Upregulation of K(2P)3.1 K+ Current Causes Action Potential Shortening in Patients With Chronic Atrial Fibrillation.
نویسندگان
چکیده
BACKGROUND Antiarrhythmic management of atrial fibrillation (AF) remains a major clinical challenge. Mechanism-based approaches to AF therapy are sought to increase effectiveness and to provide individualized patient care. K(2P)3.1 (TASK-1 [tandem of P domains in a weak inward-rectifying K+ channel-related acid-sensitive K+ channel-1]) 2-pore-domain K+ (K(2P)) channels have been implicated in action potential regulation in animal models. However, their role in the pathophysiology and treatment of paroxysmal and chronic patients with AF is unknown. METHODS AND RESULTS Right and left atrial tissue was obtained from patients with paroxysmal or chronic AF and from control subjects in sinus rhythm. Ion channel expression was analyzed by quantitative real-time polymerase chain reaction and Western blot. Membrane currents and action potentials were recorded using voltage- and current-clamp techniques. K(2P)3.1 subunits exhibited predominantly atrial expression, and atrial K(2P)3.1 transcript levels were highest among functional K(2P) channels. K(2P)3.1 mRNA and protein levels were increased in chronic AF. Enhancement of corresponding currents in the right atrium resulted in shortened action potential duration at 90% of repolarization (APD90) compared with patients in sinus rhythm. In contrast, K(2P)3.1 expression was not significantly affected in subjects with paroxysmal AF. Pharmacological K(2P)3.1 inhibition prolonged APD90 in atrial myocytes from patients with chronic AF to values observed among control subjects in sinus rhythm. CONCLUSIONS Enhancement of atrium-selective K(2P)3.1 currents contributes to APD shortening in patients with chronic AF, and K(2P)3.1 channel inhibition reverses AF-related APD shortening. These results highlight the potential of K(2P)3.1 as a novel drug target for mechanism-based AF therapy.
منابع مشابه
Response to Letter Regarding Article, "Upregulation of K2P3.1 K+ Current Causes Action Potential Shortening in Patients With Chronic Atrial Fibrillation".
We thank Dr Olschewski and colleagues for their interest in our article, and we appreciate their recapitulation of 2 key findings of our work: (1) the identification of increased atrial K 2P 3.1 (TASK-1) K channel expression, I K2P3.1 upregulation, and action potential shortening as substrate in patients with chronic atrial fibrillation (AF); and (2) the presentation of K 2P 3.1 current inhibit...
متن کاملLetter by Olschewski et al Regarding Article, "Upregulation of K2P3.1 K+ Current Causes Action Potential Shortening in Patients With Chronic Atrial Fibrillation".
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BACKGROUND Clinical and experimental evidence suggest that the parasympathetic nervous system is involved in the pathogenesis of atrial fibrillation (AF). However, it is unclear whether changes in G-protein-coupled inward rectifying K(+) current (I(K,ACh)) contribute to chronic AF. METHODS AND RESULTS In the present study, we used electrophysiological recordings and competitive reverse-transc...
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ورودعنوان ژورنال:
- Circulation
دوره 132 2 شماره
صفحات -
تاریخ انتشار 2015