Reduction in Kv Current Enhances the Temporal Dispersion of the Action Potential in Diabetic Myocytes: Insights From a Novel Repolarization Algorithm

Abstract

BackgroundDiabetes is associated with prolongation of the QT interval of the electrocardiogram and enhanced dispersion of ventricular repolarization, factors that, together with atherosclerosis and myocardial ischemia, may promote the occurrence of electrical disorders. Thus, we tested the possibility that alterations in transmembrane ionic currents reduce the repolarization reserve of myocytes, leading to action potential (AP) prolongation and enhanced beat‐to‐beat variability of repolarization.Methods and ResultsDiabetes was induced in mice with streptozotocin (STZ), and effects of hyperglycemia on electrical properties of whole heart and myocytes were studied with respect to an untreated control group (Ctrl) using electrocardiographic recordings in vivo, ex vivo perfused hearts, and single‐cell patch‐clamp analysis. Additionally, a newly developed algorithm was introduced to obtain detailed information of the impact of high glucose on AP profile. Compared to Ctrl, hyperglycemia in STZ‐treated animals was coupled with prolongation of the QT interval, enhanced temporal dispersion of electrical recovery, and susceptibility to ventricular arrhythmias, defects observed, in part, in the Akita mutant mouse model of type I diabetes. AP was prolonged and beat‐to‐beat variability of repolarization was enhanced in diabetic myocytes, with respect to Ctrl cells. Density of Kv K+ and L‐type Ca2+ currents were decreased in STZ myocytes, in comparison to cells from normoglycemic mice. Pharmacological reduction of Kv currents in Ctrl cells lengthened AP duration and increased temporal dispersion of repolarization, reiterating features identified in diabetic myocytes.ConclusionsReductions in the repolarizing K+ currents may contribute to electrical disturbances of the diabetic heart.

Electrocardiographic parameters effectively predict ventricular tachycardia/fibrillation in acute phase and abnormal cardiac function in chronic phase of ST‐segment elevation myocardial infarction

“…The potassium current is the most involved among outward currents, leading to delayed repolarization. Meanwhile, the prolonged period of repolarization renders the electrocardiac activity unstable . Furthermore, myocardial infarction induces great transmural or total dispersion of repolarization to the heart and, finally, increased heterogeneity of cardiac repolarization underlying arrhythmogenesis.…”

A New Tool for the Action Potential Repolarization Dynamic Analysis: Application to the Discrimination of Diabetic and Control Cells

“…Referring to [4], this localization could be due to changes of the Kv currents profile. In addition to the work in [2], where it is shown that these changes are due to the effect of diabetes, this new findings could help to identify which Kv currents are the most affected. Furthermore, the median value shown in Figure 6, brings additional information on the dynamics.…”

“…In previous works [2], [3] applied to a subset of the records it has been shown that automatic AP analysis can be performed accurately. It has not been demonstrated that the dynamics of the repolarization phase throughout the stimulation allows to distinguish the two populations while some specificity has been found.…”

“…It has been shown in [2] that, according to the mean AP for the two groups, it is more relevant to normalize the observations to avoid bias for the groups discrimination. To achieve this task, the previously computed parameters are normalized accordingly.…”

“…Prolongation of the AP in myocytes may represent the basis for the increased risk of arrhythmia with diabetes [1], but the determinants of these abnormalities remain to be elucidated. We have shown in [2] that the diabetic condition is associated with alterations in the temporal dynamics of the AP profile in myocytes, a factor that may originate electrical instability. This assessment has been performed by using statistics computed over APs associated to isolated left ventricular myocytes obtained from control (Ctrl)and streptozotocin-induced (STZ) diabetic mice.…”