Animal models of cardiovascular disease for pharmacologic drug development and testing: appropriateness of comparison to the human disease state and pharmacotherapeutics.

Abstract

For proper drug development, targeting and testing the use of suitable animal models that are well controlled with regard to duration, degree, and stage of the disease are vitally needed. Furthermore reliable phenotyping and genotyping with regard to functional physiology as well as cellular biochemistry and molecular biology are vital to early decision making in drug discovery, development, and successful clinical development. The use of animal models allows the design of clinical trials without the complication of having to impose "accepted treatment modalities" on top of investigative agents. With the availability of human myocardium for study as a result of cardiac transplantation programs, experimental findings previously reported in several animal models of heart disease have been questioned with regard to suitability for comparison to the human condition. With the development and application of sophisticated techniques and biochemical assays to the study of heart tissue several adaptive changes have been identified and labeled "markers of heart failure." Several animal models share some of these adaptive changes in common with failing human myocardium, but not others. The goal of this report is to point out similarities and differences reported to date in failing and nonfailing human myocardium to that reported in animal models of human heart disease. This discussion indicates important dissimilarities found in several key animal models that have resulted in the development of cardioactive agents and therapeutic interventions for the treatment of human heart disease and the unexpected outcomes. Although focusing on heart failure, a vital goal of this report is to emphasize some key principles supporting the need for clear, comprehensive, and unbiased evaluation of animal models currently in use to study any disease condition, as well as the need for further model development and study in open collaborative efforts.