Species differences in cardiovascular physiology that affect pharmacology and toxicology

The accuracy with which preclinical studies performed on infrahuman mammals predict the efficacy and safety of potential new therapeutics intended for human use is a topic of interest and concern to preclinical scientists, physicians, veterinarians, regulators, and patients everywhere. Factors that impact the potential accuracy of preclinical assessments of safety and efficacy in surrogate species for humans include substantial differences in the mechanisms of cardiac repolarization and excitation–contraction coupling, as well as in the isoforms of the heart's contractile proteins. Some species are so similar to humans that they suffer the same spontaneous heart diseases — and yet so different that toxic doses of drugs or interventions that would be instantly fatal to a human have literally no effect on them. These differences are in part explained by the sometimes enormous differences in size and scale among species and in part by genetic and biochemical differences that we have only recently begun to understand. In reviewing some of the more striking species differences and similarities in cardiovascular physiology, this article hopes to stimulate interest in and inform the choices of scientists involved in surrogate model selection as they work to improve both the positive and negative predictive value of preclinical drug studies.