Late Sodium Current in Atrial Cardiomyocytes Contributes to the Induced and Spontaneous Atrial Fibrillation in Rabbit Hearts.

Increased late sodium current (INa) induces long QT syndrome 3 with increased risk of atrial fibrillation (AF). The role of atrial late INa in the induction of AF and in the treatment of AF was determined in this study. AF parameters were measured in isolated rabbit hearts exposed to late INa enhancer and inhibitors. Late INa from isolated atrial and ventricular myocytes were measured using whole-cell patch-clamp techniques. We found that induced-AF by programmed S1S2 stimulation and spontaneous episodes of AF were recorded in hearts exposed to either low (0.1-3 nM) or high (3-10 nM) concentrations of ATX-II (n = 10). Prolongations in atrial monophasic action potential duration at 90% completion of repolarization and effective refractory period by ATX-II (0.1-15 nM) were greater in hearts paced at slow than at fast rates (n = 5-10, P < 0.05). Both endogenous and ATX-II-enhanced late INa density were greater in atrial than that in ventricular myocytes (n = 9 and 8, P < 0.05). Eleclazine and ranolazine reduced AF window and AF burden in association with the inhibition of both endogenous and enhanced atrial late INa with half maximal inhibitory concentrations (IC50) of 1.14 and 9.78, and 0.94 and 8.31 µM, respectively. The IC50s for eleclazine and ranolazine to inhibit peak INa were 20.67 and 101.79 µM, respectively, in atrial myocytes. In conclusion, enhanced late INa in atrial myocytes increases the susceptibility for AF. Inhibition of either endogenous or enhanced late INa, with increased atrial potency of drugs is feasible for the treatment of AF.

Remodeling of myocardial energy and metabolic homeostasis in a sheep model of persistent atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is the most common progressive cardiac arrhythmia and is often associated with rapid contraction in both atria and ventricles. The role of atrial energy and metabolic homeostasis in AF progression is under-investigated. OBJECTIVES: To determine the remodeling of energy metabolism during persistent AF and the effect of eplerenone (EPL), an aldosterone inhibitor, on metabolic homeostasis. METHODS: A nonsustained atrial pacing sheep model was developed to simulate the progression of AF from paroxysmal to persistent. Metabolomic and proteomic analyses at termination of the experiment were used to analyze atrial tissues obtained from sheep in sham, sugar pill (SP) and EPL-treated groups. RESULTS: Proteomic analysis indicated that compared to the sham group, in SP group, fatty acid (FA) synthesis, FA oxidation, tricarboxylic acid (TCA) cycle processes and amino acids (AAs) transport and metabolism were reduced, while glycolytic processes were increased. In metabolomic analysis, the levels of intermediate metabolites of the glycolytic pathways, including 2-phosphoglyceric acid (2 PG), 1,3-bisphosphoglyceric acid (1,3 PG), and pyruvate, HBP (uridine diphosphate-N-acetylglucosamine, UDP-GlcNAc), TCA (citrate) and AAs were greater while the levels of the majority of lipid classes, including phosphatidic acid (PA), phosphatidylcholine (PC), phosphatidylglycerol (PG), glycerophosphoglycerophosphates (PGP), glycerophosphoinositols (PI) and glycerophosphoserines (PS), were decreased in the atria of SP group than in those of sham group. EPL-pretreatment decreased the expression of glut4 and increased the content of acylcarnitines and lipids, such as lyso phospholipids, phospholipids and neutral lipids. CONCLUSION: In the metabolic remodeling during AF, glucose and lipid metabolism were up- and down-regulated, respectively, to sustain TCA cycle anaplerosis. EPL partialy reversed the metabolic shifting.

Late sodium current associated cardiac electrophysiological and mechanical dysfunction.

