Two-pore-domain potassium (K_2P) channels modulate cellular excitability. The significance of stretch-activated cardiac K_2P channels (K_2P2.1, TREK-1, KCNK2; K_2P4.1, TRAAK, KCNK4; K_2P10.1, TREK-2, KCNK10) in heart disease has not been elucidated in detail. The aim of this work was to assess expression and remodeling of mechanosensitive K_2P channels in atrial fibrillation (AF) and heart failure (HF) patients in comparison to murine models.

Cardiac K_2P channel levels were quantified in atrial (A) and ventricular (V) tissue obtained from patients undergoing open heart surgery. In addition, control mice and mouse models of AF (cAMP-response element modulator (CREM)-IbΔC-X transgenic animals) or HF (cardiac dysfunction induced by transverse aortic constriction, TAC) were employed. Human and murine KCNK2 displayed highest mRNA abundance among mechanosensitive members of the K_2P channel family (V > A). Disease-associated K_2P2.1 remodeling was studied in detail. In patients with impaired left ventricular function, atrial KCNK2 (K_2P2.1) mRNA and protein expression was significantly reduced. In AF subjects, downregulation of atrial and ventricular KCNK2 (K_2P2.1) mRNA and protein levels was observed. AF-associated suppression of atrial Kcnk2 (K_2P2.1) mRNA and protein was recapitulated in CREM-transgenic mice. Ventricular Kcnk2 expression was not significantly altered in mouse models of disease.

In conclusion, mechanosensitive K_2P2.1 and K_2P10.1 K⁺ channels are expressed throughout the heart. HF- and AF-associated downregulation of KCNK2 (K_2P2.1) mRNA and protein levels suggest a mechanistic contribution to cardiac arrhythmogenesis.