extensive contraction band necrosis. The extent of hemorrhage depends on the extent of reperfusion of the infarct, as well as the extent of capillary necrosis. The larger the infarct and the longer the duration of the infarct, the greater is the hemorrhage. The degree of hemorrhage may be variable and nonuniform because blood flow depends on the residual area of coronary narrowing and the amount of thrombolysis. Within a few hours of reperfusion, neutrophils are evident within the area of necrosis, but they are usually sparse (Fig. 37–11). In contrast to nonreperfused infarcts, neutrophils do not show concentration at the margins. However, reperfused infarcts often demonstrate areas of necrosis at the periphery, with interdigitation with noninfarcted myocardium. Macrophages begin to appear by day 2 or 3, and stromal cells show enlarged nuclei and nucleoli by days 3 and 4 (see Fig. 37–11). Neutrophil debris, which may be concentrated at the border areas in cases of incomplete reperfusion, is seen by 3 to 5 days. Fibroblasts appear by days 3 to 5, with an accelerated rate of healing compared with nonreperfused infarcts. By 1 week, there is collagen deposition with disappearance of neutrophils and prominence of macrophages containing pigment derived from ingested myocytes (see Fig. 37–11). Angiogenesis is prominent, and lymphocytes are often seen. Infarcts at 5 to 10 days are more cellular, and there is prominent myocytolysis (loss of myofibrils). As early as 2 to 3 weeks, subendocardial infarcts may be fully healed (see Fig. 37–11). Five to 10 layers of subendocardial myocytes are spared without necrosis. However, myofibrillar loss, which is a result of ischemia not severe enough to cause cell death, is prominent in this subendocardial zone. Larger infarcts and those reperfused after 6 hours take longer to heal. Infarcts reperfused after 6 hours show larger areas of hemorrhage compared with occlusions of shorter duration and more immediate reperfusion (see Fig. 37–9). However, myocytes maintain their striations and become stretched and elongated, and because they do not respond to calcium influx, they do not show significant contraction band necrosis. Even though reperfusion should occur within 6 hours of occlusion for maximal myocyte salvage, there appears to be some benefit in opening an artery regardless of the duration of coronary occlusion.

In Vivo Pathology of Myocardial Infarction

Histologic evaluation has been classically considered the gold standard for the evaluation of myocardial tissue. However, it is poorly suited for serial measurements into the required follow-up clinical field. Conversely, several imaging modalities have been developed for the in vivo characterization of the heart, including PET, single-photon emission computed tomography (SPECT),⁸⁷ and computed tomography (CT).⁸⁸ However, the noninvasive technique of cardiac magnetic resonance (CMR) has captured most of the attention in preclinical and clinical arenas because it offers a combination of high spatial resolution and high soft tissue contrast with no ionizing radiation.⁸⁹ In fact, CMR is able to perform in vivo tissue characterization, which is considered a surrogate for histologic evaluation.

Testing the efficacy of cardioprotective therapies in clinical and preclinical trials benefits from measuring both infarct size and area at risk to calculate the amount of myocardial salvage. By subtracting infarct size from area at risk (the so-called salvaged index), it can better quantify the efficacy of a therapy (ie, proportion of potential myocardial loss = area at risk that finally is salvaged).^41,90 CMR has become the in vivo gold standard for quantifying salvage myocardium. Depiction and quantification of area at risk by CMR rely on the concept that the entire area at risk shows an edematous reaction, regardless of the outcome (death or salvage) of the tissue. Hyperintense areas on qualitative T2-weighted CMR imaging have been classically proposed as having a good correlation with post-MI edema and, thus, with area at risk.⁹¹ However, it is still a matter of controversy whether these hyperintense areas can accurately track the real area at risk.^92,93 Newer quantitative CMR methods such as T1 and T2 mapping, which allow actual tissue characterization by measuring intrinsic tissue properties in the form of T1 and T2 relaxation times, respectively, may overcome some of the limitations of qualitative CMR imaging, providing accurate measures of tissue properties,⁹⁴ including post-MI edema (Fig. 37–12).^95,96 Indeed, infarct core T1 values have been inversely associated with adverse remodeling and outcomes after MI.⁹⁷