Late sodium current (INaL) is a small sustained inward current observed during the cardiac action potential plateau phase following decay of the early peak INa. The endogenous INaL is relatively small in normal hearts but exerts functionally significant effects on cardiomyocyte repolarization with potentially pro-arrhythmic effects in hearts with reduced repolarization reserve. Enhanced INa,L occurs in long QT syndrome 3 (LQTS 3) patients, and under a number of pathological and pharmacological cardiovascular conditions, including bradycardia, myocardial ischemia, reperfusion injury, and heart failure. It may there play important roles in arrhythmogenesis and mechanical dysfunction. Experimental and clinical research suggests that INaL inhibition may prevent and treat cardiac arrhythmias and improve ventricular pump function. Selective INa,L inhibitors, exemplified by ranolazine, GS-967 and GS-458967 have little or no effect on peak sodium current and/or IKr, and carry no or minimal pro-arrhythmic risk compared to those associated with administration of classical class I or III antiarrhythmic drugs, particularly in patients with ischemic heart disease. This increased understanding of INaL may be encouraging to clinicians in use of INaL inhibitors to treat cardiac arrhythmias and mechanical dysfunction directly associated with enhanced INaL such as LQTS type 3, and myocardial ischemia. This review discusses the roles of endogenous and enhanced INaL in arrhythmogenesis and mechanical dysfunction, and the basic and clinical research of INaL inhibitors.

High Concentrations of Uric Acid Inhibit Endothelial Cell Migration via miR-663 Which Regulates Phosphatase and Tensin Homolog by Targeting Transforming Growth Factor-ß1.

BACKGROUND: Whether microRNAs participate in endothelial dysfunction HUA remains unknown. A previous study indicated that miR-663 was the most significantly differentially expressed endothelial microRNA under HUA conditions. Some studies have demonstrated that the miR-663 target gene and TGF-ß1, promoted endothelial cell migration by inhibiting PTEN deleted on chromosome 10. Therefore, we hypothesized that HUA inhibits endothelial migration via miR-663, which regulates PTEN by targeting TGF-ß1. METHODS: PCR analysis was performed to determine miR-663 expression levels. A luciferase assay was performed to validate whether miR-663 targets TGF-ß1 directly. Western blot analysis was performed to determine TGF-ß1 and PTEN expression levels. An miR-663 inhibitor and TGF-ß1- and PTEN-specific siRNAs were transfected into EA.hy926 cells to inhibit miR-663, TGF-ß1, and PTEN expression, respectively. A wound healing assay was performed to determine the migratory ability of EA.hy926 cells. RESULTS: miR-663 had higher expression levels in HUA-stimulated endothelial cells and in the sera of hyperuricemic patients and animals. TGF-ß1 was targeted directly by miR-663. Endothelial miR-663 was up-regulated under HUA conditions, and HUA inhibited endothelial cell migration via miR-663, which targeted TGF-ß1. Thus, TGF-ß1 regulated cell migration in a PTEN-dependent manner. CONCLUSION: HUA inhibits endothelial cell migration via miR-663, which regulates PTEN by targeting TGF-ß1.

High concentrations of uric acid inhibit angiogenesis via regulation of the Krüppel-like factor 2-vascular endothelial growth factor-A axis by miR-92a.

BACKGROUND: Angiogenesis is a critical component of many pathological conditions, and microRNAs (miRNAs) are indispensable in angiogenesis. It is unclear whether miRNAs regulate angiogenesis in the presence of high concentrations of uric acid (HUA), and the underlying mechanisms remain unknown. METHODS AND RESULTS: It was found that HUA inhibited the angiogenic ability of endothelial cells. miRNA expression profiling was conducted using microarray assays in HUA-stimulated endothelial cells. Eighteen differentially expressed miRNAs were subjected to bioinformatic analyses. The results indicated that miR-92a was negatively regulated and was closely related to angiogenesis. Furthermore, the effects of miR-92a on HUA-stimulated endothelial cell angiogenesis and the underlying mechanisms were investigated in dual-luciferase reporter assays, electrophoretic mobility shift assays, immunoblot assays, and tube formation assays. It was determined that Krüppel-like factor 2 (KLF2) is a target gene of miR-92a, and KLF2 binds the vascular endothelial growth factor-A (VEGFA) promoter to inhibit its expression. miR-92a and VEGFA overexpression or KLF2 downregulation alleviates the HUA-mediated inhibition of angiogenesis in endothelial cells in vitro. CONCLUSIONS: This study reported that there is a novel pathway regulating angiogenesis under HUA conditions. In the presence of HUA, miR-92a downregulation increased KLF2 expression, subsequently inhibiting VEGFA, which resulted in decreased angiogenesis. Thus, this study reports a possible mechanism for cardiovascular injury caused by hyperuricemia and suggests that the miR-92a-KLF2-VEGFA axis may be a target for hyperuricemia treatment.

