THE ROLE OF CARDIOVASCULAR PATHOLOGY IN PRACTICE

Necropsy plays a vital role in medical and scientific discovery.^1–4 Indeed, necropsy permits recognition of disease patterns, facilitates understanding of pathophysiology, validates technical processes (imaging, serological tests), and helps to assess therapeutic efficacy and toxicities. It also is a method to detect diagnostic errors, and to provide knowledge that can be applied to future cases. Collectively these activities advance medical diagnosis and patient care.

Gross or histopathological lesions can be detected in most cats who have clinical evidence of cardiac morbidity or mortality. Thus necropsy can help to characterize congenital and acquired cardiovascular disorders. This is particularly germane when seeking to discover heart disease in breeding animals, and when searching to discern cardiac cause in sudden, unexpected death. Interaction between practitioner and pathologist is essential to maximize clinical insight, confirm diagnosis, and determine pathological consequences of heart disease. Accordingly dissection techniques are best guided by clinical and imaging information.

CARDIOVASCULAR PATHOLOGY IN HEART FAILURE

Heart failure is not a disease but a clinical syndrome. It is the consequence of advanced pathophysiological progression from congenital or acquired cardiovascular disease, or cardiac injury. Heart disease may impose a pressure or volume overload, alter cardiac contractile or relaxation characteristics, cause abnormalities of heart rate and rhythm, or result in ion channel disruption.^5–7

Compensatory hypertrophy represents a major cardiac adjustment to increased cardiac work.^5,6 Concentric hypertrophy is a typical response to pressure overloads such as aortic stenosis or arterial hypertension, and is related to increased ventricular systolic wall tension and increased afterload.⁸ Sarcomeres are added in parallel with little change in chamber diameter. Eccentric hypertrophy causes a proportional increase in ventricular wall thickness and internal chamber diameter via synthesis of sarcomeres in series, and is a common adaptation in states of volume overload.⁹

Myocyte cell death can occur via necrosis or programmed death (apoptosis).^10,11 Cellular necrosis is a passive process resulting from lethal insult. It is characterized by cell membrane rupture and associated inflammation. Changes include cellular swelling, loss of membrane integrity and breakdown, nuclear chromatin clumping into poorly defined masses, swelling and disruption of sarcoplasmic reticulum and mitochondria, formation of granular mitochondrial matrix densities, and loss of calcium and electrolyte homeostasis. Apoptosis occurs in the absence of cell membrane rupture and inflammation; is an active, regulated, energy-requiring process under genetic control; and is characterized by nuclear DNA fragmentation. Nuclear chromatin becomes compacted and segmented into sharply delineated masses along the nuclear margins, the cytoplasm condenses, nuclear fragmentation occurs, and the cell surface develops pediculated protuberances and separates into membrane-bound apoptotic bodies that are phagocytized by adjacent cells.

Alterations of connective tissue play important roles in heart disease. The heart is composed of parenchyma and stroma. Parenchyma consists of cardiac myocytes, which are highly differentiated and perform specialized functions. Stroma contains cellular elements including fibroblasts and macrophages that are not well differentiated, and whose physiological behavior and phenotype are affected by circulating and local chemical mediators and signals.¹² Fibrosis represents disproportionate stromal growth with increased myocardial collagen content and may be reactive or reparative. Pathological myocardial remodeling results when either form of fibrosis occurs.

Myocytes are enmeshed in a stromal framework containing collagen, elastin, and other elements.¹³ The interstitial matrix, of which collagen is the major component, represents networks of pericellular, interstitial, and fascicular connective tissue. Myocardial cells are diffusely interconnected by this connective tissue framework, which is composed of struts, pericellular weaves, and coiled perimysial fibers. This internal myocardial skeletal framework is thought to participate in myocardial function, integrate individual myocytes into three-dimensional conformational changes during systole, and contribute to myocardial compliance during diastole.^14,15 Matrix components can be visualized histologically by specialized staining techniques.

Pulmonary edema is the consequence of left-sided heart failure associated with diastolic dysfunction, myocardial failure, or volume overload. Edematous lungs are wet, heavy, and ooze edema fluid from cut sections. Edema fluid may appear pinkish and sometimes foamy. Microscopically, edema fluid is acidophilic or faintly granular, filling alveoli, interstitium, and lymphatics. Protein content is very low. Capillaries and lymphatics are distended. Intraalveolar hemorrhage may be apparent. Alveolar macrophages (“heart failure” cells) containing erythrocytes or hemosiderin may be present and increase with duration of edema. Chronic cardiogenic edema and associated pulmonary hypertension may cause muscular hypertrophy of small pulmonary arteries and fibrous thickening of pulmonary capillary walls. Occasionally in fulminant, terminal pulmonary edema, leukocytes accumulate in pulmonary capillaries, endothelial damage and alveolar type I epithelial cells are noted, and fibrin-rich fluid fills the alveoli.

