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

Abstract

In preclinical studies of pharmaceutical agents, the beagle dog is a commonly used model for the detection of cardiotoxicity. Incidental findings, postmortem changes, and artifacts must be distinguished histopathologically from test item-related findings in the heart. In this retrospective analysis, cardiac sections from 88 control beagles (41 male, 47 female; ages 5-18 months) in preclinical studies were examined histopathologically. The most common finding was thickening of the tunica media of intramural coronary arteries, most likely a postmortem change. The second most common finding was the presence of vacuoles within Purkinje fibers. Dilated lymphatic and blood vessels at the insertion of chordae tendineae were noted more commonly in males than in females and were considered a normal anatomic feature. Mesothelial-lined papillary fronds along the epicardial surface of the atria were present in several dogs, as were small infiltrates of inflammatory cells usually within the myocardium. In summary, control beagles' hearts frequently have incidental findings that must be differentiated from test item-related pathologic changes. Historical control data can be useful for the interpretation of incidental and test item-related findings in the beagle heart.

Characterizing “Adversity” of Pathology Findings in Nonclinical Toxicity Studies

“…In a classical presentation, the characteristic histopathologic features and lesion distribution, clinical signs, and other corroborative study results would aid in the differentiation; however, there are examples in which only the dose-response curve and overall incidence of histomorphologically identical lesions are distinctive, such as treatment with benzodiazepines, endothelin receptor antagonists, vasodilators, or immunomodulators (Clemo et al 2003). Therefore, the sensitive recording of spontaneous arterial lesions in Beagle dogs, leading to robust historical control data, is essential to interpret such lesions (Bodié and Decker 2014).…”

Characterization of Spontaneous Vascular Findings in the Papillary Muscles of Beagle Dogs

“…Recent publications describe thickening of the tunica media of arteries as more likely to be a manifestation of postmortem hypercontraction. 12,13 This conclusion was supported in one example by lack of staining for Ki67 in the media. 12 In the current study, hypertrophied vessels were evaluated using VVG staining to examine the morphology of the IEL and the presence of intimal hyperplasia, and MT to examine the deposition of collagen within the media.…”

“…12,13 This conclusion was supported in one example by lack of staining for Ki67 in the media. 12 In the current study, hypertrophied vessels were evaluated using VVG staining to examine the morphology of the IEL and the presence of intimal hyperplasia, and MT to examine the deposition of collagen within the media. Demonstration of frequent disruption or loss of the IEL in these vessels argues that this form of vascular remodeling is not artifactual, and in fact represents a physiologic response to the physical stress and microenvironmental conditions of these vessels within the PM.…”

“…These papillary proliferations are composed of loose connective tissue and lined by mesothelium and reported as incidental findings in beagle dogs. 12,14 This finding was present in the right appendage in 5 (17%) of 30 dogs and in the left atrial appendage in 2 (7%) of 30.…”

“…8 In dogs, the posterior PM is variably supplied by the septal branch of the left coronary artery and/or left circumflex artery, while the anterior PM is supplied by several branches of the left and right coronary arteries. 10,11 Trimming practices for nonclinical toxicity studies as documented in the literature are vague and include methodology such as "left ventricle (including apex and papillary muscle)" 12 or "papillary muscle." 13 Importantly, due to potential variations in necropsy and trimming practices, it is possible that different PMs are evaluated by a pathologist for any given animal within a study.…”