Smilacis Glabrae Rhizoma reduces oxidative stress caused by hyperuricemia via upregulation of catalase.

BACKGROUND/AIMS: Reports have suggested that the traditional Chinese medicine Smilacis Glabrae Rhizoma attenuates hyperuricemia, but its mechanism is unclear. Our previous study demonstrated that uric acid could induce the generation of reactive oxygen species(ROS), which subsequently cause endothelial dysfunction. Therefore, we focused on the oxidative stress process. In this study, we would use LC-MS and bioinformatic analysis to investigate the underlying mechanism. METHODS: We utilized LC-MS to reveal the differential protein expression in the kidneys of rats in the hyperuricemia group and the Smilacis Glabrae Rhizoma treatment group and then subjected the differentially expressed proteins to bioinformatic analysis. We also determined the serum ROS level of the two groups. According the above results, we built our hypothesis and performed in vitro experiments to validate this hypothesis. RESULTS: We found that catalase was upregulated in the group treated with Smilacis Glabrae Rhizoma, and the level of reactive oxygen species was higher in the hyperuricemia group. Thus, we speculated that Smilacis Glabrae Rhizoma could alleviate oxidative stress by upregulating catalase. In vitro experiments, we found that high concentrations of uric acid reduced catalase expression in endothelial cells, which was alleviated by Smilacis Glabrae Rhizoma and resulted in a reduction of reactive oxygen species. Knockdown of catalase led to an increase in reactive oxygen species. CONCLUSION: We demonstrated that Smilacis Glabrae Rhizoma could alleviate the oxidative stress caused by hyperuricemia by upregulating catalase expression. This finding could represent a new application for Smilacis Glabrae Rhizoma in the treatment of hyperuricemia.

Identification of the dominant loop of a dual-loop macro-reentry left atrial flutter without prior intervention using high-density mapping technology: A case report.

BACKGROUND: Left atrial flutter without prior cardiac interventions is uncommon, especially dual-loop macro-reentry atrial flutter. The critical step to ablate dual-loop macro-reentry atrial flutter is to identify the dominant loop and key isthmus. Although entrainment mapping could help identify the dominant loop and key isthmus, it may alter or terminate tachycardia. High-density mapping allows the generation of electroanatomic maps without altering or terminating tachycardia. CASE SUMMARY: Here, we report a case of symptomatic left atrial flutter without prior intervention. In this case, high-density mapping revealed a dual-loop macro-reentry around the mitral annulus and central scar of the anterior wall. The propagation result showed that the dominant loop was around the mitral annulus, and the key isthmus was between the central scar and mitral annulus. The atrial flutter terminated successfully after ablation was performed. CONCLUSION: In this case, we demonstrate that high-density mapping technology may help identify the dominant loop of dual-loop atrial flutter without entrainment, which makes ablation easier.

Mean Platelet Volume to Platelet Count Ratio Predicts Left Atrial Stasis in Patients with Non-Valvular Atrial Fibrillation.

