Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility.

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel NaV1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on NaV1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings.

Cardioversion Safety - Are We Doing Enough?

There is a considerable periprocedural risk of thromboembolic events in atrial fibrillation patients undergoing cardioversion, and treatment with anticoagulants is therefore a hallmark of cardioversion safety. Based on retrospective subgroup analyses and prospective studies, non-vitamin K anticoagulants are at least as efficient as vitamin K-antagonists in preventing thromboembolic complications after cardioversion. The risk of thromboembolic complications after cardioversion very much depends on the comorbidities in a given patient, and especially heart failure, diabetes, and age >75 years carry a markedly increased risk. Cardioversion has been considered safe within a 48-h time window after onset of atrial fibrillation without prior treatment with anticoagulants, but recent studies have set this practice into question based on e.g. erratic debut assessment of atrial fibrillation. Therefore, a simple and more practical approach is here suggested, where early cardioversion is performed only in hemodynamically unstable patients.

Increase in Cardiac Ischemia-Reperfusion Injuries in Opa1+/- Mouse Model.

BACKGROUND: Recent data suggests the involvement of mitochondrial dynamics in cardiac ischemia/reperfusion (I/R) injuries. Whilst excessive mitochondrial fission has been described as detrimental, the role of fusion proteins in this context remains uncertain. OBJECTIVES: To investigate whether Opa1 (protein involved in mitochondrial inner-membrane fusion) deficiency affects I/R injuries. METHODS AND RESULTS: We examined mice exhibiting Opa1delTTAG mutations (Opa1+/-), showing 70% Opa1 protein expression in the myocardium as compared to their wild-type (WT) littermates. Cardiac left-ventricular systolic function assessed by means of echocardiography was observed to be similar in 3-month-old WT and Opa1+/- mice. After subjection to I/R, infarct size was significantly greater in Opa1+/- than in WTs both in vivo (43.2±4.1% vs. 28.4±3.5%, respectively; p<0.01) and ex vivo (71.1±3.2% vs. 59.6±8.5%, respectively; p<0.05). No difference was observed in the expression of other main fission/fusion protein, oxidative phosphorylation, apoptotic markers, or mitochondrial permeability transition pore (mPTP) function. Analysis of calcium transients in isolated ventricular cardiomyocytes demonstrated a lower sarcoplasmic reticulum Ca2+ uptake, whereas cytosolic Ca2+ removal from the Na+/Ca2+ exchanger (NCX) was increased, whilst SERCA2a, phospholamban, and NCX protein expression levels were unaffected in Opa1+/- compared to WT mice. Simultaneous whole-cell patch-clamp recordings of mitochondrial Ca2+ movements and ventricular action potential (AP) showed impairment of dynamic mitochondrial Ca2+ uptake and a marked increase in the AP late repolarization phase in conjunction with greater occurrence of arrhythmia in Opa1+/- mice. CONCLUSION: Opa1 deficiency was associated with increased sensitivity to I/R, imbalance in dynamic mitochondrial Ca2+ uptake, and subsequent increase in NCX activity.

Remote ischemic conditioning: Current clinical perspectives.

Remote ischemic conditioning (RIC) constitutes a promising method in which a tissue or organ is exposed to intermittent ischemia/reperfusion periods enabling it to provide protection to a distant target organ. RIC has been tested in various clinical settings through its simple application by means of intermittent inflation of a blood pressure cuff placed on a limb, primarily evaluating its potential abilities to decrease myocardial injury biomarkers. Its use on other organs, such as the kidneys or brain, has recently been a topic of research. To date, no study has yet been powerful enough to reach a conclusion on the potential benefit of RIC on clinical outcomes. The future role of RIC in the clinical arena could be clarified by the large phase III trials currently underway targeting major outcomes as primary endpoints.

Remote ischemic conditioning and cardioprotection: a systematic review and meta-analysis of randomized clinical trials.

Remote ischemic conditioning (RIC) represents an innovative cardioprotective method that has been investigated in numerous clinical studies providing miscellaneous results. This systematic review and meta-analysis sought to assess RIC-induced effects on myocardial injury biomarkers and clinical outcomes in clinical situations at risk of myocardial ischemia/reperfusion damage. PubMed and Cochrane databases were searched for randomized clinical trials testing any RIC protocol versus a control in a situation or procedure at risk of cardiac ischemia/reperfusion damage, including coronary angioplasty and cardiac or major vascular surgery. Data were collected from publications reporting biological markers of myocardial injury or clinical events, including major adverse cardiovascular and cerebral events (MACCE), all-cause mortality, myocardial infarction incidence, and repeat revascularization. Standardized mean difference (SMD) (continuous outcomes) and odds ratios (OR) (dichotomous outcomes) were compared between groups. Heterogeneity was investigated by means of meta-analysis regression. A total of 53 articles (44 studies) were identified by the search, with 5,317 patients included in the systematic meta-analysis. RIC significantly reduced troponin area under curve (AUC) (SMD -0.27, 95% confidence interval (CI): [-0.36, -0.18]; p < 0.01) and troponin peak (SMD: -0.22, 95% CI: [-0.30, -0.15]; p < 0.01). The same reduction was observed with creatine kinase MB (CK-MB) AUC and peak. Long-term MACCE and all-cause mortality were significantly lower in the RIC group (OR: 0.42, 95% CI [0.28, 0.64]; p < 0.01 vs. OR: 0.27, 95% CI [0.13, 0.58]; p < 0.01, respectively), as was myocardial infarction incidence (OR: 0.54, 95% CI [0.40, 0.73]; p < 0.01). We observed no difference regarding repeat revascularization. RIC appears to be an effective method for reducing ischemia/reperfusion myocardial injury, and our findings suggest that it may reduce long-term clinical events.

CCK-A receptor activates RhoA through G alpha 12/13 in NIH3T3 cells.

Cholecystokinin (CCK) is a major regulator of pancreatic acinar cells and was shown previously to be capable of inducing cytoskeletal changes in these cells. In the present study, using NIH3T3 cells stably transfected with CCK-A receptors as a model cell, we demonstrate that CCK can induce actin stress fibers through a G13- and RhoA-dependent mechanism. CCK induced stress fibers within minutes similar to those induced by lysophosphatidic acid (LPA), the active component of serum. The effects of CCK were mimicked by active RhoV14 and blocked by dominant-negative RhoN19, Clostridium botulinum C3 transferase, and the Rho-kinase inhibitor Y-27632. CCK rapidly induced active Rho in cells as shown with a pull-down assay using the Rho binding domain of rhotekin and by a serum response element (SRE)-luciferase reporter assay. To evaluate the G protein mediating the action of CCK, cells were transfected with active alpha-subunits; Galpha13 and Galpha12 but not Galphaq induced stress fibers and in some cases cell rounding. A p115 Rho guanine nucleotide exchange factor (GEF) regulator of G protein signaling (RGS) domain known to interact with G12/13 inhibited active alpha12/13-and CCK-induced stress fibers, whereas RGS2 and RGS4, which are known to inhibit Gq, had no effect. Cotransfection with plasmids coding for the G protein alpha-subunit carboxy-terminal peptide from alpha13 and, to a lesser extent alpha12, also inhibited the effect of CCK, whereas the peptide from alphaq did not. These results show that in NIH3T3 cells bearing CCK-A receptors, CCK activates Rho primarily through G13, leading to rearrangement of the actin cytoskeleton.