Background-Recently, elevation of circulating muscle-specific microRNA (miRNA) levels has been reported in patients with acute myocardial infarction. However, it is still unclear from which part of the myocardium or under what conditions miRNAs are released into circulating blood. The purpose of this study was to identify the source of elevated levels of circulating miRNAs and their function in cardiovascular diseases. Methods and Results-Serum levels of miRNA (miR)-1 and miR-133a were increased significantly in patients not only with acute myocardial infarction but also with unstable angina pectoris and Takotsubo cardiomyopathy without elevation of serum creatine phosphokinase or cardiac troponin. MicroRNA microarray analysis of the heart from a mouse model of myocardial infarction indicated that the levels of miR-1, miR-133a, miR-208a, and miR-499 were significantly reduced in the infarcted myocardium. In situ hybridization of miR-133a also showed that miR-133a levels were very low in the infarcted and peri-infarcted myocardium. It has been shown that circulating miRNAs are localized inside exosomes, which are released after Ca 2ϩ stimulation. We stimulated H9c2 cardiomyoblasts with A23187 and measured miR-133a levels in the exosome fraction of the culture medium. A23187 induced a dose-dependent release of miR-133a, and significant elevation was observed only at concentrations where dead cells were detected. We also found that miR-133a-containing exosomes reduced the luciferase activity of 293FT cells transfected with an miR-133a sensor vector. Conclusions-These results suggest that elevated levels of circulating miR-133a in patients with cardiovascular diseases originate mainly from the injured myocardium. Circulating miR-133a can be used as a marker for cardiomyocyte death, and it may have functions in cardiovascular diseases. (Circ Cardiovasc Genet. 2011;4:446-454.)Key Words: circulating microRNA Ⅲ myocardial infarction Ⅲ cell death Ⅲ calcium ionophore M icroRNAs (miRNAs) are endogenous, single-stranded, Ϸ22-nucleotide noncoding RNAs. MicroRNAs are generally regarded as negative regulators of gene expression through inhibition of translation and/or promotion of mRNA degradation by base-pairing to complementary sequences within the 3Ј untranslated region (3ЈUTR) of protein-coding mRNA transcripts. 1 The first miRNA assigned to a specific function was lin-4, which targets lin-14 during temporal pattern formation in Caenorhabditis elegans. 2 Since then, a variety of miRNAs have been discovered. More than 500 miRNAs have been cloned and sequenced in humans, and the estimated number of miRNA genes may be as high as 1000 in the human genome. 3 Each miRNA regulates dozens to hundreds of distinct target genes; thus miRNAs are estimated to regulate the expression of more than one-third of human protein-coding genes. 4 Clinical Perspective on p 454The implications of miRNAs in the pathological process of the cardiovascular system have been recognized recently, and research on miRNAs in relation to cardiovascular dise...

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Background — Although coronary stents have been proved effective in reducing clinical cardiac events for up to 3 to 5 years, longer term clinical and angiographic outcomes have not yet been fully clarified. Methods and Results — To evaluate longer term (7 to 11 years) outcome, clinical and angiographic follow-up information was analyzed in 405 patients with successful stenting in native coronary arteries. Primary or secondary stabilization, which was defined as freedom from death, coronary artery bypass grafting, and target lesion-percutaneous coronary intervention (TL-PCI) during the 14 months after the initial procedure or after the last TL-PCI, was achieved in 373 patients (92%) overall. Only 7 patients (1.7%) underwent TL-PCI more than twice. After the initial 14-month period, freedom from TL-PCI reached a plateau at 84.9% to 80.7% over 1 to 8 years. However, quantitative angiographic analysis in 179 lesions revealed a triphasic luminal response characterized by an early restenosis phase until 6 months, an intermediate-term regression phase from 6 months to 3 years, and a late renarrowing phase beyond 4 years. Minimal luminal diameter in 131 patients with complete serial data were 2.62±0.4 mm immediately after stenting, 2.0±0.49 mm at 6 months, 2.19±0.49 mm at 3 years, and 1.85±0.56 mm beyond 4 years ( P <0.0001). Conclusions — The efficacy and safety of coronary stenting seemed to be clinically sustained at 7 to 11 years of follow-up. However, late luminal renarrowing beyond 4 years was common, which demonstrates the need for further follow-up.

We identified a novel SCN5A mutation associated with familial AF. The mutant channels displayed a gain-of-function type modulation of cardiac Na+ channels, which is a novel mechanism predisposing to increased atrial excitability and familial AF. This is a new phenotype resulting from the SCN5A gain-of-function mutations and is distinct from LQTS3.

