Lu Ren

Inhibition of late sodium current suppresses calcium-related ventricular arrhythmias by reducing the phosphorylation of CaMK-II and sodium channel expressions

Cardiac arrhythmias associated with intracellular calcium inhomeostasis are refractory to antiarrhythmic therapy. We hypothesized that late sodium current (INa) contributed to the calcium-related arrhythmias. Monophasic action potential duration at 90% completion of repolarization (MAPD90) was significantly increased and ventricular arrhythmias were observed in hearts with increased intracellular calcium concentration ([Ca2+]i) by using Bay K 8644, and the increase became greater in hearts treated with a combination of ATX-II and Bay K 8644 compared to Bay K 8644 alone. The prolongations caused by Bay K 8644 and frequent episodes of ventricular tachycardias, both in absence and presence of ATX-II, were significantly attenuated or abolished by late INa inhibitors TTX and eleclazine. In rabbit ventricular myocytes, Bay K 8644 increased ICaL density, calcium transient and myocyte contraction. TTX and eleclazine decreased the amplitude of late INa, the reverse use dependence of MAPD90 at slower heart rate, and attenuated the increase of intracellular calcium transient and myocyte contraction. TTX diminished the phosphorylation of CaMKII-δ and Nav 1.5 in hearts treated with Bay K 8644 and ATX-II. In conclusion, late INa contributes to ventricular arrhythmias and its inhibition is plausible to treat arrhythmias in hearts with increased [Ca2+]i

Statin Use and the Risk of Cataracts: A Systematic Review and Meta‐Analysis

Background Cataracts are the main cause of poor vision and blindness worldwide. The effects of statin administration on cataracts remain debated. Therefore, we conducted a systematic review and meta‐analysis to determine whether statin use affects the risk of cataracts. Methods and Results We performed a systematic search of the electronic databases PubMed, EMBASE, and the Cochrane Library through January 2016. Weighted averages were reported as relative risk values with 95% CIs. Statistical heterogeneity scores were assessed with the standard Cochrans Q test and the I2 statistic. A total of 6 cohort studies, 6 case–control studies, and 5 randomized controlled trials, together involving more than 313 200 patients, were included in our study. The pooled estimates of cohort studies indicated that the use of statins moderately increases the risk of cataracts (relative risk, 1.13; 95% CI, 1.01–1.25). The pooled estimates of case–control studies (relative risk=1.10, 95% CI, 0.99–1.23) and randomized controlled trials (relative risk, 0.89; 95% CI, 0.72–1.10) indicated that the use of statins does not increase the risk of cataracts. The sensitivity analysis confirmed the stability of the results. Heterogeneity was found among the cohort and case–control studies. Conclusions Based on the present meta‐analysis of these studies, we could only conclude that there is no clear evidence showing that statin use increases the risk of cataracts. The most likely case is that there is no association between statin use and cataracts. Because of the considerable benefits of statins in cardiovascular patients, this issue should not deter their use.

ASSA14-03-46 Inhibition of late sodium current reduces the reverse rate dependence of action potential duration prolongation induced by L-type calcium channel activator

