Animal Models to Study Cardiac Arrhythmias

Abstract

Cardiac arrhythmias are a significant cause of morbidity and mortality worldwide, accounting for 10% to 15% of all deaths. Although most arrhythmias are due to acquired heart disease, inherited channelopathies and cardiomyopathies disproportionately affect children and young adults. Arrhythmogenesis is complex, involving anatomic structure, ion channels and regulatory proteins, and the interplay between cells in the conduction system, cardiomyocytes, fibroblasts, and the immune system. Animal models of arrhythmia are powerful tools for studying not only molecular and cellular mechanism of arrhythmogenesis but also more complex mechanisms at the whole heart level, and for testing therapeutic interventions. This review summarizes basic and clinical arrhythmia mechanisms followed by an in-depth review of published animal models of genetic and acquired arrhythmia disorders.

Keywords: atrial fibrillation; cardiomyopathies; channelopathies; models, animals; morbidity.

Figure 1:. Schematic of the cardiac conduction system and clinical classification of cardiac arrhythmias.

SA – Sinoatrial; AV – Atrioventricular (Illustration credit: Ben Smith)

Figure 2:. The ventricular action potential and ionic currents in humans and mice.

Note the differences in action potential shape, which is caused primarily by differences in ionic currents circled in red. I_Na – Na current; I_Ca(L) – L-type Ca current, I_Ca(T) – T-type Ca current; I_NaCa – Na-Ca-Exchange current; I_to – Transient outward K-current; I_ss – Rapidly activating steady-state K-currents; I_K1 – Inward rectifier K-current; I_Ks – slowly activating delayed rectifier K-current; I_Kr – rapidly activating delayed rectifier K-current; I_NaK – NaK-ATPase pump current. Please note that current densities (pA/pF) measured in single cells vary drastically with experimental conditions and voltage clamp protocols. Current densities were chosen to reflect relative contributions to the AP.

Figure 3:. Tissue-targeted CASQ2 knock-out mice help decipher the anatomical origin of ventricular ectopy in CPVT.

Based on a combination of tissue-targeting and in silico modeling, the PMJ was identified as the likely origin of ventricular ectopy in CPVT. DAD – delayed afterdepolarization. (Illustration credit: Ben Smith)