Myocardial Response to Injury

Allen P. Burke, M.D.

Fabio R. Tavora, M.D., Ph.D.

General

Myocyte injury results from a variety of insults, including ischemia, inflammation, toxic insults, and physical forces such as trauma or increased wall tension. The specific diseases or entities and their pathologic manifestations are covered in detail in other chapters. There are relatively few “final common pathways” that are seen from diverse causes and that are, in many cases, nonspecific for a particular disease. A list of terms describing myocardial injury is provided in Table 139.1.

Evaluation of Myocardial Injury

Clinically, cardiac injury is equated to myocyte necrosis and is assessed by measuring the release of cardiomyocyte constituents such as cardiac troponins and creatine kinase into the serum or plasma. Chronic injury causes abnormalities in cardiac function and wall motion, assessed by cardiac imaging. Experimentally, ischemic myocytes can be histologically detected by the in vivo injection of antimyosin antibody prior to animal sacrifice, allowing immunohistochemical visualization of irreversibly damaged myocytes with sarcolemmal disruption that have allowed intracytoplasmic passage of the antibody. A clinical correlate in human patients is the use of antimyosin nuclear medicine scanning to visualize areas of myocardial ischemia.

Histologically, light microscopic alterations in myocyte cytoplasm, nucleus, and cell size and shape allow assessment of myocyte injury from a practical standpoint. Because histologic manifestations of ischemia occur hours after onset, however, special techniques are necessary to diagnose recent myocardial infarction. Tetrazolium salts stain viable myocardium in gross heart specimens, but not ischemic regions, as tetrazolium compounds are cleaved into visible formazan dyes on exposure to dehydrogenase enzymes, which are exquisitely sensitive to ischemia.

Immunohistochemical staining for substances that enter the cell with sarcolemmal disruption, such as complement, troponin, fibronexin, and connexin-43, has been used to detect early ischemic cell death in forensic autopsies.¹^,² Ultrastructural evaluation of myocytes is helpful in determining changes in cell size, nuclear shape, cytoplasmic organelles, and other constituents, which reflect cardiac injury. However, other than in the evaluation of anthracycline toxicity and exclusion of specific cardiomyopathies, electron microscopy has limited practical diagnostic use, because many ultrastructural changes are nonspecific, and application for autopsy is hindered by postmortem changes that mimic ischemia.

TABLE 139.1 Terms Used in Describing Myocardial Injury

Designation	Context	Notes
Hypereosinophilia	Early ischemic necrosis	Loss of membrane integrity demonstrated by identifying leaked proteins into cytosol (oncosis)
Pyknosis and karyorrhexis	Myocardial infarction	Degeneration of cellular nuclei (including neutrophils and endothelial cells), predominantly apoptotic
Autophagy	Heart failure Reperfusion injury	Lysosomal mediated process that eliminates damaged proteins and organelles
Coagulative necrosis	Myocardial infarction	Zones of necrotic myocytes with distinguishable borders and dissolving internal structure
Contraction bands	Acute catecholamine injury Fixation artifact	May be seen in resuscitation or biopsy artifact (cold fixatives in biopsies)
Contraction band necrosis	Chronic catecholamine injury Reperfusion injury	“Brain death” lesions “Single cell necrosis”
Ischemia-reperfusion injury	Reperfusion infarction	Hemorrhagic infarct with contraction bands and diffuse sparse neutrophilic inflammation
Myocytolysis	Chronic ischemia Contraction band necrosis (obsolete)	Vacuolization caused by intracellular edema and myofibrillar loss
Replacement fibrosis	Healed infarct, cardiomyopathy	Localized reparative fibrosis after infarction or large areas of necrosis of other cause
Interstitial fibrosis	Hypertensive hypertrophy, heart failure	Diffuse increased epimysial and perimysial collagen
Lipofuscin	Senescence	Autofluorescent, finely granular yellow-brown pigment containing lysosomal residues
Basophilic degeneration	Senescence, cardiomyopathy	Intracytoplasmic PAS-positive glycoprotein, resembles amyloid
Sarcoplasmic and T-tubular dilatation	Drug toxicity, cardiomyopathy	Enlargement and dilatation of sarcotubules and T tubules, leading to myocyte vacuolization if diffuse

Myocyte Cell Death

Ischemic Cell Death (Oncosis)

The initial phase in ischemic coagulative necrosis is marked by loss of cell membrane integrity, resulting in mitochondrial swelling and swelling of the nucleus and cytoplasm. The free passage of intracellular and extracellular materials results in “oncosis” (cell swelling) and can be histologically manifested by hypereosinophilia and eventual loss of cytoplasmic detail (Fig. 139.1). The demonstration of intracytoplasmic antigens not normally present, such as complement, may be useful in demonstrating small foci of ischemic cell death, such as seen in autopsy hearts in ischemic cardiomyopathy or heart biopsies soon after transplant. Individual myocytes with sarcolemmal damage, as evidenced by complement labeling, are present in biopsies of patients with heart failure in <0.1% of myocytes.³

In contrast to apoptosis, necrosis is considered to be an unregulated form of cell death. However, there has been described an intermediate form of necrotic cell death, seen especially in myocarditis, termed “necroptosis” or “programmed necrosis” that is initiated by tumor necrosis factor and characterized by mitochondrial fission resulting in cell death.⁴

Apoptosis (Programmed Cell Death)