Background: The mean platelet volume to platelet count ratio (MPV/PC) has been investigated in the diagnosis, prognosis and risk stratification in several diseases. However, the predictive role of MPV/PC in left atrial stasis (LAS) of non-valvular atrial fibrillation (NVAF) patients remains unknown. Methods: A total of 217 consecutive NVAF patients undergoing transesophageal echocardiogram (TEE) evaluation were retrospectively enrolled. The demographic, clinical, admission laboratory and TEE data were extracted and analyzed. Patients were categorized into those with or without LAS. The associations between the MPV/PC ratio and LAS were assessed by multivariate logistic regression analysis. Results: There were 24.9% (n = 54) patients with LAS according to TEE. Compared with patients without LAS, the MPV/PC ratio was significantly higher in those with LAS (5.6±1.6 vs 4.8±1.0, P < 0.001). After multivariable adjustment, higher MPV/PC ratio levels (OR 1.747, 95% CI 1.193-2.559, P = 0.004) were positively associated with LAS, with the optimal cut-point for LAS prediction of 5.36 (area under the curve, AUC = 0.683, sensitivity 48%, specificity 73%, 95% CI 0.589-0.777, P < 0.001). The stratification analysis showed that a significant positive correlation between MPV/PC ratio ≥5.36 and LAS in patients of male, younger (<65 years), paroxysmal AF, without history of stroke/TIA, CHA2DS2-VASc score ≥2, left atrial diameter (LAD) ≥40mm and left atrial volume index (LAVI) >34mL/m2 (all P < 0.05). Conclusion: Increasing MPV/PC ratio was associated with an increased risk of LAS, which was mainly reflected in the subgroups of male, younger (<65 years), paroxysmal AF, without history of stroke/TIA, CHA2DS2-VASc score ≥2, LAD ≥40mm and LAVI >34mL/m2 patients.

Late sodium current in synergism with Ca2+/calmodulin-dependent protein kinase II contributes to ß-adrenergic activation-induced atrial fibrillation.

Atrial fibrillation (AF) is frequently associated with ß-adrenergic stimulation, especially in patients with structural heart diseases. The objective of this study was to determine the synergism of late sodium current (late INa) and Ca2+/calmodulin-dependent protein kinase (CaMKII)-mediated arrhythmogenic activities in ß-adrenergic overactivation-associated AF. Monophasic action potential, conduction properties, protein phosphorylation, ion currents and cellular trigger activities were measured from rabbit-isolated hearts, atrial tissue and atrial myocytes, respectively. Isoproterenol (ISO, 1-15 nM) increased atrial conduction inhomogeneity index, phospho-Nav1.5 and phospho-CaMKII protein levels and late INa by 108%, 65%, 135% and 87%, respectively, and induced triggered activities and episodes of AF in all hearts studied (p < 0.05). Sea anemone toxin II (ATX-II, 2 nM) was insufficient to induce any atrial arrhythmias, whereas the propensities of AF were greater in hearts treated with a combination of ATX-II and ISO. Ranolazine, eleclazine and KN-93 abolished ISO-induced AF, attenuated the phosphorylation of Nav1.5 and CaMKII, and reversed the increase of late INa (p < 0.05) in a synergistic mode. Overall, late INa in association with the activation of CaMKII potentiates ß-adrenergic stimulation-induced AF and the inhibition of both late INa and CaMKII exerted synergistic anti-arrhythmic effects to suppress atrial arrhythmic activities associated with catecholaminergic activation. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.

Cardiac Computed Tomography Versus Transesophageal Echocardiography for the Detection of Left Atrial Appendage Thrombus: A Systemic Review and Meta-Analysis.