It has been assumed for a long time that, in the context of MI, myocardial edema appears early after ischemia/reperfusion and persists in a stable form for at least 1 week.^98,99 This notion set the basis for the retrospective evaluation of area at risk during this time window. However, the accepted evolution of post-MI edema has been recently challenged using reference histologic and CMR imaging techniques in a human-like preclinical MI model suggesting that the postinfarction edematous reaction is not stable, but rather follows a bimodal pattern.^95,100 An initial wave of edema appears abruptly upon reperfusion and dissipates at 24 hours and is a result of reperfusion itself, whereas a deferred wave of edema appears several days after MI, increasing to a maximum on postreperfusion day 7. The latter second wave of postinfarction edematous reaction is a result of early healing processes (Fig. 37–13).¹⁰¹ Nonreperfused hearts exhibit different dynamics of the bimodal edema phenomenon, with a delay in healing.¹⁰¹ This novel finding has important biologic, diagnostic, prognostic, and therapeutic implications.

Macroscopic scar fibrosis after MI can be accurately detected and quantified by delayed enhancement sequences both in CMR and CT,¹⁰² with its size and distribution being well correlated with remodeling and prognosis.^{102,103,104,105} In addition, evaluation of delayed enhancement may facilitate the study of scarring-related ventricular arrhythmias after MI.¹⁰⁶ Conversely, conventional delayed gadolinium enhancement CMR sequences are less suitable for in vivo detection of microscopic fibrosis as a result of smaller collagen deposits, as occurs in the remote myocardium.^107,108 However, relying on quantification of the T1 relaxation times in remote myocardial areas before (native T1)¹⁰⁹ and after contrast enhancement equilibrium (myocardial extracellular volume fraction),¹⁰⁷ CMR can provide noninvasive prognostic information associated with left ventricular remodeling and cardiac events after MI.¹⁰⁹

Finally, novel noninvasive imaging methods such as CMR, SPECT, or PET, using targeted imaging agents, allow imaging of the molecular processes underlying the post-MI immune cell response¹¹⁰ and subsequent remodeling.¹¹¹ These probes can target apoptosis, necrosis, inflammatory cells, angiogenesis, and extracellular matrix, and have been assessed in preclinical models. However, translating this work to the patient in a cost-effective, clinically beneficial manner remains a significant challenge.¹¹²

Myocardial Remodeling After Myocardial Infarction

Myocardial remodeling is defined as changes in size, shape, and function of the heart occurring secondary to molecular, cellular, and interstitial events after MI. Left ventricular remodeling begins within the first few hours after an infarct and continues to progress, and the infarcted myocardium undergoes rapid turnover during the first 1 to 2 weeks after MI. Myocardial remodeling is influenced by both the severity of the infarct and recurrent infarction.

MI generates a systemic inflammatory response, with activation of the complement cascade, transforming growth factor-β, and chemokines and free radical generation. In the first 24 hours of reperfusion, neutrophils, monocytes, and lymphocytes infiltrate the myocardium, and resident mast cells release preformed mediators that initiates the cytokine cascade. Cytokine-stimulated myocytes in the ischemic border zone, expressing intercellular adhesion molecule-1, may be susceptible to neutrophil-mediated cytotoxic injury. During the healing phase, infiltrating monocytes differentiate into macrophages, which, along with mast cells, accumulate in the healing scar, inducing fibroblast proliferation. Classically activated M1 macrophages are the first line of defense that influence the subsequent phase of the healing process by M2 macrophages. The prolonged presence of M1 macrophages extends the proinflammatory environment and causes expansion of the infarcted area. A delayed transition to M2 macrophages thus hampers the formation of scar tissue, predisposing to heart failure development as a result of expansion of the injured ventricular wall (negative remodeling). Improved healing may be attained by modulating macrophage polarization toward the M2 phenotype, thus promoting the resolution of inflammation and improved infarct healing.¹¹³ The differentiation of M1 to M2 requires the presence of T regulatory cells and stimulator of cytokine signaling-1, whereas for M1, polarization occurs in the presence of interferon regulator factor-5, collapsing response mediators-2, and stimulator of cytokine signaling-3. Additionally, in studies where M2 polarization has been enhanced, resolution of inflammation has been observed, with early infarct healing resulting in the prevention of negative remodeling.¹¹³ Monocytes are recruited from the spleen and further differentiate at the injury site, as has been shown in animal models. Patients with acute MI show a higher splenic metabolic activity, as determined by whole-body fluorine-18–fluorodeoxyglucose PET-CT,¹¹⁴ similar to that described in mice.¹¹⁵

The complications of MI may manifest immediately or may appear late and depend on the location and extent of infarction. The acute complications consist of arrhythmias and sudden death, cardiogenic shock, infarct extension, fibrinous pericarditis, cardiac rupture (including papillary muscle rupture), and mural thrombus and embolization.

