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Cardiac Valvular Pathology: Comparative Pathology and Animal Models of Acquired Cardiac Valvular DiseasesLilly Research Laboratories, Eli Lilly and Co., Greenfield, Indiana, USA Correspondence: Address correspondence to: Kevin B. Donnelly, Lilly Research Laboratories, PO Box 708, Greenfield, IN 46140, USA; e-mail: k.donnelly{at}lilly.com. 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.
Key Words: cardiac valve • valvulopathy • valvular injury • valvular disease • fenfluramine • phentermine • animal model • 5-HT Abbreviations: AV, atrioventricular valve • VEC, valvular endothelial cells • VIC, valvular interstitial cells • ECM, extracellular matrix • SMA, smooth muscle actin • TGF-β, transforming growth factor-β • AVS, aortic valvular stenosis • MVP, mitral valve prolapse • 5-HT, 5-hydroxytryptamine • SLE, systemic lupus erythematosus • APLAS, antiphospholipid antibody syndrome • MDMA, 3,4-methylenedioxyamphetamine • MDA, 3,4-methylenedioxyamphetyamine • EMC, endocardial myxomatous change • 5-HTT, 5-hydroxytryptamine transporter • SD, Sprague-Dawley • HF HC, high-fat high-carbohydrate • LDLr- -, low density lipoprotein receptor knockout • ApoE- -, apolipoprotein E-deficient • eNOS, endothelial nitric oxide synthase • MFS, Marfan syndrome
Toxicologic Pathology, Vol. 36, No. 2,
204-217 (2008) |
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