Abstract
In a patient with right ventricular outflow tract (RVOT) tachycardia, we identified a heterozygous point mutation in the selectivity filter of the stretch‐activated K2P potassium channel TREK‐1 (KCNK2 or K2P2.1). This mutation introduces abnormal sodium permeability to TREK‐1. In addition, mutant channels exhibit a hypersensitivity to stretch‐activation, suggesting that the selectivity filter is directly involved in stretch‐induced activation and desensitization. Increased sodium permeability and stretch‐sensitivity of mutant TREK‐1 channels may trigger arrhythmias in areas of the heart with high physical strain such as the RVOT. We present a pharmacological strategy to rescue the selectivity defect of the TREK‐1 pore. Our findings provide important insights for future studies of K2P channel stretch‐activation and the role of TREK‐1 in mechano‐electrical feedback in the heart.
Highlights
Right ventricular outflow tract ventricular tachycardia (RVOT-ventricular tachycardias (VTs)) is a common form of monomorphic ventricular tachycardia (VT)characterized by the absence of structural heart disease and a mostly unknown etiology (Srivathsan et al, 2005)
We systematically investigated the role of K2P channels for inherited forms of cardiac arrhythmias (Friedrich et al, 2014)
A fast, broad complex tachycardia with a rate of 240 beats/ min was noted during exercise (left bundle branch block (LBBB) with inferior axis), indicating right ventricular outflow tract (RVOT)-VT (Fig 1A)
Summary
Right ventricular outflow tract ventricular tachycardia (RVOT-VT) is a common form of monomorphic ventricular tachycardia (VT)characterized by the absence of structural heart disease and a mostly unknown etiology (Srivathsan et al, 2005). Gene mutations in two-pore domain potassium (K2P) channels have been discovered as a cause for familial or sporadic forms of migraine (Lafreniere et al, 2010) (TRESK), Birk-Barel syndrome (Barel et al, 2008) (TASK-3), and a progressive cardiac conduction disorder (Friedrich et al, 2014) (TASK-4). These discoveries provide direct proof for the pathophysiological relevance of K2P “leak” channels. TREK-1 is one of the most studied cardiac K2P channels, its physiological role in the human heart and cardiac arrhythmias remained elusive
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