Arrhythmias and Sudden Death

Arrhythmias after MI are varied and include atrial arrhythmias, ventricular arrhythmias (the major source of sudden death), and conduction system disturbances. Almost 90% of patients develop a cardiac rhythm abnormality after acute infarction.

Atrial fibrillation occurs in approximately 5% to 10% of patients after infarction, especially in older patients with heart failure,¹¹⁶ and is associated with increased risk of mortality in MI patients.¹¹⁷ Adequate rate control is important to reduce myocardial oxygen demand and to improve cardiac performance and can be performed by administration of β-blockers, digoxin, or amiodarone. Urgent cardioversion may be considered in patients presenting with hemodynamic instability.^118,119

Ventricular tachyarrhythmias that occur after reperfusion period may be a manifestation of a serious underlying condition, such as continuing myocardial ischemia, heart failure, altered autonomic tone, hypoxia, and electrolyte and acid-base disturbances. Ventricular fibrillation occurs in approximately 4.5% of patients, with the greatest incidence in the first hour.¹²⁰ Sudden death occurs in 25% of patients after MI, often before patients reach the hospital. The proportion of deaths from ischemic heart disease that are sudden is almost 60%.

The long-term prognostic significance of early (< 48 hours) ventricular fibrillation or sustained ventricular tachycardia in patients with acute MI is still controversial. Ventricular arrhythmias are important markers of electrical instability and are helpful in predicting patients who will die suddenly after MI.¹²¹ Several types of tachyarrhythmias are associated with decreased survival, including subacute and late premature ventricular complexes, nonsustained ventricular tachycardia of late onset, and sustained monomorphic ventricular tachycardia in the acute post-MI phase. Early mortality is higher when ventricular fibrillation occurs in the acute phase after infarction, but if the patient survives, long-term prognosis is unaffected.¹²² The early administration of β-blockers in the context of acute MI and no contraindications seem to reduce the burden of ventricular arrhythmias.^{123,124,125,126}

The mechanism of postinfarct arrhythmias involves the adjoining ischemic but noninfarcted myocardium. In this acidotic arrhythmogenic zone, there is the release of metabolites such as potassium, calcium, and catecholamines, with low levels ATP and hypoxemia. Later in the course of MI, arrhythmias may occur as a result of scar tissue surrounding viable myocytes.¹²⁷ Experimental data suggest an association between sodium (Na⁺) channel loss of function and sudden cardiac death. An effect of oxidative stress on Na⁺ channel function has been postulated to play a role in postinfarct arrhythmias. Na⁺ channel dysfunction may involve lipid peroxidation.¹²⁸

Arrhythmias in the remodeled ischemic myocardium evolve from sites of slow conduction near the border zone, which is characterized by rate-dependent slowing and reentry. It is believed that blockade of the Na⁺ channel is responsible for this slowing because cells of the epicardial border zone show postrepolarization refractoriness, a key requirement for the initiation of ischemia-related ventricular tachycardia.

Emerging clinical imaging techniques are being used to measure areas at risk for arrhythmias. Infarct surface area and mass, as measured by cardiac magnetic resonance imaging (MRI), are better identifiers of patients who have a substrate for inducible ventricular tachycardia than left ventricular ejection fraction.^129,130,131 The extent of the peri-infarct zone measured by MRI is correlated with the risk of arrhythmias.^129,130,131 The role of adrenergic imbalance in the generation of arrhythmias associated with acute coronary syndromes has been emphasized.¹²⁹

After acute infarction, 25% of patients experience a cardiac conduction disturbance within 24 hours. Bradyarrhythmias during the first few hours of acute MI are triggered by inferior MI and are usually benign, with conduction disease beyond the first 24 hours requiring the most attention. Conduction disturbances (right bundle branch block and left anterior fascicular block) resulting from anterior MI are associated with higher mortality because of necrosis of the conduction system.