Effusions (abdominal, pleural, and/or pericardial) generally are sterile, obstructive transudates early in right-sided heart failure, and can become modified transudates in chronic heart failure. They are characteristically modified transudates, pale yellow or serosanguineous, with 2 to 5 g/dL of protein. Cytological smears contain a mixture of blood cells and lymphocytes with a nucleated cell-to-red cell ratio roughly equal to blood, and some mesothelial cells. With time the effusion acquires greater numbers of inflammatory cells and increased protein. In long-standing effusions, mesothelial cells and macrophages may exhibit erythrophagia.¹⁶ Occasionally chylous effusion may occur and appears milky white with mostly lymphocytes and variable numbers of neutrophils, depending on duration and degree of pleuritis.¹⁷ With long-standing pleural effusions of modified transudate or chyle, pleuritis may develop, cause lung lobe borders to become fibrotic, or even collapse. Chronic ascites or pericardial effusion may result in fibrin deposition.

MYOCARDIAL DISEASES (CARDIOMYOPATHIES)

Myocardial disorders constitute the majority of feline heart disease^3,4,17a–22 They may be primary (idiopathic) or occur secondary to systemic or metabolic conditions.

IDIOPATHIC HYPERTROPHIC CARDIOMYOPATHY

Feline hypertrophic cardiomyopathy (HCM) is the most common form of cardiomyopathy. This heterogeneous disorder has diverse morphological features and broad clinical presentation.^{3,4,17a–20,22}

Gross Pathology (Figure 43-1)

Most affected cats have diffuse but asymmetrical distribution of left ventricular (LV) hypertrophy involving substantial portions of ventricular septum and LV free wall. Less commonly, segmental patterns of hypertrophy occur, often with abrupt transitions in wall thickness or involvement of noncontiguous segments. The LV cavity is reduced and the left atrium (LA) is enlarged and often hypertrophied. Absolute and relative heart weights are increased substantially. Heart weight in relation to body weight is significantly greater in cats (6.4 ± 0.1 g/kg) with HCM, compared with normal cats (mean, 4.8 ± 0.1 g/kg). Necropsy of 51 HCM cats recorded maximal ventricular septal thickness of 9.0 ± 0.2 mm (controls, 5.0 ± 0.2 mm) and anterolateral LV free wall thickness of 9.0 ± 0.1 mm (controls, 6.0 ± 0.3 mm). Focal, endocardial fibrosis is common. In cats with dynamic LV outflow obstruction, a fibrous, mural endocardial plaque is evident at the basal septum in apposition to the anterior mitral valve leaflet. The anterior mitral valve leaflet also is thickened in these cases. Pulmonary edema is present in more than half of necropsied cases and pleural effusion is evident in about 20 per cent. Arterial thromboembolism occurs in a high percentage of necropsied cases. Atrial or ventricular ball thrombi occasionally are present. Aneurysmal thinning of the LV apex is common.

Figure 43-1 Hearts from cats with hypertrophic cardiomyopathy illustrating wide phenotypic variability characteristic of this disease. Notice substantial and diffuse left ventricular hypertrophy in A to D (concentric hypertrophy as indicated by all segments of the ventricular septum and LV caudal wall, which are similarly hypertrophied in A and D). Segmental left ventricular hypertrophy is associated predominantly with the basal ventricular septum in E and F.

(From Fox PR: Hypertrophic cardiomyopathy: clinical and pathologic correlates, J Vet Cardiol 5:39, 2003.)

Histopathology (Figures 43-2 and 43-3)

The most characteristic histological features include disorganized myocyte architecture, small intramural coronary arterial arteriosclerosis, and increased matrix or replacement fibrosis. Myocytes may be hypertrophied and have large, rectangular, hyperchromic nuclei. In a series of 51 HCM cats, ventricular septal myofiber disorganization was recorded from 15 (30 per cent); septal disorganization comprising 5 per cent or more of relevant tissue sections was present in 14 (27 per cent); and extensive myocyte disarray (≥25 per cent) was present in seven (14 per cent).²¹ Cellular disorganization was predominantly type I pattern, which involved small foci of adjacent cardiac muscle cells. Abnormally thick intramural coronary arteries, usually with reduced lumens, were noted in 74 per cent of cats, and were most prevalent in sections with moderate or severe fibrosis. Medial and intimal thickening was associated with increased connective tissue elements (and much less commonly, smooth muscle cells). Interstitial myocardial fibrous tissue or replacement fibrosis was present in 53 per cent of cats. Myocyte fiber disarray also can be observed in the right ventricle of some affected patients.

Figure 43-2 Cellular architecture from cats with hypertrophic cardiomyopathy illustrating myofiber disarray. A and B, Basal interventricular septum. C, RV wall. In B and C, interstitial fibrosis also is evident and marked. (H&E stain [A] and Masson trichrome [B and C]. Magnification × 40.)

(From Fox PR: Hypertrophic cardiomyopathy: clinical and pathologic correlates, J Vet Cardiol 5:39, 2003.)

Figure 43-3 Arteriosclerosis (small vessel disease) of intramural coronary arteries in the left ventricle from three cats with hypertrophic cardiomyopathy. A, Abnormal intramural coronary artery with thickened wall and narrowed lumen caused by proliferation of smooth muscle and increased connective tissue elements. B, Arteriosclerosis with mild interstitial fibrosis. C, Region of replacement fibrosis surrounds arteriosclerotic arteriole.

(From Fox PR: Hypertrophic cardiomyopathy: clinical and pathologic correlates, J Vet Cardiol 5:39, 2003.)

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