Abstract 223: Remodeling of K-ATP Channel Expression and Function in Type-2 Diabetes Mellitus
Diabetes mellitus (DM) is associated with enhanced propensity for ventricular tachyarrhythmias (VT). We found that DM hearts exhibit attenuated APD shortening in response to ischemia (Fig). We hypothesized that altered KATP channel expression & function underlie this impaired electrophysiological (EP) adaptation.
Methods: We investigated differential effects of the SUR2a activator Pinacidil (PIN, 100 uM) and the SUR1 activator Diazoxide (DZX, 30 uM) on EP properties in Zucker Diabetic Fatty (ZDF) and control (ctrl) rats at baseline and in response to no flow ischemia. We measured the mRNA expression of KATP channel subunits (Kir6.1, Kir6.2, SUR1a, SUR1b, SUR2a, and SUR2b) in normal and ZDF animals.
Results: PIN caused comparable APD shortening in ctrl & ZDF hearts during baseline perfusion and promoted early onset of sustained VT within 6 min of ischemia in ctrl & ZDF hearts. In contrast, DZX did not alter APD (p=NS) or cause arrhythmias in either group during baseline perfusion. However, DZX accelerated APD shortening and promoted VT in all (8/8) ZDF hearts during ischemia (Fig 1). The putative molecular mechanism underlying the differential proarrhythmic sensitivity of ZDF vs ctrl hearts to DZX was investigated. We found marked upregulation of Kir6.1 (by 3.7X p<0.001) and SUR1b (by 2.8X p<0.001) mRNA levels with no changes in Kir6.2, SUR1a, SUR2a, or SUR2b expression in ZDF.
Conclusion: Remodeling of KATP channel subunits likely underlies the differential sensitivity of ZDF hearts to DZX. Our findings indicate that this classically cardioprotective agent should be avoided in DM patients at risk of ischemic events. Upregulation of Kir6.1 & SUR1b may be markers of proarrhythmia.
Author Disclosures: J. Hu: None. C. Xie: None. F.G. Akar: None.
This research has received full or partial funding support from the American Heart Association, Founders Affiliate (Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, Vermont).
- © 2015 by American Heart Association, Inc.