Cardiogenic Shock

Heart failure after MI ranges from pulmonary congestion to profound organ hypoperfusion or cardiogenic shock. Cardiogenic shock is caused by decreased systemic cardiac output in the presence of adequate intravascular volume. Cardiogenic shock after MI usually occurs if there is loss of at least 40% of the left ventricular mass, either acutely or in combination with scarred myocardium from old healed infarcts.^132,133 In approximately 10% of patients who develop cardiogenic shock, shock occurs before hospitalization immediately upon presentation. Much more commonly, shock develops while the patient is in the hospital, presumably from infarct extension (Fig. 37–14A). Cardiogenic shock accounts for almost half of the short-term deaths after MI. The remainder of deaths are the result of cardiac rupture and arrhythmias. Patients with extension of infarction (reinfarction) into subendocardial zones remote from the larger infarct may develop cardiogenic shock (Fig. 37–14B). In turn, cardiogenic shock renders the remaining viable myocardium prone to ischemic necrosis because of poor perfusion. In patients presenting with cardiogenic shock, transthoracic (and transesophageal if necessary) echocardiography is mandatory to exclude mechanical complications and to evaluate left ventricular ejection fraction and right ventricular function. Management of cardiogenic shock includes medical therapy with inotropic (dobutamine) and/or vasopressor agents (norepinephrine), mechanical circulatory support, and emergent revascularization.^118,119

Two related but distinct complications of MI are infarct extension and infarct expansion, or remodeling (see the Evolution of Myocardial Infarction section). Infarct extension results from an incremental increase in absolute necrotic myocardium and may be the result of infarction remote from the original infarct in either the right or left ventricle (see Fig. 37–14). Infarct extension usually occurs between 2 and 10 days after infarction, at a time when ECG changes are evolving and the troponin I or T is still high. However, the rapidly decreasing serum creatine kinase myocardial band (CK-MB) after the first 24 hours may be useful for the detection of infarct extension along with new Q wave on electrocardiography. The risk factors associated with infarct expansion are cardiogenic shock, subendocardial infarct, female gender, and previous infarcts.

Cardiac Rupture

Left ventricular free wall rupture results in cardiac tamponade, and if there is prolonged survival, pseudoaneurysm formation. The incidence of rupture of the left ventricular free wall is between 10% and 20%; patients with first infarct have a rate of approximately 18%.¹³⁴ In contrast, rupture of the ventricular septum is only 2%.¹³⁴ Left ventricular wall rupture is much more common than right ventricle rupture. Although reperfusion therapy has reduced the incidence of cardiac rupture, late thrombolytic therapy may increase the risk of cardiac rupture (Fig. 37–15).

Factors associated with cardiac rupture include female gender, age older than 60 years, hypertension, and first MI. Additional risk factors include multivessel atherosclerotic disease, absence of ventricular hypertrophy, poor collateral flow, transmural infarct involving at least 20% of the wall, and location of the infarct in the mid anterior or lateral wall of the left ventricle.¹³⁴ Transthoracic echocardiography is a fast and sensitive test for the diagnosis; contrast echocardiography also has been suggested.¹³⁵

Defective cardiac remodeling, involving matrix metalloproteinases and the extracellular matrix, may predispose the heart to rupture. In addition to surgery, management includes hemodynamic monitoring, β-blockers, and angiotensin-converting enzyme inhibitors in select cases.¹³⁶

Cardiac rupture usually occurs within 1 to 4 days after the infarct, which is when coagulation necrosis and neutrophilic infiltration are at their peak and have weakened the left ventricular wall. However, at least 13% to 28% of ruptures occur within 24 hours of onset of infarction when inflammation and necrosis are not prominent.¹³⁴ Infarcts with rupture contain more extensive inflammation and are more likely to demonstrate eosinophils compared with nonruptured infarcts.¹³⁷ Rupture most frequently occurs at the border of the infarcted region with the viable myocardium. Ruptures usually are not seen beyond 10 days after healing occurs. However, ruptures in infarcts with healing generally occur in the center of the infarct, unlike earlier ruptures (see Fig. 37–15). Nearly half the deaths from cardiac rupture occur as out-of-hospital sudden deaths and, therefore, are never seen by a clinician. The mortality in the prethrombolytic era was extremely high, with 50% mortality in surgically treated patients and 90% mortality in medically treated patients. Surgical options include both open procedures and percutaneous seals.¹³⁸

