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Published on: February 14, 2017
Cardiac valvular pathology: comparative pathology and animal models of acquired cardiac valvular diseases
1Lilly Research Laboratories, Eli Lilly and Co., Greenfield, Indiana 46140, USA. k.donnelly@lilly.com
Abstract:
Recent voluntary withdrawal of the ergoline-derivative Alzheimers' drug Pergolide (Permax) resulting from demonstrated risk of cardiac valve injury illustrates the increased importance of valve injury in pharmaceutical toxicology. Following the 2001 landmark discovery of cardiac valve injury associated with the widely prescribed anti-obesity drug combination fenfluramine-phentermine, and subsequent withdrawal, the need to understand and assess cardiac valve biology and pathology both preclinically and clinically has been accentuated. Unique aspects of the developmental biology, anatomy, and physiology of cardiac valves compared to main cardiac tissue have been discovered, and key elements of the pathophysiology of various valvular injury mechanisms have been described. Although general clinical cardiac valvular disease in humans has been well characterized, animal modeling of valvular injury has proved to be difficult and undersubscribed. Additionally, both the preclinical, pharmaceutical, toxicologic assessment of valvular injury and the understanding of species-comparative valvular pathology have been limited. As discoveries and awareness grows, the purpose of this paper is to review the structure and function of cardiac valves, mechanisms, and outcomes of the common acquired human cardiac valve diseases, including those that are drug-related; to summarize comparative laboratory animal valvular pathology; and to review the literature of contemporary animal models of valvular injury.
Insights
Drug-induced cardiac valve injury is a growing concern in pharmaceutical toxicology. This review covers cardiac valve structure, disease mechanisms, and animal models for preclinical assessment.
Area of Science:
- Cardiovascular Toxicology
- Drug Safety Evaluation
- Valvular Pathology
Background:
- Cardiac valve injury is increasingly recognized as a significant risk in pharmaceutical toxicology, highlighted by drug withdrawals like Pergolide.
- Previous drug-induced valve injuries, such as fenfluramine-phentermine, have intensified the need for robust preclinical and clinical assessment of cardiac valves.
- Understanding the unique biology and pathology of cardiac valves is crucial for evaluating drug safety.
Purpose of the Study:
- To review the structure and function of cardiac valves.
- To describe mechanisms and outcomes of acquired human cardiac valve diseases, including drug-related cases.
- To summarize comparative animal models for valvular injury and assess their utility in preclinical toxicology.
Main Methods:
- Literature review of cardiac valve structure, function, and disease.
- Analysis of drug-induced valvular pathology and human case studies.
- Survey of existing animal models for valvular injury and their limitations.
Main Results:
- Cardiac valves possess unique biological characteristics distinct from other cardiac tissues.
- Drug-related valvular injury mechanisms and pathological outcomes are being elucidated.
- Development of reliable animal models for preclinical assessment of valvular injury remains challenging.
Conclusions:
- Accurate preclinical assessment of drug-induced cardiac valve injury requires a deeper understanding of valve biology and pathology.
- Comparative pathology across species is limited, hindering the translation of animal model findings.
- Further research into robust animal models is essential for improving pharmaceutical safety and preventing drug-induced valvular disease.
