A much larger I to and expression of additional K + channels are responsible for the typical triangular AP shape and shorter AP duration (APD) in mouse and rat (versus nonrodents) ventricular myocytes ( 16). It has been shown, for example, that the presence of a more prominent “spike and dome” morphology is due to a large transient outward current I to in species like rabbit and human, while I to is virtually absent in the guinea pig, which lacks the AP notch ( 15). Specifically, varying expression and regulation of ion channels and transporters, notably K + channels ( 11– 14), are mechanistically associated with species-specific action potential (AP) properties. To accommodate for these quite different working regimes, evolution has led to several differences in the ionic mechanisms controlling excitation-contraction coupling (ECC) ( 6, 10). For example, body and heart weights, as well as stroke volume, vary across approximately three orders of magnitude, and resting heart rate is about 10-fold higher in mouse versus human (~600 bpm versus 60 bpm) ( 8).
Despite genetic similarities, differences in cardiac function among mammals are evident at both organ and cellular levels. The species most commonly used for preclinical assessment of cardiac electrophysiologic outcomes are small mammals ( 6, 7), including mice ( 8) and rabbits ( 9). We demonstrate that this approach is well suited to predicting the effects of perturbations across different species or experimental conditions and suggest its integration into mechanistic studies and drug development pipelines. We then tested our translators against experimental data describing the response to stimuli, such as ion channel block, change in beating rate, and β-adrenergic challenge. We trained these statistical operators using a broad dataset obtained by simulating populations of our biophysically detailed computational models of action potential and Ca 2+ transient in mouse, rabbit, and human. Here, we built a suite of translators for quantitatively mapping electrophysiological responses in ventricular myocytes across species.
However, interspecies differences in the mechanisms regulating excitation-contraction coupling can limit the translation of experimental findings from animal models to human physiology and undermine the assessment of drugs’ efficacy and safety. Animal experimentation is key in the evaluation of cardiac efficacy and safety of novel therapeutic compounds.