Myocardial rupture, in addition to the free wall, may involve solely the papillary muscle or the ventricular septum. Ruptures of the ventricular septum are classified into simple or complex. Simple ruptures have a discrete defect and a direct through-and-through communication across the septum, are usually associated with anterior MI, and are located in the apex. Complex ruptures are characterized by extensive hemorrhage with irregular serpiginous borders of the necrotic muscle, usually occur in inferior infarcts, and involve the basal inferoposterior septum.¹³⁹ The diagnosis is confirmed by echocardiography. Intra-aortic balloon pump may stabilize patients in preparation for surgery. Mortality remains high in all patients, especially for those with inferobasal defects.¹¹⁹ Percutaneous closure is a less invasive option that might allow for initial hemodynamic stabilization, but experience with this approach is limited.¹¹⁸

Rupture of papillary muscle is less common than septal or free wall rupture and may occur as a complication of small subendocardial or larger transmural MIs. More than 80% of infarcts underlying papillary muscle rupture involve the posteromedial muscle, which has a single blood supply from the right coronary artery (see Fig. 37–15). Because the anterolateral papillary muscle has a dual blood supply from the LAD and the left circumflex coronary artery, it rarely undergoes isolated ischemic rupture. However, it may rarely rupture if there is a single supply via one diagonal branch. Patients with papillary muscle rupture present with sudden mitral regurgitation with variable severity. Pulmonary edema and cardiogenic shock may occur rapidly. Diagnosis is made by transthoracic and/or transesophageal echocardiography, including three-dimensional and transgastric imaging.¹⁴⁰ Treatment is based on afterload reduction if blood pressure allows, including intravenous diuretics, vasodilator/inotropic support, and intra-aortic balloon pump, which may stabilize patients in preparation for surgery. Operative mortality is high, but there is good long-term survival after operative repair.¹⁴¹

Right-Sided and Atrial Infarction

Right ventricular infarction is a common complication of inferior transmural MI (see Fig. 37–14B). Its pathophysiology and clinical manifestations are distinctly different from those of left ventricular infarction. Necropsy studies demonstrate right ventricular infarction in 14% to 60% of patients who die with inferior left ventricular MI and is usually seen as a triad of findings consisting of inferior-posterior wall, posterior septum, and posterior right ventricular wall necrosis, which is contiguous, and, rarely, with anterolateral right ventricular wall extension.¹⁴² It has been reported that 78% of right ventricular infarctions occurring in patients with inferior left ventricular infarcts had concomitant right ventricular hypertrophy.¹⁴³ Isolated right ventricular infarction may occur infrequently in the absence of coronary disease in patients with chronic lung disease and right ventricular hypertrophy.¹⁴⁴ Atrial infarction occurs in 10% of all left ventricular inferior wall infarcts and typically involves the right atrium.^145,146

Right ventricular cardiogenic shock after acute infarction is associated with younger age, lower prevalence of previous infarctions, fewer anterior infarct locations, and less multivessel disease.¹⁴⁷ It frequently presents with the triad of hypotension, clear lung fields, and raised jugular venous pressure. ECG and echocardiography confirm diagnosis. Treatment is based on fluid loading, inotropic/vasopressor support, and emergency revascularization if not performed before. Mechanical circulatory support should be considered in suitable patients with refractory cardiogenic shock.

Pericardial Effusion and Pericarditis

Pericardial effusion is reported in 25% of patients with acute MI and is more common in patients with anterior MI, large infarcts, and congestive heart failure.^148,149 Pericardial effusion secondary to acute MI may occur as a transudative effusion or as an exudate in association with acute pericarditis. Importantly, the diagnosis of left ventricular rupture should be considered until proven otherwise in patients with moderate to severe pericardial effusion early after MI.^150,151

MI-associated pericarditis is a common cause of chest pain after MI, with its frequency depending on how it is defined. The incidence of acute pericarditis after MI has decreased with reperfusion therapy.¹⁵² Pericarditis occurs less often than pericardial effusion and is seen only in patients with transmural acute MI. Pericarditis, in contrast to postinfarction effusions, may be localized to the area of necrosis and is accompanied by chest pain. Pericardial involvement is related to the infarct size and is associated with poor prognosis. CMR has emerged as an accurate imaging modality to assess post-MI pericardial injury.^153,154 Pericarditis consists of fibrin deposition in addition to inflammation and may be present from day 1 after infarction to as late as 6 weeks after infarction. Pericardial effusion after MI usually takes several months to reabsorb. Anticoagulation should be discontinued in the presence of a significant (≥ 1 cm) or enlarging pericardial effusion.

