Cardiac dynamics: Alternans and arrhythmogenesis

Abstract

Pre-existing heterogeneities present in cardiac tissue are essential for maintaining the normal electrical and mechanical functions of the heart. Exacerbation of such heterogeneities or the emergence of dynamic factors can produce repolarization alternans, which are beat-to-beat alternations in the action potential time course. Traditionally, this was explained by restitution, but additional factors, such as cardiac memory, calcium handling dynamics, refractory period restitution, and mechano-electric feedback, are increasingly recognized as the underlying causes. The aim of this article is to review the mechanisms that generate cardiac repolarization alternans and convert spatially concordant alternans to the more arrhythmogenic spatially discordant alternans. This is followed by a discussion on how alternans generate arrhythmias in a number of clinical scenarios, and concluded by an outline of future therapeutic targets for anti-arrhythmic therapy.

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

“…In addition, Ca 2+ alternans can be induced in cardiac cells by making sarcoplasmic release of calcium strongly dependent upon the SR Ca 2+ content. Compelling evidence suggests that action potential duration alternans, whether in the atria or the ventricles, are driven by Ca 2+ alternans, which are attributable to ryanodine receptor refractoriness 44. Moreover, calcium homeostasis is an important regulator of mitochondrial synthesis.…”

Animal models for the study of primary and secondary hypertension in humans

“…Different pharmacological, environmental and genetic models using different animal species have provided useful and valuable information on the aetiology, pathophysiology and complications of human cardiovascular and metabolic disorders, and a platform to examine the efficacy of pharmacotherapy (105–118). However, a major limitation of these experimental models is the anatomical differences between these animal species and humans (119).…”

Electrophysiological mechanisms of long and short QT syndromes

“…Similarly, CV is not reduced unless the specific mutation produces loss-of-function mutations in Na + channels, which may give rise to overlapping phenotype of LQTS with Brugada syndrome and conduction defect [24], [25], [26], [27]. Moreover, the emergence of APD alternans, attributed to increased steepness of APD restitution together with the abnormal repolarization gradient can lead to unidirectional conduction block and thereby reentry [28], [29].…”

“…Recent work in mice demonstrated shortening in ERP in concert with APD [37], leading to decreased λ and a higher risk of circus-type reentry. Abnormal APD restitution leading to APD alternans is unlikely to play a role in SQTS because only long diastolic intervals are engaged where the restitution curve is flat, unlike the case of LQTS where it was possible to engage the steep portion of the restitution curve at low diastolic intervals [28]. CV may be increased due to ERP shortening, but this would not be expected to be pro-arrhythmic since this would increase rather than decrease λ [38].…”