Standard Morphologic Evaluation of the Heart in the Laboratory Dog and Monkey

Abstract

The nonrodent species most commonly utilized in preclinical safety studies are the purpose-bred beagle dog and cynomolgus macaque (Macaca fascicularis). Potential effects of a new chemical entity (NCE) on the heart pose serious concerns; consequently in vivo testing is focused on detection of functional alterations as well as morphological changes. Macroscopic and microscopic evaluation of the heart is based on a standard survey of key structures to properly assess presence of spontaneous and potential drug-induced lesions. Evaluation of historical controls to determine type and frequency of background change is valuable, as studies with non-rodent species generally have a small sample size. Archived control dog and monkey data were retrospectively reviewed, including terminal body weight (BW), heart weight (HW), and archival glass slides of heart. Control dogs had minimal background changes that included myxomatous or cartilagenous change in the cardiac skeleton and a variable degree of vacuolation in Purkinje fibers. Control monkey hearts commonly contained inflammatory cell infiltrates, myocyte anisokaryosis, and handling artifacts, while myocyte degeneration, squamous plaques, pigment, and intimal plaques were occasionally observed. These findings highlight the utility of consistently recorded and readily accessible archived control data when attempting to discern background spontaneous changes and artifacts from test-article induced changes.

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

“…38, No. 4, 2010 SPONTANEOUS FINDINGS IN CYNOMOLGUS MONKEYScause focal or multifocal damage to the myocardium (Keenan and Vidal 2006;Lowenstine 2003). Intranuclear (pseudo) inclusion bodies in hypertrophic cardiac myofibers resulting from intranuclear invagination of cytoplasmic organelles, including mitochondria, have been reported in man (Engedal et al 1977).…”

“…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.…”

“…Some of the findings such as myocardial karyomegaly, myocardial degeneration/fibrosis (Keenan and Vidal 2006;Zabka et al 2009); mucopolysaccharide accumulation in the subendocardial areas, heart valves, great vessels and aorta (Scott 1999); collagenofibrotic-like lesions of the glomeruli (Adachi et al 2005); inflammatory cell infiltration of the uvea (Sinha et al 2006); lymphocytic thyroiditis (Guzman and Radi 2007); pigment deposits in the lung (Drevon-Gaillot et al 2006;Ito et al 1992); mineralization in the brain (Wadsworth et al 1995;Yanai et al 1994); adrenohepatic fusion (Mousa and van Esch 2004); accessory spleen in the pancreas (Lau 1973); cuboidal metaplasia of the parietal layer of the Bowman's capsule (Kaspareit et al 2004); and subcapsular hemorrhage and fibrosis in the liver (Shimoi et al 1998) have all been reported previously. However, mineralization of adventitial blood vessels and unidentified vascular remnants suspected to be vestiges of umbilical blood vessels (also seen in the dog) have not been reported to the best of our knowledge.…”

Incidental Histopathological Findings in Hearts of Control Beagle Dogs in Toxicity Studies

“…Another incidental finding that may be difficult to differentiate from a true pathologic condition is Purkinje fiber vacuolization. Purkinje fiber vacuolization in the hearts of control dogs has been previously reported (Keenan and Vidal 2006). Regular round vacuoles are frequently present in normal Purkinje fibers in dogs and humans, and these vacuoles actually correspond with the regions of the sarcoplasm that contain few myofibrils (Urasawa et al 2008).…”

Letter to the Editor

“…Vidal et al did not include such a contemporaneous control group in their study, but they instead compared their results solely to those from a previous review of cardiac pathology in primarily Indonesian-origin cynomologus monkeys at the authors' facility (Keenan and Vidal 2006).…”