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.

Xanthine Oxidase Inhibitor Allopurinol Prevents Oxidative Stress‐Mediated Atrial Remodeling in Alloxan‐Induced Diabetes Mellitus Rabbits

“…Repolarization abnormalities can result in early or delayed afterdepolarizations, which can initiate triggered activity when their magnitudes are sufficiently large to reach the threshold potential for sodium channel reactivation. They can also increase the dispersion of repolarization, promoting unidirectional conduction block and reentry 27, 28…”

“…They can also increase the dispersion of repolarization, promoting unidirectional conduction block and reentry. 27,28 Several oxidative stress mechanisms have been proposed to explain the development and perpetuation of AF in the context of diabetes mellitus. 29 An excellent study demonstrated that maximal capacity for mitochondrial oxidation of palmitoyl-carnitine is decreased while mitochondrial H 2 O 2 emission during oxidation of carbohydrate-and lipid-based substrates is increased, corresponding to increased local oxidative stress in the tissue, demonstrating mitochondria to be the main source of ROS.…”

Mouse models of atherosclerosis: a historical perspective and recent advances

“…The observations of this remarkable characteristic supported the discovery of the essential role of cholesterol in atherosclerosis development. Animal models have been extensively used for the study of human cardiovascular diseases [29–40], and their use has led to opportunities for translational application [32, 41–45]. In this review, the different models for examining atherosclerosis, their own advantages and disadvantages (Table 1) and the molecular pathways involved (Table 2), will be discussed in turn.…”

Transverse cardiac slicing and optical imaging for analysis of transmural gradients in membrane potential and Ca2+ transients in murine heart

“…The models include ion channelopathies with minimal structural abnormalities, and those of structural heart disease (Choy et al . ). The former group includes catecholaminergic polymorphic ventricular tachycardia (CPVT) (Wehrens et al .…”