Postinfarction syndrome (Dressler syndrome) consists of pleuropericardial chest pain, friction rub, fever, leukocytosis, and pulmonary infiltrates; occurs weeks to months after MI; and is often recurrent. Previously reported to occur in 3% to 4% of patients with MI, its incidence had been greatly reduced because of the extensive use of thrombolysis/primary percutaneous angioplasty and treatments that dramatically decrease the size of myocardial necrosis and modulate the immune system.^152,155

Chronic Congestive Heart Failure

Patients with large acute MI and persistent ischemia are the most likely to develop heart failure. The occurrence of heart failure has long been recognized as a strong predictor of increased morbidity and mortality after MI. The therapeutic impact of renin-angiotensin system inhibition, early blockade, and aggressive reperfusion strategies has been investigated in a number of clinical trials.¹⁵⁶ Newer approaches, including inhibition of nitric oxide synthase and new mechanical support devices, may further decrease mortality, which nevertheless remains high.¹⁵⁷

At autopsy, congestive heart failure is characterized by dilatation of both atria and the ventricles, which show either a large healed infarct (Fig. 37–16) or multiple smaller infarcts with or without a transmural scar.¹⁵⁸ Scarring of the inferior wall of the left ventricle often involves the posteromedial papillary muscle, which gives rise to mitral regurgitation, contributing to congestive heart failure (see Fig. 37–16).¹⁵⁸ Microscopically, the subendocardial regions of ischemia show myocytes with myofibrillar loss and that are rich in glycogen, suggesting a state of hibernation (see Hibernating Myocardium section).¹⁵⁹ It is sometimes difficult to differentiate ischemic cardiomyopathy from idiopathic dilated cardiomyopathy when infarcts are few and small and only one-vessel disease is present; in such situations, we tend to call this idiopathic dilated cardiomyopathy with incidental coronary artery disease.

True and False Aneurysms

The overall incidence of left ventricular aneurysm is currently nearly 12%.¹⁶⁰ Angiographically, single-vessel disease, proximal LAD stenosis, total LAD occlusion, end-diastolic pressure, and left ventricular score are higher in patients who develop aneurysms after infarction, as compared to nonaneurysmal infarcts. By multivariate analysis, single-vessel disease, absence of previous angina, total LAD occlusion, and female gender are independent determinants of left ventricular aneurysm formation after anterior infarction.¹⁶¹ Patients receiving reperfusion therapy and exhibiting a patent infarct-related artery have a lower incidence of aneurysm formation.¹⁶⁰

A large acute transmural myocardial infarct that has undergone expansion is the most likely infarct that will result in a true aneurysm. The pulsatile force from the blood in the cavity stretches and thins the necrotic muscle, which heals, forming the wall of a true aneurysm. An aneurysm is defined clinically as a discrete, thinned segment of the left ventricle that protrudes during both systole and diastole and has a broad neck (Fig. 37–17). Morphologically, the wall of a true aneurysm develops after MI and consists of fibrous tissue with or without interspersed myocytes. In contrast, a false aneurysm has a small neck (from a prior rupture of the free wall of the left ventricle caused by infarct and is contained by the adherent pericardium), and a wall of the aneurysm is formed by fibrous pericardium (not from the left ventricular MI and healing). The aneurysm is usually filled by a thrombus that is organizing (see Fig. 37–17). False aneurysms often require urgent surgical repair because of their propensity to rupture; false aneurysms may also give rise to congestive heart failure. The cavity of the false aneurysm is usually filled with large blood clots, both old and new. The presence of hypertension and the use of steroids and nonsteroidal anti-inflammatory drugs may promote aneurysm formation.¹⁶²

Aneurysms are usually associated with two-or-more-vessel coronary disease with poorly developed collaterals.¹⁶³ Four of five aneurysms involve the anteroapical wall of the left ventricle and are four times more frequent in this wall than in the inferior or posterior wall. The pericardium is usually adherent to the aneurysm and may calcify. True aneurysms rarely rupture; rupture is more common of a false aneurysm (see Fig. 37–17). The cavity of the aneurysm usually contains an organizing thrombus, and the patient may present with embolic complications. The mortality is significantly higher in patients with aneurysm than without.

