Cardiac disease and arrhythmogenesis: Mechanistic insights from mouse models

Abstract

The mouse is the second mammalian species, after the human, in which substantial amount of the genomic information has been analyzed. With advances in transgenic technology, mutagenesis is now much easier to carry out in mice. Consequently, an increasing number of transgenic mouse systems have been generated for the study of cardiac arrhythmias in ion channelopathies and cardiomyopathies. Mouse hearts are also amenable to physical manipulation such as coronary artery ligation and transverse aortic constriction to induce heart failure, radiofrequency ablation of the AV node to model complete AV block and even implantation of a miniature pacemaker to induce cardiac dyssynchrony. Last but not least, pharmacological models, despite being simplistic, have enabled us to understand the physiological mechanisms of arrhythmias and evaluate the anti-arrhythmic properties of experimental agents, such as gap junction modulators, that may be exert therapeutic effects in other cardiac diseases. In this article, we examine these in turn, demonstrating that primary inherited arrhythmic syndromes are now recognized to be more complex than abnormality in a particular ion channel, involving alterations in gene expression and structural remodelling. Conversely, in cardiomyopathies and heart failure, mutations in ion channels and proteins have been identified as underlying causes, and electrophysiological remodelling are recognized pathological features. Transgenic techniques causing mutagenesis in mice are extremely powerful in dissecting the relative contributions of different genes play in producing disease phenotypes. Mouse models can serve as useful systems in which to explore how protein defects contribute to arrhythmias and direct future therapy.

Keywords: Cardiac arrhythmia; Cardiomyopathy; Conduction; Ion channelopathy; Mouse model; Repolarization.

Fig. 1

Genetic, physical and pharmacological models in mouse hearts.

Fig. 2

Experimental setup for Langendorff perfusion, which monophasic action potential (MAP) recordings during simultaneous pacing.

Fig. 3

Afterdepolarization phenomena: early afterdepolarization (EAD) occurs early (phase 2) or late (phase 3), and delayed afterdepolarization (DAD) occurs during phase 4 of the action potential. When sufficiently large, these can result in triggered activity.

Fig. 4

Circus-type reentry requires a structural or functional obstacle (gray center) around which an action potential can circulate.

Fig. 5

Hypokalaemia prolongs APDs, which predisposes to triggered activity (left). This AP prolongation and reduced refractoriness together form a re-entrant substrate. The use of programmed electrical stimulation can reliably provoke ventricular arrhythmias (right).

Fig. 6

Hypokalaemia exacerbates APD alternans at fast heart rates (left) due to steep APD restitution (right).