Reduced Na+ current density underlies impaired propagation in the diabetic rabbit ventricle

Abstract

Diabetes is associated with an increased risk of sudden cardiac death, but the underlying mechanisms remain unclear. Our goal was to investigate changes occurring in the action potential duration (APD) and conduction velocity (CV) in the diabetic rabbit ventricle, and delineate the principal ionic determinants. A rabbit model of alloxan-induced diabetes was utilized. Optical imaging was used to record electrical activity in isolated Langendorff-perfused hearts in normo-, hypo- and hyper-kalemia ([K+]o=4, 2, 12 mM respectively). Patch clamp experiments were conducted to record Na+ current (INa) in isolated ventricular myocytes. The mRNA/protein expression levels for Nav1.5 (the α-subunit of INa) and connexin-43 (Cx43), as well as fibrosis levels were examined. Computer simulations were performed to interpret experimental data. We found that the APD was not different, but that the CV was significantly reduced in diabetic hearts in normo-, hypo-, and, in hyper-kalemic conditions (13%, 17% and 33% reduction in diabetic vs. control, respectively). The cell capacitance (Cm) was increased (by ~14%), and the density of INa was reduced by ~32% in diabetes compared to controls, but the other biophysical properties of INa were unaltered. The mRNA/protein expression levels for Cx43 were unaltered. For Nav1.5, the mRNA expression was not changed, and though the protein level tended to be less in diabetic hearts, this reduction was not statistically significant. Staining showed no difference in fibrosis levels between the control and diabetic ventricles. Computer simulations showed that the reduced magnitude of INa was a key determinant of impaired propagation in the diabetic ventricle, which may have important implications for arrhythmogenesis.

Type 2 Diabetes Induces Prolonged P-wave Duration without Left Atrial Enlargement

“…These results suggest that the generation of depolarization was not impaired in the atrium of T2DM rats. We note that our observation of unaltered density of I Na is inconsistent with the previous study of Stables et al ( 21 ), showing that the I Na density was reduced by ~32% in diabetic rabbit myocytes. One reason for this discrepancy might be the differences in diabetic model types (type 1 in their study vs. type 2 in ours) and the duration of diabetes (21weeks in their study vs. 8 weeks in our study).…”

Diet-induced pre-diabetes slows cardiac conductance and promotes arrhythmogenesis

“…Other mechanisms that may contribute to decreased conduction velocity is a decrease in cardiomyocyte excitability due to altered Na + -channel activity or changes in cell size. Altered I Na density and increased cell capacitance have previously been related to conduction disturbances in the heart of alloxan-induced diabetic rabbits [ 34 ]. However, we found no difference in Na + -channel activity between FFFRs and controls in isolated ventricular cardiomyocytes.…”

Disease Modifiers of Inherited SCN5A Channelopathy

“…It is therefore plausible that diabetes increases disease severity in LQT3 patients, but evidence for such a modulatory effect is currently lacking. On the other hand, a decrease in Na V 1.5 expression and I Na has been reported in rabbit and rat models of diabetes ( 129 , 130 ), which may have important implications for BrS.…”