ABSTRACT
Diseases of the cardiovascular system and related events are among the leading cause of death; and within the pharmaceutical industry, drug-related cardiovascular toxicity continues to be a major cause for compound attrition nonclinically and clinically. Understanding the potential mechanism of action leading to toxicity requires a thorough working knowledge of the embryology, anatomy, physiology, biochemistry, pharmacology, and molecular biology of the cardiovascular system. Understanding the pathophysiology of cardiac structure and function remodeling is essential in identifying candidate biomarkers that are either predictors or early reporters of key events such as changes in extracellular matrix composition, particularly fibrillar collagen. In hamsters, strain-specific background cardiac pathology, including myocardial necrosis, inflammation, fibrosis, and mineralization, can eventually lead to cardiomyopathy and congestive heart failure. Etiologic factors for drug-induced aortic aneurysms, ruptures and dissections in humans include systemic hypertension, hyperlipidemia, and atherosclerosis. Spontaneous heart lesions are fairly common in non-human primates, rodents, and to some extent rabbits, but relatively uncommon in dogs and minipigs.
