Sex hormones and arrhythmia in myocardial ischemia

The mechanisms by which gender affects cardiac electrophysiological parameters and alters the predisposition to certain arrhythmias are not well understood, although differences in the expression and function of ion channels and in the activation of the autonomic nervous system may contribute. In their study Philp and coworkers address the issue of the effect of 17β-estradiol on ventricular vulnerability in a rat model of ischemia. Their data show that there is a dose-dependent antiarrhythmic activity of 17β-estradiol administration with suppression ventricular premature beats, ventricular tachycardia and ventricular fibrillation during ischemia. Furthermore they show a dose-dependent blockage of ICaL by 17β-estradiol which is again stronger in female than in male mice. They postulate that the shown gender-selective, concentration-dependent inhibition of ICaL is sufficient to account for the reduction in ischaemia-induced arrhythmia. With this data they have added important information on the influence of sex hormones on cardiac electrophysiology under pathophysiological conditions

Gender-dependent attenuation of cardiac potassium currents in type 2 diabetic db/db mice

Single ventricular myocytes were prepared from control db/+ and insulin-resistant diabetic db/db male mice at 6 and 12 weeks of age. Peak and sustained outward potassium currents were measured using whole-cell voltage clamp methods. At 6 weeks currents were fully developed in control and diabetic mice, with no differences in the density of either current. By 12 weeks both currents were significantly attenuated in the diabetic mice, but could be augmented by in vitro incubation with the angiotensin-converting enzyme (ACE) inhibitor quinapril (1 μm, 5–9 h). In cells from female db/db mice (12 weeks of age), K(+) currents were not attenuated and no effects of quinapril were observed. To investigate whether lack of insulin action accounts for these gender differences, cells were also isolated from cardiomyocte-specific insulin receptor knockout (CIRKO) mice. Both K(+) currents were significantly attenuated in cells from male and female CIRKO mice, and action potentials were significantly prolonged. Incubation with quinapril did not augment K(+) currents. Our results demonstrate that type 2 diabetes is associated with gender-selective attenuation of K(+) currents in cardiomyocytes, which may underlie gender differences in the development of some cardiac arrhythmias. The mechanism for attenuation of K(+) currents in cells from male mice is due, at least in part, to an autocrine effect resulting from activation of a cardiac renin–angiotensin system. Insulin is not involved in these gender differences, since the absence of insulin action in CIRKO mice diminishes K(+) currents in cells from both males and females

Dispersion of repolarization and refractoriness are determinants of arrhythmia phenotype in transgenic mice with long QT

Enhanced dispersion of repolarization (DR) and refractoriness may be a unifying mechanism central to arrhythmia genesis in the long QT (LQT) syndrome. The role of DR in promoting arrhythmias was investigated in several strains of molecularly engineered mice: (a) Kv4.2 dominant negative transgenic (Kv4.2DN) that lacks the fast component of the transient outward current, Ito,f, have action potential (AP) and QT prolongation, but no spontaneous arrhythmias, (b) Kv1.4 targeted mice (Kv1.4−/−) that lack the slow component of Ito (Ito,s), have no QT prolongation and no spontaneous arrhythmias, and (c) double transgenic (Kv4.2DN×Kv1.4−/−) mice that lack both Ito,f and Ito,s, have AP and QT prolongation, and spontaneous ventricular tachyarrhythmias. Hearts were perfused, stained with di-4-ANEPPS and optically mapped. Activation patterns and conduction velocities were similar between the strains but AP duration at 75% recovery (APD75) was longer in Kv4.2DN (28.0 ± 2.5 ms, P < 0.01, n = 6), Kv1.4−/− (28.4 ± 0.4 ms, P < 0.01, n = 5) and Kv4.2DN×Kv1.4−/− (34.3 ± 2.6 ms, P < 0.01, n = 6) mice than controls (20.3 ± 1.0 ms, n = 5). Dispersion of refractoriness between apex and base was markedly reduced in Kv4.2DN (0.3 ± 0.5 ms, n = 6, P < 0.05) but enhanced in Kv1.4−/− (14.2 ± 2.0 ms, n = 5, P < 0.05) and Kv4.2DN×Kv1.4−/− (15.0 ± 3 ms, n = 5, P < 0.5) mice compared with controls (10 ± 2 ms, n = 5). A premature pulse elicited ventricular tachycardia (VT) in Kv1.4−/− (n = 4/5) and Kv4.2DN×Kv1.4−/− hearts (n = 5/5) but not Kv4.2DN hearts (n = 0/6). Voltage-clamp recordings showed that Ito,f was 30% greater in myocytes from the apex than base which may account for the absence of DR in Kv4.2DN mice. Thus, dispersion of repolarization (DR) appears to be an important determinant of arrhythmia vulnerability