New drugs vs. old concepts: A fresh look at antiarrhythmics

Abstract

Common arrhythmias, particularly atrial fibrillation (AF) and ventricular tachycardia/fibrillation (VT/VF) are a major public health concern. Classic antiarrhythmic (AA) drugs for AF are of limited effectiveness, and pose the risk of life-threatening VT/VF. For VT/VF, implantable cardiac defibrillators appear to be the unique, yet unsatisfactory, solution. Very few AA drugs have been successful in the last few decades, due to safety concerns or limited benefits in comparison to existing therapy. The Vaughan-Williams classification (one drug for one molecular target) appears too restrictive in light of current knowledge of molecular and cellular mechanisms. New AA drugs such as atrial-specific and/or multichannel blockers, upstream therapy and anti-remodeling drugs, are emerging. We focus on the cellular mechanisms related to abnormal Na⁺ and Ca²⁺ handling in AF, heart failure, and inherited arrhythmias, and on novel strategies aimed at normalizing ionic homeostasis. Drugs that prevent excessive Na⁺ entry (ranolazine) and aberrant diastolic Ca²⁺ release via the ryanodine receptor RyR2 (rycals, dantrolene, and flecainide) exhibit very interesting antiarrhythmic properties. These drugs act by normalizing, rather than blocking, channel activity. Ranolazine preferentially blocks abnormal persistent (vs. normal peak) Na⁺ currents, with minimal effects on normal channel function (cell excitability, and conduction). A similar "normalization" concept also applies to RyR2 stabilizers, which only prevent aberrant opening and diastolic Ca²⁺ leakage in diseased tissues, with no effect on normal function during systole. The different mechanisms of action of AA drugs may increase the therapeutic options available for the safe treatment of arrhythmias in a wide variety of pathophysiological situations.

Carbon Monoxide Induces Cardiac Arrhythmia via Induction of the Late Na+ Current

“…The beneficial effects of ranolazine were most striking in vivo, where the incidence of CO-induced sudden arrhythmic death decreased markedly. Furthermore, the ability of the drug to normalize repolarization time ( Figure 6) is consistent with its proposed antiarrhythmic mechanism (46). A recent large-scale epidemiologic study has highlighted the fact that, in addition to common occurrences of acute CO poisoning, environmental CO exposure is a major cause of emergency hospital admissions, with cardiac rhythm disturbances identified as a prominent feature (1).…”

“…Furthermore, CO exposure led to a pronounced lengthening of ventricular repolarization time (QTc interval) and an increased QT variability (QT STV ), factors that are associated with high occurrences of spontaneous ventricular arrhythmias. QT lengthening and an increase of QT variability are also well-known prognostic markers of ventricular arrhythmic events likely to be associated with an increase of the late Na 1 current (45,46). Ranolazine is a well-characterized inhibitor of the late Na 1 current with significant selectivity over the transient Na 1 current (26,33).…”

Amino-terminus oligomerization regulates cardiac ryanodine receptor function

“…Accordingly, conditions that weaken or disrupt these oligomeric interactions within the RyR2 N-terminus could lead to SR Ca 2+ leak during the diastolic phase in cardiac myocytes. RyR2 bearing CPVT mutations are known to result in 'hypersensitive' channels and diastolic Ca 2+ leak, often leading to delayed after-depolarizations and fatal arrhythmias (Blayney and Lai, 2009;Thireau et al, 2011). In light of the present findings, the potential involvement of RyR2 N-terminus tetramerization in the pathogenesis of CPVT is very plausible and this prospect should be further investigated.…”

Biodegradable polymeric nanocapsules prevent cardiotoxicity of antitrypanosomal lychnopholide

“…Redox-sensitive alterations of Na + and Ca 2+ handling proteins as well as modifications of key regulating kinases of these proteins have critical physiological roles and high pathological relevance 43 . Interestingly, Na + overload due to ROS-dependent activation of sustained Na + currents may participate to increase SR Ca 2+ load 32,44 thereby explaining the concomitant increase of the Ca 2+ transient and the RyR2 leakage induced by LYC. These mechanisms are highly pathophysiologic 43 .…”