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Updated: May 31, 2026
Viral Transgene Expression in Rodent Hearts and the Assessment of Cardiac Arrhythmia Risk
Published on: July 27, 2022
Morphologic aspects of rodent cardiotoxicity in a retrospective evaluation of National Toxicology Program studies
Micheal P Jokinen1, Warren G Lieuallen, Michael C Boyle
1Charles River Laboratories-Pathology Associates, Durham, North Carolina, USA.
Abstract:
The heart is increasingly recognized as a target for toxicity. As studies in laboratory rodents are commonly used to investigate the potential toxicity of various agents, the identification and characterization of lesions of cardiotoxicity is of utmost importance. Although morphologic criteria have been established for degenerative myocardial lesions in rats and mice, differentiation of spontaneously occurring lesions from toxin-induced or toxin-related lesions remains difficult. A retrospective light microscopic evaluation was performed on the hearts of F344 rats and B6C3F(1) mice from National Toxicology Program (NTP) studies of six chemicals identified in the NTP database in which treatment-induced myocardial toxicity was present. Two previously defined myocardial lesions were observed: "cardiomyopathy" that occurred spontaneously or as a treatment-related effect and "myocardial degeneration" that occurred as a treatment-related effect. Both lesions consisted of the same basic elements, beginning with myofiber degeneration and necrosis, with varying amounts of inflammation, interstitial cell proliferation, and eventual fibrosis. This observation is indicative of the heart's limited repertoire of responses to myocardial injury, regardless of the nature of the inciting agent. A prominent differentiating factor between spontaneous and treatment-induced lesions was distribution and lesion onset. Once the respective lesions had undergone fibrosis, however, they generally appeared morphologically indistinguishable.
Insights
Differentiating heart lesions in rodents is challenging. This study found that while spontaneous and toxin-induced cardiotoxicity share basic features, their distribution and onset can help distinguish them, though fibrosis makes them indistinguishable.
Area of Science:
- Toxicology
- Cardiovascular Pathology
- Rodent Models
Background:
- The heart is a key target for chemical toxicity.
- Identifying cardiotoxicity in rodent studies is crucial for safety assessments.
- Distinguishing spontaneous from induced cardiac lesions in rodents is difficult.
Purpose of the Study:
- To evaluate and differentiate spontaneous versus treatment-induced myocardial lesions in rodents.
- To characterize the morphology and progression of cardiac lesions in toxicology studies.
Main Methods:
- Retrospective light microscopic evaluation of rodent hearts from National Toxicology Program (NTP) studies.
- Analysis of hearts from F344 rats and B6C3F(1) mice with known treatment-induced myocardial toxicity.
Main Results:
- Two myocardial lesions were observed: "cardiomyopathy" (spontaneous or treatment-related) and "myocardial degeneration" (treatment-related).
- Both lesions involve myofiber degeneration, necrosis, inflammation, proliferation, and fibrosis, indicating a limited cardiac response to injury.
- Distribution and onset were key differentiators for spontaneous versus treatment-induced lesions.
Conclusions:
- Rodent hearts exhibit a limited range of responses to various cardiotoxic agents.
- Morphological similarities, especially after fibrosis, can obscure the origin of cardiac lesions.
- Careful assessment of lesion distribution and onset is vital for accurate cardiotoxicity diagnosis in toxicology studies.
