Mechanisms of atrial fibrillation

Abstract

Atrial fibrillation (AF) is the most common sustained arrhythmia, currently affecting over 33 million individuals worldwide, and its prevalence is expected to more than double over the next 40 years. AF is associated with a twofold increase in premature mortality, and important major adverse cardiovascular events such as heart failure, severe stroke and myocardial infarction. Significant effort has been made over a number of years to define the underlying cellular, molecular and electrophysiological changes that predispose to the induction and maintenance of AF in patients. Progress has been limited by the realisation that AF is a complex arrhythmia that can be the end result of various different pathophysiological processes, with significant heterogeneity between individual patients (and between species). In this focused Review article, we aim to succinctly summarise for the non-specialist the current state of knowledge regarding the mechanisms of AF. We address all aspects of pathophysiology, including the basic electrophysiological and structural changes within the left atrium, the genetics of AF and the links to comorbidities and wider systemic and metabolic perturbations that may be upstream contributors to development of AF. Finally, we outline the translational implications for current and future rhythm control strategies in patients with AF.

Pro-Arrhythmic Signaling of Thyroid Hormones and Its Relevance in Subclinical Hyperthyroidism

“…Concerning AF, the cardiomyocyte sleeves overlapping the pulmonary veins along with Ca 2+ handling disorders are the sources of the ectopic electrical activity, while re-entry circuits are promoted by the atrial tissue heterogeneity and disorders in the intercellular electrical coupling mediated by connexin (Cx) channels [3,5,8,9,[30][31][32][33][34]. The association of AF with the atrial Cx37 and Cx40 gene polymorphisms [35], as well as somatic mutations in GJA5 (encoding Cx40), have been identified in AF [36,37].…”

“…Management of AF includes antiarrhythmic drug therapies that are often ineffective in terminating AF or preventing its recurrences, possibly because these drugs target a single pathophysiological mechanism [8]. Catheter ablation of the arrhythmogenic triggers, another option of AF treatment, does not prevent recurrence of AF, probably because of the persistence of the arrhythmogenic substrate [55,57].…”

“…Likewise, TH replacement therapy exerts an impact on the AF ablation outcome [92]. Despite sophisticated invasive approaches, the recurrence of AF remains an unresolved problem in clinical practice, challenging for further research [8].…”

“…An abnormal Ca 2+ cycling and Ca 2+ leak through the ryanodine receptor (RyR) in sarcoplasmic reticulum are involved in the occurrence of triggered activity such as EAD or DAD, followed by premature contraction [170]. DAD may occur during tachycardia in hyperthyroidism and contribute directly to increased susceptibility of the heart to AF and VF [8]. Moreover, TH increased the I Na current, resulting in an increase in intracellular Ca 2+ likely via an accelerated reverse mode of Na + /Ca 2+ exchanger [167].…”

“…Atrial fibrillation (AF) and ventricular fibrillation (VF) are clinically relevant and potentially life-threatening arrhythmias. Despite some differences, both AF and VF have been assumed to occur due to abnormalities in the electrical activity involved in impulse initiation and impulse propagation [1][2][3][4][5][6][7][8][9]. The former is due to an enhanced automaticity of the cardiomyocytes (i.e., pacemaker-like activity) or triggered activity expressed as early after-depolarization (EAD) or delayed after-depolarization (DAD).…”