Diet-induced obesity causes long QT and reduces transcription of voltage-gated potassium channels

Abstract

In humans, obesity is associated with long QT, increased frequency of premature ventricular complexes, and sudden cardiac death. The mechanisms of the pro-arrhythmic electrophysiologic remodeling of obesity are poorly understood. We tested the hypothesis that there is decreased expression of voltage-gated potassium channels in the obese heart, leading to long QT. Using implanted telemeters, we found that diet-induced obese (DIO) wild-type mice have impaired cardiac repolarization, demonstrated by long QT, as well as more frequent ventricular ectopy, similar to obese humans. DIO mice have reduced protein and mRNA levels of the potassium channel Kv1.5 caused by a reduction of the transcription factor cyclic AMP response element binding protein (CREB) in DIO hearts. We found that CREB knock-down by siRNA reduces Kv1.5, CREB binds to the Kv1.5 promoter in the heart, and CREB increases transcription of mouse and human Kv1.5 promoters. The reduction in CREB protein during lipotoxicity can be rescued by inhibiting protein kinase D (PKD). Our results identify a mechanism for obesity-induced electrophysiologic remodeling in the heart, namely PKD-induced reduction of CREB, which in turn decreases expression of the potassium channel Kv1.5.

Prevalence of QT interval prolongation in inflammatory bowel disease

“…Underlying factors could be likely associated with sleep apnea or changes in cardiac morphology because of inappropriate left ventricular mass as suggested by the Losartan Intervention for Endpoint Reduction (LIFE) study (47,48). The mechanistic causes in turn have been postulated to be related to defective calcium inactivation and decreased expression of voltage-gated potassium channels leading to altered myocyte action potentials (49,50). Our results also appear to suggest that obese patients with IBD are at an increased risk for QT interval prolongation.…”

Health Benefits of Long-Term Weight-Loss Maintenance

“…The metabolic mechanisms associated with weight gain include insulin resistance often accompanied by hyperinsulinemia, impaired glucose tolerance, and eventually type 2 diabetes as well as atherogenic dyslipoproteinemias, fatty liver disease, prolonged QT interval (89), myocardial fatty infiltration with impaired myocardial energetic efficiency (147), and increased thrombogenesis (169). In addition, obesity-related hypoventilation syndromes (e.g., chronic hypercapnia and obstructive sleep apnea) have been associated with increased cardiovascular morbidity and mortality (150).…”

Extracellular signal-regulated kinase activation during cardiac hypertrophy reduces sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) transcription

“…ERK is upregulated in human heart failure from both ischemic and non-ischemic causes [10]. ERK is also activated in the hearts of diet-induced obesity wild-type mice and the LMNA mutant mouse model of cardiomyopathy, and pharmacologic ERK inhibition improves cardiac function in the transgenic model [11, 12]. Further, Erk2 T188S (which functions as a dominant negative for both ERK1 and ERK2) transgenic mice have a reduced hypertrophic response [13].…”