Species-Dependent Mechanisms of Cardiac Arrhythmia: A Cellular Focus

Abstract

Although ventricular arrhythmia remains a leading cause of morbidity and mortality, available antiarrhythmic drugs have limited efficacy. Disappointing progress in the development of novel, clinically relevant antiarrhythmic agents may partly be attributed to discrepancies between humans and animal models used in preclinical testing. However, such differences are at present difficult to predict, requiring improved understanding of arrhythmia mechanisms across species. To this end, we presently review interspecies similarities and differences in fundamental cardiomyocyte electrophysiology and current understanding of the mechanisms underlying the generation of afterdepolarizations and reentry. We specifically highlight patent shortcomings in small rodents to reproduce cellular and tissue-level arrhythmia substrate believed to be critical in human ventricle. Despite greater ease of translation from larger animal models, discrepancies remain and interpretation can be complicated by incomplete knowledge of human ventricular physiology due to low availability of explanted tissue. We therefore point to the benefits of mathematical modeling as a translational bridge to understanding and treating human arrhythmia.

Keywords: arrhythmia; cardiomyocyte; electrophysiology; species.

Figure 1.

Computational models represent the most concise, precise, and simple means of storing current information of myocyte electrophysiology. They also present the most simple means of comparing dynamic characteristics between species or those resulting from disease. Human: the left ventricular epicardial model of Grandi et al, which has been widely used by others.^, The relatively fast and large transient outward current is a characteristic of epicardial myocytes, and humans exhibit more subtle expression of the delayed rectifiers than other larger mammals. In particular, the rapidly activating delayed rectifier dominates over the slowly activating form, which has important implications for repolarization reserve. Canine: epicardial model from Hund and Rudy (see also the work by Benson et al and Panthee et al), showing the pronounced I_to,f expression in these cells, which is responsible for the characteristic peak and dome action potential (AP) of this cell type and alters time courses of both I_CaL and sarcoplasmic reticulum calcium release. Rabbit: the rabbit model of Shannon et al (see also the work by Restrepo et al) was one of the first to accurately reflect large mammal excitation-contraction coupling. Like humans, rabbits rely more heavily on I_Kr for late repolarization, and this has made them a popular model for studying long QT–associated arrhythmia mechanisms. Guinea pig: Luo and Rudy developed the first biophysically detailed models of ventricular myocyte electrophysiology. These models have been continually revised, and here, we show output of the Faber-Rudy model published in 2007. Note the high expression of all currents, and particularly I_Ks, which makes a major contribution to the stability of the phase 2 plateau. Inward (reverse mode) I_NaCa is only substantial in this model at high intracellular Na (15 mM), and normal [Na]_i is ~7 mM. Mouse: the detailed mouse model of Morotti et al (see also the work by Gray et al and Schilling et al) showing how high expression of both I_to,f and I_Kur overwhelms all inward currents in these cells and thereby markedly abbreviates the AP. This eliminates almost all opportunities for activation of I_Ks and I_Kr, both of which are included in the model.

Figure 2.

Early afterdepolarization (EAD) mechanisms differ across species and tissues. (A) Schematic representation of EAD mechanisms in large mammal ventricular myocytes. The long action potential plateau observed in ventricular myocytes from humans and other large mammals promotes EADs that initiate within the activation range of I_CaL. As a result, the broad range of maneuvers or defects that can destabilize repolarization in these cells converge at I_CaL reactivation, which carries most of the inward current in all cases. In some cases, discoordinated intracellular calcium release (systolic calcium waves) can act as the initiating factor and generate sufficient I_NaCa to drive these reactivation events. Because I_NaCa is favored at negative potentials, these types of events are more likely to generate an EAD during terminal repolarization and still I_CaL carries most of the current during the EAD upstroke. (B) Murine EADs involve fundamentally different mechanisms. At left, an action potential clamp experiment showing the lidocaine-sensitive current during an EAD waveform is recorded in a mouse ventricular myocyte. At these concentrations, lidocaine binds primarily to inactivated Na⁺ channels, and this current indicates a reactivating component of I_Na. Because this component is sensitive to the trajectory of repolarization, it represents nonequilibrium dynamics rather than window-range reactivation. At right, the same EAD waveform is imposed on a mouse ventricular myocyte model, which shows that compared with the other major inward currents, I_Na is by far the greatest contributor to EADs in mice. (C) EAD mechanisms associated with reinitiation of atrial fibrillation (AF) in a human atrial myocyte model. Rapid pacing and acetylcholine administration can be used to simulate atrial fibrillation in atria of large mammals (AF). When the pacing is stopped to simulate termination of AF, spontaneous EADs occur at sinus rates, as has been observed in canine atria. These events result from I_Na reactivation very similar to that occurring in the mouse ventricle. This may be important in certain specific contexts of human atrial disease.