Electrocardiographic characteristics and SCN5A mutations in idiopathic ventricular fibrillation associated with early repolarization.
ABSTRACT Recently, we and others reported that early repolarization (J wave) is associated with idiopathic ventricular fibrillation. However, its clinical and genetic characteristics are unclear.
This study included 50 patients (44 men; age, 45 ± 17 years) with idiopathic ventricular fibrillation associated with early repolarization, and 250 age- and sex-matched healthy controls. All of the patients had experienced arrhythmia events, and 8 (16%) had a family history of sudden death. Ventricular fibrillation was inducible by programmed electric stimulation in 15 of 29 patients (52%). The heart rate was slower and the PR interval and QRS duration were longer in patients with idiopathic ventricular fibrillation than in controls. We identified nonsynonymous variants in SCN5A (resulting in A226D, L846R, and R367H) in 3 unrelated patients. These variants occur at residues that are highly conserved across mammals. His-ventricular interval was prolonged in all of the patients carrying an SCN5A mutation. Sodium channel blocker challenge resulted in an augmentation of early repolarization or development of ventricular fibrillation in all of 3 patients, but none was diagnosed with Brugada syndrome. In heterologous expression studies, all of the mutant channels failed to generate any currents. Immunostaining revealed a trafficking defect in A226D channels and normal trafficking in R367H and L846R channels.
We found reductions in heart rate and cardiac conduction and loss-of-function mutations in SCN5A in patients with idiopathic ventricular fibrillation associated with early repolarization. These findings support the hypothesis that decreased sodium current enhances ventricular fibrillation susceptibility.
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ABSTRACT: Early repolarization (ER) has been accepted as a benign ECG variant for decades. Two seminal studies challenged this notion and have demonstrated that ER pattern is associated with an increased risk of arrhythmic and cardiac mortality in patients with idiopathic ventricular fibrillation (IVF) and in the general population. Recent clinical studies demonstrate its varying impact as an arrhythmogenic substrate on different diseases. For example, in ER syndrome, a primary electrical disease, ER appears as a major arrhythmogenic substrate for development of VF whereas in patients with coronary artery disease, an ER pattern may exist as a silent substrate, increasing the risk of VF during episodes of cardiac ischaemia. Due to the high prevalence of an ER pattern in the general population and a low VF event rate, it remains challenging to differentiate a malignant ER pattern from a benign form. Recent research suggests that a J-wave amplitude of more than 0.1 mV combined with a descending/horizontal ST segment may constitute a malignant ER pattern. Further studies are however necessary to evaluate its prognostic value for cardiac and arrhythmic death in the general population as well as in cases with a malignant ER pattern. While genetic testing has revealed putative causal DNA variants in sporadic cases, the lack of co-segregation with the disease in affected families suggests that ER syndrome is not monogenic but is likely a complex disorder influenced by multiple genetic as well as environmental factors.Journal of Interventional Cardiac Electrophysiology 02/2014; · 1.39 Impact Factor
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ABSTRACT: Voltage sensor domains (VSDs) are a feature of voltage gated ion channels (VGICs) and voltage sensitive proteins. They are composed of four transmembrane (TM) segments (S1-S4). Currents leaking through VSDs are called omega or gating pore currents. Gating pores are caused by mutations of the highly conserved positively charged amino acids in the S4 segment that disrupt interactions between the S4 segment and the gating charge transfer center (GCTC). The GCTC separates the intracellular and extracellular water crevices. The disruption of S4-GCTC interactions allows these crevices to communicate and create a fast activating and non-inactivating alternative cation-selective permeation pathway of low conductance, or a gating pore. Gating pore currents have recently been shown to cause periodic paralysis phenotypes. There is also increasing evidence that gating pores are linked to several other familial diseases. For example, gating pores in Nav1.5 and Kv7.2 channels may underlie mixed arrhythmias associated with dilated cardiomyopathy (DCM) phenotypes and peripheral nerve hyperexcitability (PNH), respectively. There is little evidence for the existence of gating pore blockers. Moreover, it is known that a number of toxins bind to the VSD of a specific domain of Na(+) channels. These toxins may thus modulate gating pore currents. This focus on the VSD motif opens up a new area of research centered on developing molecules to treat a number of cell excitability disorders such as epilepsy, cardiac arrhythmias, and pain. The purpose of the present review is to summarize existing knowledge of the pathophysiology, biophysics, and pharmacology of gating pore currents and to serve as a guide for future studies aimed at improving our understanding of gating pores and their pathophysiological roles.Frontiers in Pharmacology 04/2014; 5:53.
- Archivos de cardiología de México 03/2014;