Differential regulation of K _Ca 2.1 ( KCNN1 ) K ⁺ channel expression by histone deacetylases in atrial fibrillation with concomitant heart failure

Abstract

Atrial fibrillation (AF) with concomitant heart failure (HF) poses a significant therapeutic challenge. Mechanism‐based approaches may optimize AF therapy. Small‐conductance, calcium‐activated K+ (KCa, KCNN) channels contribute to cardiac action potential repolarization. KCNN1 exhibits predominant atrial expression and is downregulated in chronic AF patients with preserved cardiac function. Epigenetic regulation is suggested by AF suppression following histone deacetylase (HDAC) inhibition. We hypothesized that HDAC‐dependent KCNN1 remodeling contributes to arrhythmogenesis in AF complicated by HF. The aim of this study was to assess KCNN1 and HDAC1–7 and 9 transcript levels in AF/HF patients and in a pig model of atrial tachypacing‐induced AF with reduced left ventricular function. In HL‐1 atrial myocytes, tachypacing and anti‐Hdac siRNAs were employed to investigate effects on Kcnn1 mRNA levels. KCNN1 expression displayed side‐specific remodeling in AF/HF patients with upregulation in left and suppression in right atrium. In pigs, KCNN1 remodeling showed intermediate phenotypes. HDAC levels were differentially altered in humans and pigs, reflecting highly variable epigenetic regulation. Tachypacing recapitulated downregulation of Hdacs 1, 3, 4, 6, and 7 with a tendency towards reduced Kcnn1 levels in vitro, indicating that atrial high rates induce remodeling. Finally, Kcnn1 expression was decreased by knockdown of Hdacs 2, 3, 6, and 7 and enhanced by genetic Hdac9 inactivation, while anti‐Hdac 1, 4, and 5 siRNAs did not affect Kcnn1 transcript levels. In conclusion, KCNN1 and HDAC expression is differentially remodeled in AF complicated by HF. Direct regulation of KCNN1 by HDACs in atrial myocytes provides a basis for mechanism‐based antiarrhythmic therapy.

Trigger-Specific Remodeling of KCa2 Potassium Channels in Models of Atrial Fibrillation

“…Previous protein analyses were confined to animals studied after 14 days atrial burst pacing due to limited sample availability and indicated a tendency towards decreased K Ca 2.1 protein expression in RA tissue. 18 Furthermore, reduced expression of the right atrial K Ca 2.2 and K Ca 2.3 protein after 14 days AF in pigs has been reported previously. 16 Tachypacing-Related Remodeling of K Ca 2…”

“…Paroxysmal AF was associated with reduced expression of KCNN1 (−73%, n = 10, P = 0.010), KCNN2 (−62%, n = 10, P = 0.010), and KCNN3 (−50%, n = 10, P = 0.003) compared to HF patients with SR (n = 10) (Figure 1C), as reported earlier. 16,18 In HF patients with cAF, KCNN expression was similarly suppressed by 78% (KCNN1, n = 10, P < 0.0001), 55% (KCNN2, n = 10, P = 0.010), and 48% (KCNN3, n = 10, P= 0.037), respectively (Figure 1C). 16,18 K Ca 2 Channel Remodeling in a Porcine AF/HF Model…”

“…16,18 In HF patients with cAF, KCNN expression was similarly suppressed by 78% (KCNN1, n = 10, P < 0.0001), 55% (KCNN2, n = 10, P = 0.010), and 48% (KCNN3, n = 10, P= 0.037), respectively (Figure 1C). 16,18 K Ca 2 Channel Remodeling in a Porcine AF/HF Model…”

“…The patient cohort with detailed characteristics has been reported previously. 1,[16][17][18] Atrial tissue samples were obtained from the Heidelberg CardioBiobank (Department of Cardiology, University Hospital Heidelberg, Heidelberg, Germany) and quality controlled by the tissue bank of the National Center for Tumor Diseases (NCT, Heidelberg, Germany) in accordance with the regulations of the tissue bank. Cardiac tissue samples were dissected immediately following explantation of the recipient's heart in the operating room.…”

“…(A) Key characteristics of study patients (LA, left atrium; LVEF, left ventricular ejection fraction; see Supplementary Table1for details). Please note that patient characteristics have been published previously.1,[16][17][18] (B) Representative apical 4-chamber echocardiography view of a patient with severely reduced LVEF and sinus rhythm (SR). (C) KCNN mRNA levels normalized to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and respective SR control, obtained from patients with SR, paroxysmal (pAF), or chronic AF (cAF).…”