Abstract 20958: Diltiazem Treatment Attenuates Arrhythmogenesis During Diabetic Cardiomyopathy by Stabilizing Ryanodine Receptors-Mediated Sarcoplasmic Reticulum Calcium Release
Diabetes increases the risk of ventricular arrhythmias, for which the underlying mechanisms are not well known, and specific therapies for this patient population are not well defined. The potential beneficial effect of diltiazem (DILT), a widely prescribed calcium (Ca) channel blocker, to treat arrhythmia has not been investigated in diabetes. We hypothesized that impaired Ca handling may contribute to arrhythmogenesis, which will be restored by long-term treatment with DILT in a model of diabetic cardiomyopathy. Rats with streptozotocin-induced diabetes were randomized to treatment with DILT or placebo for 8 weeks, and compared to controls (n = 9 / group). Electrocardiograms were measured at baseline and at 8 weeks. Ventricular myocytes were isolated for electrophysiological measurements and confocal Ca imaging. Diabetes significantly increased QRS amplitude, QTc interval and beat-to-beat QT variability. Action potential durations (APD) were significantly prolonged and afterdepolarizations occurred in diabetic myocytes (p<0.05). DILT treatment normalized QT (interval and variability), APD (50 and 90), and reduced the occurrence of afterdepolarizations in DILT-treated compared to untreated diabetic rats. Ca transient amplitude and sarcoplasmic reticulum (SR) Ca load (estimated by measuring caffeine-evoked ∫INCX and Ca transient amplitudes) were reduced in diabetic compared to control myocytes (p<0.05). DILT therapy resulted in partial repletion of SR Ca content, thus increasing peak amplitude and partially normalizing Ca transient in diabetic myocytes. In permeabilized myocytes, Ca spark frequency (i.e., diastolic channel activity) was decreased in treated and untreated diabetic compared to control rats (p<0.05). The decreased Ca spark frequency, in the face of increased SR Ca load and Ca transient peak amplitude in treated diabetic myocytes, suggests that DILT therapy improves Ca homeostasis by blocking diastolic SR Ca leak, which subsequently attenuated arrhythmogenesis observed in vivo and in vitro during diabetes. In addition, reducing Ca influx may improve diabetic cardiomyopathy by altering Ca-dependent signaling pathways with subsequent posttranslational modifications and stabilization of ryanodine receptors.
- © 2010 by American Heart Association, Inc.