A Diagnostic Approach for Rodent Progressive Cardiomyopathy and Like Lesions in Toxicology Studies up to 28 Days in the Sprague Dawley Rat (Part 1 of 2)

Abstract

Spontaneous rodent progressive cardiomyopathy (PCM) in the Sprague Dawley rat may confound identification and/or interpretation of potential test article (TA)-related cardiotoxicity. Pathologists apply diagnostic term(s) and thresholds for diagnosing and assigning severity grades for PCM and/or PCM-like (PCM/like) lesions consistently within a study, which is necessary to identify and interpret TA-related findings. Due to differences in training and/or experiences, diagnostic terms and thresholds may vary between pathologists. Harmonized terminology and thresholds across studies will generate better historical control data, will likely enhance interpretation of study data, and may further enhance our understanding of the spontaneous change. An assessment of the diagnostic approaches of a group of 37 pathologists identified an approach that is relatively easily applied; and if adopted, it could enhance diagnostic consistency across studies. This approach uses the single "slash" term "necrosis/inflammatory cell infiltrate (NICI)" as the diagnosis for the spectrum of lesions seen in younger rats, uses no threshold for diagnosis (e.g., diagnose all lesions clearly identifiable as PCM/like), and uses aggregate lesion size of approximately ≥45% of the field of view (FOV) using a 10×/22 eyepiece and the 40× objective or approximately ≥100% of the FOV using the 60× objective as the criterion separating minimal from mild severities.

Endocrine-Disrupting Effects of Bisphenol A on the Cardiovascular System: A Review

“…Rodent progressive cardiomyopathy is a common background lesion of undetermined etiology, and even though it occurs in both genders, it affects mainly males. This injury is suspected to arise from a localized microvascular dysfunction, and the resulting lesions phenotypically progress from minor to extensive focal mononuclear cell infiltration, myocyte degeneration, and fibrosis [ 64 ]. The research work of Gear et al observed the cardiomyopathy-like lesions in the sections used for the characterization of left ventricular wall thickness and fibrosis.…”

Spontaneously occurring cardiovascular lesions in commonly used laboratory animals

“…Rats are susceptible to several naturally occurring myocardial degenerative alterations (myocyte degeneration or necrosis, inflammation, and fibrosis) that meet the definition of cardiomyopathy. These spontaneous alterations occur at varying degrees of incidence and severity in common strains of rats [31,32,35,48,49].…”

“…Some lesions might mimic those induced by chemical compounds and thus might compromise the interpretation of cardiotoxicity studies, particularly if the lesions are similar to those induced by test agents. An example of a possible spontaneous lesion complication is rodent progressive cardiomyopathy, which occurs spontaneously in young and old animals and that may be exacerbated by drug treatment or even mimic druginduced injury [31,32].…”

Using Artificial Intelligence to Detect, Classify, and Objectively Score Severity of Rodent Cardiomyopathy

“…Progressive cardiomyopathy can first be recognized as small, discrete foci of myocardial degeneration and/or necrosis accompanied by inflammatory cell infiltration. 3,[4][5][6] In later stages, necrosis and inflammation are replaced by varying degrees of fibrosis. 3,5 Mineralization, as well as cartilaginous or osseous metaplasia, may also be present.…”

“…1,5 Consequently, there is a need for consistent and sensitive detection as well as quantification of PCM-related changes to help differentiate spontaneous from test article-related findings. Recent work by Hailey et al 6,7 has shown that pathologists vary in their diagnostic criteria, terminology, and severity grading approaches with regard to PCM. Application of harmonized diagnostic criteria does increase concordance among pathologists.…”