Atrial fibrillation (AF), the most common heart rhythm disorder, is becoming increasingly prevalent among Western populations and is one of the major causes of stroke. Treatments available at present are still associated with high rates of recurrence and lack of effectiveness.
DZHK investigators from the partner site Heidelberg/Mannheim examined whether atrial fibrillation is accompanied by specific electrical changes in the atrial myocardium which could serve as starting points for mechanism-based treatments. Electrical ion channel remodeling was analyzed in a total of 122 patients with paroxysmal and chronic atrial fibrillation, as well as sinus rhythm as a control cohort. The investigation focused on the so-called two-pore-domain potassium channels (K2P). In Circulation the researchers report that, in a comparison of all functional K2P channels, the K2P channel K2P3.1 (TASK-1) was most strongly expressed in the sinus rhythm group. While paroxysmal atrial fibrillation did not provoke any change, there was a significant 60% increase in K2P3.1 expression in the patient group with chronic atrial fibrillation. For patients with chronic atrial fibrillation, patch-clamp analyses of isolated atrial cardiomyocytes showed a correlating three-fold increase in the K2P3.1 current. Up-regulation of the repolarizing K2P3.1 channel was associated with a significant 43% shortening of the atrial action potential duration (APD), a fundamental electrophysiological hallmark of chronic atrial fibrillation.
In a therapeutic approach it was possible to “correct” the pathological electrical changes by inhibiting the K2P3.1 channel in cardiomyocytes of patients with chronic atrial fibrillation. Treatment with the experimental antiarrhythmic drug A293 led to prolongation of the APD by 58%, bringing it to the level of patients with sinus rhythm.
Hence the K2P3.1 channel is a new, atrium-specific target for future mechanism-based treatments of atrial fibrillation.