Mills et al¹⁶⁴ suggested that aneurysmectomy should be performed in patients having true aneurysms because of poor prognosis. They reported a 27% 3-year survival in an autopsy series and a 70% survival in the Coronary Artery Surgery Study. Percutaneous closure has also been successfully reported.^138,165 The survival of patients with false aneurysm is also better after surgery. It has been said that more than half of false aneurysms are located in the posterior or inferior walls, but true aneurysms mostly involve the anterior wall. There is speculation regarding the reasons for these differences because large inferoposterior infarcts that could lead to aneurysms are more often fatal and posterior rupture is more often contained by the pericardium, allowing false aneurysms to develop.¹⁶⁶

Mural Thrombus and Embolization

Early data from the pre-reperfusion and thrombolytic eras suggested that, in the setting of acute MI, mural thrombus forming on the endocardial surface over the area of the acute infarction occurred in 20% of all patients, with an incidence of 40% for anterior infarcts and 60% for apical infarcts.¹⁶⁷ Currently, the reported incidence is lower.¹⁶⁸ Patients with left ventricular thrombi have poorer global left ventricular function and poorer prognosis than patients without thrombi.¹⁶⁸ The poor prognosis is secondary to complications of a large infarct and not from emboli.¹⁶⁷ It is reported that those that form thrombi have endocardial inflammation during the phase of acute infarction. The thrombi tend to organize, but the superficial portions may embolize in approximately 10% of cases (Fig. 37–18).¹⁶⁸ The usual sites of symptomatic embolization are the brain, eyes, kidney, spleen, bowel, legs, and coronary arteries. Symptomatic emboli are usually caused by larger fragments; small particles of thrombus that embolize generally do not cause symptoms. In the prethrombolytic era, embolic complications were reported in approximately 10% of cases, whereas now, they occur in 2% to 3% of patients. The risk of embolization is greatest in the first few weeks of acute MI.^168,169 Once diagnosed, mural thrombi require oral anticoagulant therapy with vitamin K antagonists for up to 6 months. However, in patients receiving dual platelet treatment, repeated imaging of the left ventricle after 3 months of therapy may allow discontinuation of anticoagulation earlier than 6 months if evidence of thrombus is no longer present, particularly if there is recovery of apical wall motion.¹¹⁹

Incidence of Coronary Thrombosis

The frequency of coronary thrombosis in sudden coronary death varies from 20% to 70%.^170,171,172 The time interval between onset of symptoms and death, the presence of concurrent conditions that may cause arrhythmias (scars, ventricular hypertrophy), and the type of prodromal symptom (stable angina, unstable angina, no apparent symptoms) all affect the incidence of thrombi in coronary sudden cardiac death. Coronary thrombosis may occur over two major substrates: rupture of thin cap fibroatheroma and plaque erosion; however, calcified nodules have been reported but are uncommon. Plaque erosions occur in men and women aged younger than 50 years and are less common. Plaque rupture is more common, occurs at all ages in adults, and is associated with hypercholesterolemia. We have shown in sudden coronary death that coronary thrombosis is most frequently the result of plaque rupture (65%), less frequently a result of plaque erosion (30%-35%), and uncommonly a result of calcified nodule (2%-5%).^60,173

Myocardial Findings

In our series of sudden coronary death with epicardial thrombosis, there is an approximate 10% incidence of acute MI and 40% incidence of healed MI; in 40%, no myocardial ischemia is identified.¹⁷³ In these cases, it is presumed that ischemia has not been manifest because of the short time interval between thrombosis and death. In sudden coronary death victims without epicardial thrombi, there is a low incidence of acute MI (4%), with a 60% rate of healed infarct and 35% without evidence of acute or healed infarct. Consequently, given that approximately 50% of cases of sudden coronary death occur in the absence of coronary thrombosis, 15% to 40% of hearts demonstrate stable coronary atherosclerotic plaque in the absence of acute or healed infarction in the ventricles. The role of cardiac hypertrophy and other arrhythmogenic factors in these deaths has not been studied in detail.

We would like to thank Dr. Saami K. Yazdani, who contributed to the previous version of this chapter in the 13th edition.