Background Transesophageal echocardiography (TEE) has been considered the gold standard for left atrial appendage (LAA) thrombus detection. Nevertheless, TEE may sometimes induce discomfort and cause complications. Cardiac computed tomography has been studied extensively for LAA thrombus detection. We performed this systemic review and meta-analysis to assess the diagnostic accuracy of cardiac computed tomography for LAA thrombus detection compared with TEE. Methods and Results A systemic search was conducted in the PubMed, Embase, and Cochrane Library databases from January 1977 to February 2021. Studies performed for assessment diagnostic accuracy of cardiac computed tomography on LAA thrombus compared with TEE were included. Summary sensitivity, specificity, and posterior probability of LAA thrombus was calculated by using bivariate random-effects model. The Quality Assessment of Diagnostic Accuracy Studies-2 tool was used for the quality assessment. A total of 27 studies involving 6960 patients were included in our study. The summary sensitivity of early imaging studies was 0.95 (95% CI, 0.79-0.99), and the specificity was 0.89 (95% CI, 0.85-0.92). The positive posterior probability was 19.11%, and the negative posterior probability was 0.16%. The summary sensitivity of delayed imaging studies was 0.98 (95% CI, 0.92-1.00), and the specificity was 1.00 (95% CI, 0.98-1.00). The positive posterior probability was 95.76%, and the negative posterior probability was 0.12%. The delayed imaging method significantly improved the specificity (1.00 versus 0.89; P<0.05) and positive posterior probability (95.76% versus 19.11%; P<0.05). Conclusions Cardiac computed tomography with a delayed imaging is a reliable alternative to TEE. It may save the patient and health care from an excess TEE. Registration URL: https://www.crd.york.ac.uk/PROSPERO; Unique identifier: CRD42021236352.

Lack of association of antihypertensive drugs with the risk and severity of COVID-19: A meta-analysis.

BACKGROUND: The association of antihypertensive drugs with the risk and severity of COVID-19 remains unknown. METHODS AND RESULTS: We systematically searched PubMed, MEDLINE, The Cochrane Library, Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, and medRxiv for publications before July 13, 2020. Cohort studies and case-control studies that contain information on the association of antihypertensive agents including angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), calcium-channel blockers (CCBs), ß-blockers, and diuretics with the risk and severity of COVID-19 were selected. The random or fixed-effects models were used to pool the odds ratio (OR) with 95% confidence interval (CI) for the outcomes. The literature search yielded 53 studies that satisfied our inclusion criteria, which comprised 39 cohort studies and 14 case-control studies. These studies included a total of 2,100,587 participants. We observed no association between prior usage of antihypertensive medications including ACEIs/ARBs, CCBs, ß-blockers, or diuretics and the risk and severity of COVID-19. Additionally, when only hypertensive patients were included, the severity and mortality were lower with prior usage of ACEIs/ARBs (overall OR of 0.81, 95% CI 0.66-0.99, p < 0.05 and overall OR of 0.77, 95% CI 0.66-0.91, p < 0.01). CONCLUSIONS: Taken together, usage of antihypertensive drugs is not associated with the risk and severity of COVID-19. Based on the current available literature, it is not recommended to abstain from the usage of these drugs in COVID-19 patients. REGISTRATION: The meta-analysis was registered on OSF (https://osf.io/ynd5g).

Assessment of Chloroquine and Hydroxychloroquine Safety Profiles: A Systematic Review and Meta-Analysis.

BACKGROUND: Chloroquine (CQ) and its derivative hydroxychloroquine (HCQ) have recently emerged as potential antiviral and immunomodulatory options for the treatment of 2019 coronavirus disease (COVID-19). To examine the safety profiles of these medications, we systematically evaluated the adverse events (AEs) of these medications from published randomized controlled trials (RCTs). METHODS: We systematically searched MEDLINE, the Cochrane library, the Cochrane Central Register of Controlled Trials (CENTRAL), and the ClinicalTrials.gov for all the RCTs comparing CQ or HCQ with placebo or other active agents, published before June 20, 2020. The random-effects or fixed-effects models were used to pool the risk estimates relative ratio (RR) with 95% confidence interval (CI) for the outcomes. RESULTS: The literature search yielded 23 and 19 studies for CQ and HCQ, respectively, that satisfied our inclusion criteria. Of these studies, we performed meta-analysis on 6 studies for CQ and 18 studies for HCQ. We did not limit our analysis to published records involving viral treatment alone; data also included the usage of either CQ or HCQ for the treatment of other diseases. The trials for the CQ consisted of a total of 2,137 participants (n = 1,077 CQ, n = 1,060 placebo), while the trials for HCQ involved 2,675 participants (n = 1,345 HCQ and n = 1,330 control). The overall mild and total AEs were significantly higher in CQ-treated non-COVID-19 patients, HCQ-treated non-COVID-19 patients, and HCQ-treated COVID-19 patients. The AEs were further categorized into four groups and analyses revealed that neurologic, gastrointestinal (GI), dermatologic, and sensory AEs were higher in participants taking CQ compared to placebo, while GI, dermatologic, sensory, and cardiovascular AEs were higher in HCQ-treated COVID-19 patients compared to control patients. Moreover, subgroup analysis suggested higher AEs with respect to dosage and duration in HCQ group. Data were acquired from studies with perceived low risk of bias, so plausible bias is unlikely to seriously affect the main findings of the current study. CONCLUSIONS: Taken together, we found that participants taking either CQ or HCQ exhibited more AEs than participants taking placebo or control. Precautionary measures should be taken when using these drugs to treat COVID-19. The meta-analysis was registered on OSF (https://osf.io/jm3d9). REGISTRATION: The meta-analysis was registered on OSF (https://osf.io/jm3d9).