Objective Late sodium current (late I Na) has been confirmed to contribute to the reverse rate dependence (RRD) of action potential duration (APD) prolongation induced by potassium inhibitor. This study is to determine the role of endogenous late sodium current in the induced RRD of APD prolongation in hearts treated with L-type calcium channel activator Bay K 8644. Methods New Zealand White rabbit isolated heart preparations were perfused with modified Krebs-Henseleit solution. Hearts were paced at increasing cycle lengths (CLs) of 400, 500, 667, 1000, 1333 and 2000 ms after atrioventricle (AV) block was introduced by themo-ablation of the AV nodal area. Epicardial monophasic action potential duration at 90% completion of an action potential (epi-MAPD90) from the left ventricular free wall were recorded and measured. Tetrodotoxin (TTX) at the concentration of 1 µmol/L was used to inhibit late I Na selectively. Results At CL of 400 ms, epi-MAPD90 was 150.5 ± 2.2 ms (n = 12). When the pacing CL was increased to 500, 667, 1000, 1333 and 2000 ms, the epi-MAPD90 was significantly increased by 10.6 ± 2.9, 27.2 ± 3.0, 39.2 ± 3.8, 48.8 ± 3.5 and 56.6 ± 5.2 ms (n = 12, p < 0.05∼0.001), respectively. Compared with control, 200 nM Bay K 8644 significantly prolonged MAPD90 at all pacing rates (n = 12, P < 0.01 vs control), and the increase was greater at longer CLs (72.8 ± 6.1 at CL of 2000 ms) than at shorter CLs (16.1 ± 2.4 at CL of 400 ms, p < 0.05). In addition, Bay K 8644 caused polymorphic ventricular tachycardia at longer CLs of 1333 and 2000 ms. In the continued presence of Bay K 8644, TTX significantly reduced the augmentation of RRD of MAPD90 and abolished the ventricular tachycardia. Conclusion Endogenous late sodium current contributes to the enhanced RRD of APD prolongation induced by L-type calcium channel activator.

ASSA14-03-47 Ivabradine prolongs action potential duration and causes atrial arrhythmia in the heart

Objective Ivabradine (IVA) selectively inhibits If current in the sinus node and is used to treat inappropriate sinus tachycardia. Previous studies indicated that IVA also inhibited IKr at concentrations higher than therapeutic range. However, the proarrhythmic risk of IVA has not been fully determined. Sea anemone toxin (ATX) –II treated hearts have an increased risk of proarrhythmia and therefore was used to detect low-risk QT prolonging drugs. The objective of this study was to determine the effect of IVA on the atrial and ventricular monophasic action potential duration (MAPD) and the arrhythmic activities in the absence and presence of ATX-II. Methods Female rabbit isolated hearts were perfused by Langendorff mode. Hearts were paced at right atria appendage, and left atrial and ventricular MAPD90 were recorded and analysed. Results When hearts were paced at 2.8 Hz, the atrial, and endocardial and epicardial ventricular MAPD90 were 49.6 ± 3, 136.3 ± 7 and 127.4 ± 4 ms. IVA (3–10 μm) significantly prolonged them by 15.9 ± 2 (n = 6, p < 0.01), 31.5 ± 4 and 23.9 ± 3 ms, respectively (n = 6, p < 0.01), in a concentration dependent manner. When the pacing rate was increased from 2.5 Hz to 3.5 Hz, IVA (6 μm) reduced LV endocardial and epicardial MAPD90 by 41.2 ± 3 and 31.6 ± 4 ms (n = 5, p < 0.05) in a reverse rate dependent mode. ATX-II (3 nM) prolonged atrial MAPD90 by 36.5 ± 5 ms, and LV endocardial and epicardial MAPD90 by 19.9 ± 3 and 19.5 ± 4 ms. In the continued presence of ATX-II (3 nM), IVA (6–10 μm) reduced the atrial MAPD90 by 14.4 ± 4 ms (n = 6, p < 0.01). Atrial arrhythmias were observed in 4 of 12 (33.3%) hearts treated with 1–10 μm IVA in the presence of 3 nM ATX-II. In contrast, IVA (3–10 μm) caused greater prolongation in presence, compared with it in absence of ATX-II, in LV endo- and epi- cardial MAPD90 by 36.2 ± 7 and 27.5 ± 5 ms (n = 6, p < 0.01). IVA did not increase the BVR of atrial MAPD90 and transmural dispersion of MAPD90, and caused no ventriculararrhythmia both in the absence and presence of ATX-II, (n = 6, p > 0.05; n = 6, p > 0.05). Conclusion IVA prolongs both atrial and ventricular MAPD and causes atrial arrhythmias in hearts when late sodium current is increased, without proarrhythmic activities in the ventricles. This result may explain the results in clinical research.