Spontaneous Cardiomyopathy in Cynomolgus Monkeys (Macaca Fascicularis)

Abstract

A previously undescribed spontaneous cardiomyopathy was identified by routine light microscopic examination of the heart from four clinically healthy purpose-bred cynomolgus monkeys that ranged from four to nine years of age and included 2 males and 2 females. Special stains of Sirius red, Masson's trichrome, and Mallory's phosphotungstic acid hematoxylin (PTAH); and immunohistochemistry using anti-CD68, troponin-I, and desmin antibodies were used to facilitate lesion characterization and assess cardiomyocyte viability. Microscopically, the apical to mid-ventricular myocardium to subendocardium had foci of cardiomyocyte disarray with cytoplasmic pallor to stippling and karyomegaly, vacuolization of the perimyseal connective tissue, a meshwork of fibrous tissue that concentrated around medium-sized blood vessels and dissected between or less often replaced affected cardiomyocytes; and a minimal, predominantly macrophage infiltrate. The disrupted cardiomyocytes were immunoreactive to desmin and troponin-I antibodies and had a normal cross-striation pattern by PTAH, indicating the chronic cardiomyopathy was not associated with active cardiomyocyte damage. The consistent distribution and morphology of the cardiomyopathy suggested a common etiology and pathogenesis. The features were reminiscent of chronic catecholamine-induced experimental cardiomyopathy and stress cardiomyopathy in monkeys and humans, respectively. This report documents another spontaneous heart lesion in clinically healthy monkeys for consideration during interpretation of toxicology studies.

Spontaneously occurring cardiovascular lesions in commonly used laboratory animals

“…Both acute and chronic necrotic lesions were present, implying that the pathogenic process was either continuous or involved multiple components. This type of lesion might be induced by the stress-associated release of catecholamines that can occur with routine handling of the monkeys during experimental procedures [86]. The histologic characteristics of the lesion were similar to the necrotic alterations reported in monkeys after catecholamine administration [87].…”

Phase 1 trial of IL-15 trans presentation blockade using humanized Mik-Beta-1 mAb in patients with T-cell large granular lymphocytic leukemia

“…Comparable cardiac abnormalities have been reported by 5 groups in studies that involved up to 510 normal, untreated cynomolgus monkeys, suggesting that these changes were unrelated to Hu-Mik␤1. [34][35][36][37] …”

Spontaneous hypertrophic cardiomyopathy in a cynomolgus macaque (<i>Macaca fascicularis</i>)

“…The gross morphological features of each type are as follows: thickening of the left ventricular (LV) wall and interventricular septum (IVS) with narrowing of the lumen in the case of hypertrophic cardiomyopathy, rounded heart because of biventricular dilation in the case of dilated (congestive) cardiomyopathy, endocardial thickening because of fibrosis in the case of restrictive cardiomyopathy, enlargement of the RV chamber in the case of arrhythmogenic RV cardiomyopathy, and left or bilateral atrial dilation with normal LV wall thickness in the case of unclassified cardiomyopathy 2 . Even though incidental small foci of myocardial degeneration frequently occur in cynomolgus macaques ( Macaca fascicularis ), a diagnosis of cardiomyopathy is rare 3 , 4 , 5 . Here, we report a case of spontaneous hypertrophic cardiomyopathy in a male cynomolgus macaque.…”

“…In cynomolgus macaques, several cases have been diagnosed as cardiomyopathy, but none of them have been diagnosed as hypertrophic cardiomyopathy. Most cardiomyopathies previously reported in cynomolgus macaques have been characterized by the degeneration or necrosis of cardiomyocytes with karyomegaly and inflammation or fibrosis 3 , 4 , 5 . Cardiomyocyte disarray and vacuolation of the perimysial connective tissue have been observed in four cases of spontaneous cardiomyopathy in cynomolgus macaques 3 .…”