Spontaneous Lesions of the Cardiovascular System in Purpose-Bred Laboratory Nonhuman Primates

Abstract

This retrospective study was performed to determine the range, occurrence and incidence of spontaneously arising histopathological findings of the cardiovascular system in purpose-bred laboratory nonhuman primates. Data were collected from 84 controlled toxicological studies with equal numbers of male and female animals and full tissue lists. Attempts were also made to standardize pathological terms used by various original pathologists. Tissue sections from 2464 animals, which included 2050 cynomolgus monkeys (Macaca fascicularis), 284 common marmosets (Callithrix jacchus) and 130 rhesus monkeys (Macaca mulatta) were examined. The most common cardiac finding was focal myocardial inflammation, subcategorized as either "inflammatory cell infiltration" (339) or "focal myocarditis" (131). Other cardiac findings included mineralization (29), endocarditis (16), pericarditis (10), squamous cysts (6) and ectopic thyroid tissue (5). Perivasculitis/vasculitis in the kidney, lung, meninges, sciatic nerve, and other tissues (206) was the most common vascular lesion. Focal myocarditis was more common in male (60%) than female (40%) animals. Cardiac mineralization and extramedullary hematopoiesis were more common in marmosets than other species while ectopic thyroid tissue was present in marmosets and cynomolgus monkeys. To our knowledge, this is the first study to demonstrate the range and incidence of spontaneous cardiovascular lesions in laboratory nonhuman primates.Keywords. Cardiovascular; spontaneous pathology; nonhuman primate; cynomolgus; rhesus; marmoset. INTRODUCTIONIn preclinical toxicology studies, drug-induced cardiovascular lesions continue to be an important area of concern, in particular with respect to assessment of cardiovascular safety of drugs intended for human use. In the course of such studies, it is not uncommon to encounter drug-induced histopathological lesions in the heart and blood vessels that are similar to those that may arise spontaneously in control animals. Since this can considerably hinder the evaluation of toxicological compounds, it is important for pathologists to be able to recognize such background changes in control animals of a test species. Although nonhuman primates are widely used in preclinical toxicology studies due to their phylogenic relationship to humans, specific information on the range of background findings is not readily available. This review was conducted in order to report and characterize the range and incidence of spontaneous background microscopic cardiovascular lesions in young, healthy cynomolgus monkeys (Macaca fascicularis), rhesus monkeys (Macaca mulatta) and common marmosets (Callithrix jacchus) purposebred for laboratory use.

Extramedullary Hematopoiesis: A New Look at the Underlying Stem Cell Niche, Theories of Development, and Occurrence in Animals

“…Perivascular and epicardial EMH were documented in a subset of marmosets in one study. 12 We also have observed hematopoietic precursor cells in pericardial fluid samples.…”

Incidences and Range of Spontaneous Findings in Control Cynomolgus Monkeys (Macaca fascicularis) Used in Toxicity Studies

“…High incidences of inflammatory lesions of the heart have been reported in cynomolgus monkeys, in which stress and the release of catecholamines were suggested as possible causes (Chamanza et al 2006). Catecholamine-induced stress was also considered to be the most likely cause of spontaneous cardiomyopathy in cynomolgus monkeys in a recent report (Zabka et al 2009).…”

“…These findings include gastritis (Drevon-Gaillot et al 2006;Scott 1999), interstitial nephritis (Bennet et al 1998;Drevon-Gaillot et al 2006), inflammatory lesions of the heart (Chamanza et al 2006;Drevon-Gaillot et al 2006;Keenan and Vidal 2006), inflammatory cell infiltrations in the liver (Foster 2005;Ito et al 1992), tension lipidosis of the liver (DrevonGaillot et al 2006), mineralization in the adrenal gland (Kast et al 1994;Majeed and Gopinath 1980), pneumoconiosis in the lungs, pigment in the lamina propria of the small intestine (Drevon-Gaillot et al 2006;Scott 1999), and lung findings associated with continuous intravenous infusion (Lilbert and Burnett 2003). In addition, a well-presented and extensive review of incidental findings and nonlesions in primates and their possible etiologies has also been published (Lowenstine 2003), and most of the findings discussed in this particular paper were evident in our study.…”

Spontaneous Cardiomyopathy in Cynomolgus Monkeys (Macaca Fascicularis)

“…Thus, it is important to characterize, by lesion morphology and distribution, the spontaneous lesions that can occur in clinically healthy monkeys in order to distinguish them from drug-induced toxicity. The literature describing such heart lesions in nonhuman primates that are purposebred (Chamanza et al 2006;Drevon-Gaillot et al 2006;Ito et al 1992;Qureshi 1979) or wild-caught (Bennet et al 1998;Lowenstine 2003) is sparse. Consistently, the most common spontaneous heart finding in purpose-bred cynomolgus (Macaca fascicularis), rhesus (Macaca mulatta), assam (Macaca assamensis), and squirrel (Saimiri sciureus) monkeys as well as common marmosets (Callithrix jacchus) was focal mononuclear leukocyte infiltrates in the interstitium or perivascular region often of the subendocardium, usually without concurrent myocyte damage and less often with minimal myocardial degeneration or necrosis (Chamanza et al 2006;Drevon-Gaillot et al 2006;Ito et al 1992;Qureshi 1979).…”