Mechanisms of K2P3.1 K+ channel and action potential regulation in atrial fibrillation and heart failure - implications for personalized antiarrhythmic therapy

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Atrial fibrillation (AF) contributes significantly to cardiovascular morbidity and mortality. The coexistence of heart failure (HF) worsens prognosis of AF patients and poses a particular therapeutic challenge. Despite recent advances the growing epidemic requires more effective antiarrhythmic strategies. Our scientific approach aims at mechanism-based development of new antiarrhythmic concepts, with a focus on recently discovered two-pore-domain K+ (K2P) 3.1 currents that regulate action potential (AP) duration. K2P3.1 channels are expressed in human atria. We revealed differential K2P3.1 remodeling in atrial arrhythmogenesis. In patients with chronic AF (cAF), increased atrial K2P3.1 levels resulted in shortened AP duration (APD), a key driver of AF-maintaining reentry. HF induces opposite effects: LV dysfunction is associated with prolonged atrial APD through reduction of repolarizing K2P3.1 K+ channels. Based on these findings we propose that patient-specific atrial K2P3.1 expression and APD remodeling associated with HF and cAF may be targets for patient-tailored antiarrhythmic therapy. To further translate this hypothesis into clinical practice, we here propose to identify the signaling mechanisms that determine differential K2P3.1 remodeling in patients with AF and HF. To this end, K2P3.1 expression and function will be studied in right atrial tissue of 250 patients with paroxysmal AF, chronic AF, and sinus rhythm undergoing cardiac surgery. Based on the hypothesis that small non-coding RNAs regulate K2P3.1expression, electrophysiological findings will be stratified according to LV function and correlated with microRNA expression profiles in human atrial tissue. Regulation of K2P3.1 current by microRNAs, and functional effects of microRNA overexpression or suppression will be elucidated in cultured atrial myocytes. The expected results will provide the scientific basis for translation of patient-tailored antiarrhythmic strategies targeting K2P3.1 channels into clinical practice.