Assessment of Hydroxychloroquine and Chloroquine Safety Profiles: A Systematic Review and Meta-Analysis.

BACKGROUND: Recently, chloroquine (CQ) and its derivative hydroxychloroquine (HCQ) have emerged as potential antiviral and immunomodulatory options for the treatment of 2019 coronavirus disease (COVID-19). To examine the safety profiles of these medications, we systematically evaluated the adverse events (AEs) of these medications from published randomized controlled trials (RCTs). METHODS: We systematically searched PubMed, MEDLINE, Cochrane, the Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, and the ClinicalTrials.gov for all the RCTs comparing CQ or HCQ with placebo or other active agents, published before March 31, 2020. The random-effects or fixed-effects models were used to pool the risk estimates relative ratio (RR) with 95% confidence interval (CI) for the outcomes. RESULTS: The literature search yielded 23 and 17 studies for CQ and HCQ, respectively, that satisfied our inclusion criteria. Of these studies, we performed meta-analysis on the ones that were placebo-controlled, which included 6 studies for CQ and 14 studies for HCQ. We did not limit our analysis to published reports involving viral treatment alone; data also included the usage of either CQ or HCQ for the treatment of other diseases. The trials for the CQ consisted of a total of 2,137 participants (n=1,077 CQ, n=1,060 placebo), while the trials for HCQ involved 1,096 participants (n=558 HCQ and n=538 placebo). The overall mild or total AEs were statistically higher comparing CQ or HCQ to placebo. The AEs were further categorized into four groups and analyses revealed that neurologic, gastrointestinal, dermatologic, and ophthalmic AEs were higher in participants taking CQ compared to placebo. Although this was not evident in HCQ treated groups, further analyses suggested that there were more AEs attributed to other organ system that were not included in the categorized meta-analyses. Additionally, meta-regression analyses revealed that total AEs was affected by dosage for the CQ group. CONCLUSIONS: Taken together, we found that participants taking either CQ or HCQ have more AEs than participants taking placebo. Precautionary measures should be taken when using these drugs to treat COVID-19.

Gating Properties of Mutant Sodium Channels and Responses to Sodium Current Inhibitors Predict Mexiletine-Sensitive Mutations of Long QT Syndrome 3.

