The coronary sinus: Novel arrhythmogenic aspects

Abstract

Despite the documented efficacy of catheter ablation in restoring and maintaining sinus rhythm in patients with atrial fibrillation (AF), antiarrhythmic drug therapy is very likely to remain a mainstay of AF management in the foreseeable future, complementary or alternative to interventional approaches. 1 However, limited efficacy of currently available "classical" antiarrhythmic drugs and their high risk of adverse effects, including ventricular proarrhythmia, have ignited numerous efforts to improve our understanding of the mechanisms underlying initiation and perpetuation of AF. The hope is that identifying profibrillatory mechanisms will aid in developing drugs that selectively target atrial candidates, leading to more effective and also safer medical treatment of AF. In this issue of the Journal of Cardiovascular Electrophysiology, Sicouri et al 2 reveal that (1) coronary sinus (CS) cardiomyocytes in situ exhibit distinct differences in their action potential characteristics, including time course and shape of repolarization and presence of spontaneous diastolic depolarization, (2) CS myocytes are susceptible to muscarinic or beta-adrenergic receptor stimulation-induced triggered activity, and (3) ranolazine, an inhibitor of the so-called late sodium current (I Na-L ) suppresses triggered activity. 2 These findings suggest CS automaticity and (para)sympathetically induced triggered activity as possible initiators of AF, providing a mechanistic explanation for the efficacy of CS ablation for rhythm control in some AF patients. 3 They further suggest that suppression of triggered activity underlies the antifibrillatory effect of ranolazine that has been reported in multiple clinical trials, 4 supporting the utility of I Na-L inhibition for halting AF. 1 | ELECTRICAL HETEROGENEITY OF THE CS As in superior vena cava sleeve preparations, 5 a subpopulation of cardiomyocytes in the CS was observed to develop spontaneous diastolic depolarizations. The magnitude of the maximal diastolic potential, as well as the rate of diastolic depolarization, progressively increased with an increase in stimulation rate and were markedly reduced by muscarinic receptor blockade. Further, bursts of subthreshold electrical stimuli evoked atropine-sensitive hyperpolarizations of similar magnitude, suggesting a role of parasympathetic innervation in mediating rapid pacing-induced hyperpolarization. CS myocytes developing diastolic depolarization were found to exhibit a biphasic dependence of dV/dt max on pacing rate that is reminiscent of supernormal conduction, whereas myocytes with stable resting membrane potential showed a monotonic decrease in dV/dt max as rate increased. When extrapolated to in vivo conditions, cell typespecific differential responses to vagal stimulation and/or high stimulation rates may accentuate local conduction heterogeneity which, combined with regional differences in CS myocyte repolarization, may promote arrhythmias. Indeed, optical voltage mapping of isolated canine atrial preparations previously demonstra...