Altered gene expression may underlie prolonged duration of the QT interval and ventricular action potential in streptozotocin-induced diabetic rat heart

Abstract

Ventricular electrical conduction has been investigated in the streptozotocin (STZ)-induced diabetic rat. Diabetes was induced with a single injection of STZ (60 mg/kg bodyweight, ip). The ECG was measured continuously, in vivo, using a biotelemetry system. Left ventricular action potentials were recorded with an extracellular suction electrode. Expression of mRNA transcripts for selected ion transport proteins was measured in left ventricle with real-time RT-PCR. At 10 weeks after STZ treatment, in vivo heart rate (HR) was reduced (267 +/- 3 vs. 329 +/- 5 BPM), QRS complex duration and QT interval were prolonged in diabetic rats compared to controls. In vitro spontaneous HR was reduced and paced heart action potential repolarization was prolonged in diabetic rats compared to controls. The mRNA expression for Kcnd2 (I (to) channel) and Kcne2 (I (kr) channel) was significantly reduced in diabetic rats compared to controls. Altered gene expression and, in particular, genes that encode K(+) channel proteins may underlie delayed propagation of electrical activity in the ventricular myocardium of STZ-induced diabetic rat.

Myocardial impulse propagation is impaired in right ventricular tissue of Zucker Diabetic Fatty (ZDF) rats

“…In addition, QRS prolongation, which may occur due to decreased CV, is found in both STZ treated rats [36] and ZDF rats [27], as well as in diabetic humans [37]. This indicates that decreased CV may be an independent risk factor for development of ventricular arrhythmias in both type 1 and 2 diabetic patients.…”

Improvement of the metabolic status recovers cardiac potassium channel synthesis in experimental diabetes

“…The reduction in all these repolarizing currents induced by diabetes may be attributed either to impaired channel protein expression (Howarth et al . ) or to altered channel biophysical properties or both. Yet, the absence of differences in inactivation half voltages, in the inactivation kinetics or in recovery from inactivation kinetics suggests an impairment of channels protein expression.…”

Glutathione oxidation unmasks proarrhythmic vulnerability of chronically hyperglycemic guinea pigs

“…Since most of these studies were performed in isolated myocytes, the relevance of cellular APD prolongation to arrhythmia propensity in the intact heart remained untested. By and large, these measurements were also performed in models that exhibited excessive (Ͼ350%) elevations in plasma glucose levels that are well beyond what is typically observed in patients with t1DM (i.e., ϳ25-50%) (13,20,33,46). Therefore, we began by examining whether APD prolongation is indeed a characteristic of this guinea pig model which exhibits a qualitatively similar rise (on a percent basis) in blood glucose levels, as clinically observed in patients.…”

“…This distinction is important because unlike rodents, patients with t1DM do not exhibit heart rate corrected QT-interval prolongation in the absence of confounding factors, such as diabetic ketoacidosis (24) or spontaneous hypoglycemia (11). Clinically, these additional stimuli are required to unmask pathological QT-interval prolongation in patients with t1DM (11,14,17,24).More importantly, most EP studies in t1DM have been performed in animal models that exhibited highly artificial rises (Ͼ300%) in blood glucose levels that are well beyond what is commonly encountered in patients with diabetes (20,33,36,40,46). Such extreme levels of hyperglycemia, which are known to affect ion channels, preclude the direct translation of some of these earlier findings to humans.…”

“…More importantly, most EP studies in t1DM have been performed in animal models that exhibited highly artificial rises (Ͼ300%) in blood glucose levels that are well beyond what is commonly encountered in patients with diabetes (20,33,36,40,46). Such extreme levels of hyperglycemia, which are known to affect ion channels, preclude the direct translation of some of these earlier findings to humans.…”