BACKGROUND: Long QT syndrome 3 (LQT3) is caused by SCN5A mutations. Late sodium current (late I Na) inhibitors are current-specific to treat patients with LQT3, but the mechanisms underlying mexiletine (MEX) -sensitive (N1325S and R1623Q) and -insensitive (M1652R) mutations remains to be elucidated. METHODS: LQT3 patients with causative mutations were treated with oral MEX following i.v. lidocaine. Whole-cell patch-clamp techniques and molecular remodeling were used to determine the mechanisms underlying the sensitivity to MEX. RESULTS: Intravenous administration of lidocaine followed by MEX orally in LQT patients with N1325S and R1623Q sodium channel mutation shortened QTc interval, abolished arrhythmias, and completely normalized the ECG. In HEK293 cells, the steady-state inactivation curves of the M1652R channels were rightward shifted by 5.6 mV relative to the WT channel. In contrast, the R1623Q mutation caused a leftward shift of the steady-state inactivation curve by 15.2 mV compared with WT channel, and N1325S mutation did not affect steady-state inactivation (n = 5-13, P < 0.05). The extent of the window current was expanded in all three mutant channels compared with WT. All three mutations increased late I Na with the greatest amplitude in the M1652R channel (n = 9-15, P < 0.05). MEX caused a hyperpolarizing shift of the steady-state inactivation and delayed the recovery of all three mutant channels. Furthermore, it suppressed late I Na in N1325S and R1623Q to a greater extent compared to that of M1652R mutant channel. Mutations altered the sensitivity of Nav1.5 to MEX through allosteric mechanisms by changing the conformation of Nav1.5 to become more or less favorable for MEX binding. Late I Na inhibitors suppressed late I Na in N1325S and R1623Q to a greater extent than that in the M1652R mutation (n = 4-7, P < 0.05). CONCLUSION: The N1325S, R1623Q, and M1652R mutations are associated with a variable augmentation of late I Na, which was reversed by MEX. M1652R mutation changes the conformation of Nav1.5 that disrupt the inactivation of channel affecting MEX binding, corresponding to the poor response to MEX. The lidocaine test, molecular modeling, and drugs screening in cells expressing mutant channels are useful for predicting the effectiveness of late I Na inhibitors.

AGEs impair Kv channel-mediated vasodilation of coronary arteries by activating the NF-κB signaling pathway in ZDF rats.

Excessive formation of advanced glycation end products (AGEs) impairs voltage-gated potassium (Kv) channels in rat coronary artery smooth muscle cells (CSMCs), resulting in weakened Kv-mediated coronary vasodilation. We hypothesized that induction of the nuclear factor-κB (NF-κB) signaling pathway by AGEs plays a significant role in the regulation of Kv channel-mediated vasodilation in Zucker diabetic fatty (ZDF) rats. Assays of mRNA transcripts, protein expression, and intracellular localization as well as patch-clamp experiments in cultured CSMCs revealed that AGEs significantly induced activation of the NF-κB signaling pathway, reduced Kv1.2/1.5 expression, and inhibited Kv currents. In addition, silencing of the receptor for AGEs (RAGE) or p65 with siRNA and treatment with alagrebrium (ALA) or pyrrolidine dithiocarbamate (PDTC) alleviated the AGE-induced impairment of Kv channels in CSMCs. Compared with Zucker lean (ZL) rats, the amount of AGEs, RAGE protein expression, and NF-κB activity in coronary arteries were higher in ZDF rats; whereas Kv1.2/1.5 expression was significantly lower in ZDF rats. Reduced Kv1.2/1.5 expression in coronary arteries and impaired Kv-mediated coronary relaxation tested by wire myography in ZDF rats were markedly improved by treatment with aminoguanidine (AG), ALA, or PDTC. These effects were accompanied by diminished NF-κB activity, inflammation, and oxidative stress. Taken together, these results indicate that an increased interaction between AGEs and RAGE in diabetic rats leads to impaired Kv channel-mediated coronary vasodilation. Moreover, activation of the NF-κB signaling pathway and a subsequent increase of inflammation and oxidative stress may play an important role in AGE-induced impairment of coronary vasodilation in diabetes.

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 Cochran's 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.

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 (I Na) 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 I Na inhibitors TTX and eleclazine. In rabbit ventricular myocytes, Bay K 8644 increased I CaL density, calcium transient and myocyte contraction. TTX and eleclazine decreased the amplitude of late I Na, 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 I Na contributes to ventricular arrhythmias and its inhibition is plausible to treat arrhythmias in hearts with increased [Ca2+]i.