Neutrophil apoptosis may be seen in the karyorrhectic inflammatory cells surrounding an evolving myocardial infarction. Apoptosis is uncommonly visualized in the cardiac myocytes, as cardiomyocytes undergo programmed cell death at a very low rate in failing hearts. Techniques such as in situ end labeling of DNA fragments, electron microscopy, or immunohistochemical staining for caspases are required to detect myocyte apoptosis. In heart failure of all causes, far fewer than 1% of cardiomyocytes are shown to have features of apoptosis by nick end labeling or immunohistochemistry, with a wide range reported, from <0.01% to <1% of cells.³^,⁵ Apoptotic myocytes are removed by macrophages through phagocytosis without triggering inflammation. Immunoelectron microscopy shows cytochrome c release from the mitochondria into the cytoplasm and annexin V translocation in the outer plasma cell layer.⁶

Pyknosis and Karyorrhexis

Pyknosis is the irreversible condensation of chromatin, and karyorrhexis is the subsequent fragmentation of cell nuclei undergoing apoptotic or other types of cell death. Pyknosis and karyorrhexis are features of cell death that are readily appreciated by light microscopy, and involve myocytes, endothelial cells, and inflammatory cells in areas of myocardial infarction. These nuclear changes have been used in the evaluation of reperfusion injury in experimental models⁷ and as a marker of early transplant rejection.⁸ The terms “pyknosis” and “karyorrhexis” are most commonly used in reference to acute myocardial infarction, as indicators of breakdown of neutrophils at the margins of nonreperfused infarcts that occurs at about 3 days and thereafter.

FIGURE 139.1 ▲ Myocyte necrosis (oncosis). There is a zone of hypereosinophilia in a case of acute subendocardial infarction.

Autophagy

Autophagy mediates the degradation of damaged cytoplasmic proteins and organelles that accumulate with cellular stress or hypoxia and is associated with myocardial necrosis and impairment of lysosomal degradation.⁶ It may be present not only in heart failure but also in myocarditis and reperfusion injury. Prolonged activation of autophagy can lead to cell death.⁹ Autophagy sequesters altered cytoplasmic proteins in lysosomes (autophagosomes) that can be visualized only by ultrastructural methods (Fig. 139.2). Morphologically, autophagic vacuoles contain mitochondria, glycogen granules, and myelin-like figures; by immunolabeling, proteins including ubiquitin, cathepsin D, and Rab7 can be identified within them.¹⁰ Heart biopsies with idiopathic dilated cardiomyopathy may show evidence of autophagic vacuoles in over 10% of biopsies, and ultrastructural morphologic features of apoptosis, oncosis, and autophagocytosis often coexist.⁶^,¹¹ Danon cardiomyopathy is characterized by a dramatic accumulation of autophagic vacuoles because of deficiency in LAMP-2 protein that inhibits uptake of proteins into lysosomes for degeneration. An early form of autophagy has been termed “mitophagy,” a cardioprotective response that removes damaged
mitochondria and that is inactivated by increased oxidative stress and apoptotic proteases, allowing for the programmed cell death to occur.

FIGURE 139.2 ▲ Autophagic vacuoles. A. Multiple adjacent cells are affected with myofibrillar loss and autophagic vacuoles. B. A portion of a myocyte is replaced by autophagic debris.

FIGURE 139.3 ▲ Coagulative necrosis. The infarct myocytes show patchy loss of cross-striations, nuclear loss, and hypereosinophilia, with visible cell borders.

Myocyte Necrosis

Coagulative Necrosis

In general, coagulative necrosis indicates dead tissue that softens as in a gel but maintains its architecture and is seen in the heart and other organs typically in response to an infarct. Histologically, infarcted myocardium demonstrates necrotic myocytes with intact nuclei and cell borders (in early stages), hypereosinophilic cytoplasm indicative of denatured proteins, and an absence of identifiable cross-striations (Fig. 139.3). Later, a polymorphonuclear leukocytic infiltration is followed by macrophage digestion. The histologic evolution of myocardial ischemia is discussed in detail in Chapter 151.

Contraction Band Necrosis

Contraction bands are seen in both striated muscle and smooth muscle and represent a hypercontracted state of the cell in which transverse bands of condensed myofilaments are visible at the light microscopic level. Although sometimes used interchangeably, “contraction bands” are not the same as “contraction band necrosis,” in which there are also features of cell necrosis (hypereosinophilia and loss of normal striations). Contraction bands are a common finding at autopsy in patients who have been resuscitated with exogenous pressor agents (Fig. 139.4). Contraction band necrosis, on the other hand, can be extensive, especially in areas of reperfusion infarction, and is characterized by fragmentation of hypercontracted myocytes, irregular cross-bands of coagulated sarcomeres, and a macrophage reaction (Fig. 139.5).¹² Single or small clusters of necrotic cells with contraction bands and a mononuclear cell infiltrate are referred to as “single cell necrosis” and are an indicator of systemic increase in catecholamines. For this reason, the term “brain death lesions” has been used to describe focal contraction band necrosis because of their common occurrence in patients with cerebral hypoxia maintained on life support.¹³ Contraction band necrosis may undergo calcification in patients on chronic pressor support for shock who have hypercalcemia and renal failure (Fig. 139.5B).

FIGURE 139.4 ▲ Contraction bands. There are thickened transverse bands corresponding to overlapping myofibrils (arrows). There is no evidence of necrosis.

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