In the catheter ablation for AF, we found no significant reduction in the 1-year incidence of recurrent atrial tachyarrhythmias by ATP-guided PVI compared with conventional PVI.

Background: Recently, the Academic Research Consortium for High Bleeding Risk (ARC-HBR) has been proposed to standardize the definition of HBR, which was arbitrarily defined as a Bleeding Academic Research Consortium 3 or 5 bleeding ≥4% at 1-year. However, the prevalence and the expected bleeding event rate of HBR patients defined by ARC-HBR criteria are currently unknown in the real-world percutaneous coronary intervention practice. Methods: We applied the ARC-HBR criteria in the CREDO-Kyoto (Coronary Revascularization Demonstrating Outcome Study in Kyoto) registry cohort-2, a multicenter registry that enrolled 13 058 consecutive patients who underwent their first percutaneous coronary intervention. The primary bleeding end point was defined as the Global Utilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries moderate/severe bleeding. There were 5570 patients (43%) in the HBR group and 7488 patients in the no-HBR group. Results: Cumulative incidence of the primary bleeding end point was much higher in the HBR group than in the no-HBR group (10.4% versus 3.4% at 1-year, and 18.9% versus 6.6% at 5-year, P <0.0001). Presence of each ARC-HBR major or even minor criterion, in isolation, with the exception of liver cirrhosis and prior ischemic stroke, was also associated with major bleeding risk higher than 4% at 1-year. Cumulative 5-year incidence of the primary bleeding end point got incrementally higher as the number of the ARC-HBR major criteria increased (≥3 majors: 49.9%, 2 majors: 30.6%, 1 major: 18.5%, ≥2 minors: 14.7%, and no-HBR: 6.6%, P <0.0001). Conclusions: ARC-HBR criteria successfully identified those patients with very HBR after percutaneous coronary intervention, who represented 43% of patients in this all-comers registry.

Background: Despite recommendations in the guidelines and consensus documents, there has been no randomized controlled trial evaluating oral anticoagulation (OAC) alone without antiplatelet therapy (APT) in patients with atrial fibrillation and stable coronary artery disease beyond 1 year after coronary stenting. Methods: This study was a prospective, multicenter, open-label, noninferiority trial comparing OAC alone to combined OAC and single APT among patients with atrial fibrillation beyond 1 year after stenting in a 1:1 randomization fashion. The primary end point was a composite of all-cause death, myocardial infarction, stroke, or systemic embolism. The major secondary end point was a composite of the primary end point or major bleeding according to the International Society on Thrombosis and Haemostasis classification. Although the trial was designed to enroll 2000 patients during 12 months, enrollment was prematurely terminated after enrolling 696 patients in 38 months. Results: Mean age was 75.0±7.6 years, and 85.2% of patients were men. OAC was warfarin in 75.2% and direct oral anticoagulants in 24.8% of patients. The mean CHADS 2 score was 2.5±1.2. During a median follow-up interval of 2.5 years, the primary end point occurred in 54 patients (15.7%) in the OAC-alone group and in 47 patients (13.6%) in the combined OAC and APT group (hazard ratio, 1.16; 95% CI, 0.79–1.72; P =0.20 for noninferiority, P =0.45 for superiority). The major secondary end point occurred in 67 patients (19.5%) in the OAC-alone group and in 67 patients (19.4%) in the combined OAC and APT group (hazard ratio, 0.99; 95% CI, 0.71–1.39; P =0.016 for noninferiority, P =0.96 for superiority). Myocardial infarction occurred in 8 (2.3%) and 4 (1.2%) patients, whereas stroke or systemic embolism occurred in 13 (3.8%) and 19 (5.5%) patients, respectively. Major bleeding occurred in 27 (7.8%) and 36 (10.4%) patients, respectively. Conclusions: This randomized trial did not establish noninferiority of OAC alone to combined OAC and APT in patients with atrial fibrillation and stable coronary artery disease beyond 1 year after stenting. Because patient enrollment was prematurely terminated, the study was underpowered and inconclusive. Future larger studies are required to establish the optimal antithrombotic regimen in this population. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01962545.

KCNE5 modulates I(to), and its novel variants appeared to cause IVF, especially BrS, in male patients through gain-of-function effects on I(to). Screening for KCNE5 variants is relevant for BrS or IVF.