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-The influences of antiplatelet therapy discontinuation on the risk of stent thrombosis and long-term clinical outcomes after drug-eluting stent implantation have not yet been addressed adequately. Methods and Results-In an observational study in Japan, 2-year outcomes were assessed in 10 778 patients undergoing sirolimus-eluting stent implantation. Data on status of antiplatelet therapy during follow-up were collected prospectively. Incidences of definite stent thrombosis were 0.34% at 30 days, 0.54% at 1 year, and 0.77% at 2 years. Thienopyridine use was maintained in 97%, 62%, and 50% of patients at 30 days, 1 year, and 2 years, respectively. Patients who discontinued both thienopyridine and aspirin had a significantly higher rate of stent thrombosis than those who continued both in the intervals of 31 to 180 days, 181 to 365 days, and 366 to 548 days after stent implantation (1.76% versus 0.1%, PϽ0.001; 0.72% versus 0.07%, Pϭ0.02; and 2.1% versus 0.14%, Pϭ0.004, respectively). When discontinuation of aspirin was taken into account, patients who discontinued thienopyridine only did not have an excess of stent thrombosis in any of the time intervals studied. Adjusted rates of death or myocardial infarction at 24 months were 4.1% for patients taking thienopyridine and 4.1% for patients not taking thienopyridine (Pϭ0.99) in the 6-month landmark analysis. Conclusions-Discontinuation of both thienopyridine and aspirin, but not discontinuation of thienopyridine therapy only, was associated with an increased risk of stent thrombosis. Landmark analysis did not suggest an apparent clinical benefit of thienopyridine use beyond 6 months after sirolimus-eluting stent implantation. (Circulation. 2009;119:987-995.)

Aim:Severe gastrointestinal bleeding sometimes occurs in patients with aortic stenosis (AS), known as Heyde's syndrome. This syndrome is thought to be caused by acquired von Willebrand syndrome and is characterized by reduced large von Willebrand factor (vWF) multimers. However, the relationship between the severity of AS and loss of large vWF multimers is unclear. Methods: We examined 31 consecutive patients with severe AS. Quantitative evaluation for loss of large vWF multimers was performed using the conventional large vWF ratio and novel large vWF multimer index. This novel index was defined as the ratio of large multimers of patients to those of controls. Results: Loss of large vWF multimers, defined as the large vWF multimer index 80%, was detected in 21 patients (67.7%). The large vWF multimer ratio and the large vWF multimer index were inversely correlated with the peak aortic gradient (R 0.58, p 0.0007, and R 0.64, p 0.0001, respectively). Anemia defined as hemoglobin 9.0 g/dl was observed in 12 patients (38.7%), who were regarded as Heyde's syndrome. Aortic valve replacement was performed in 7 of these patients, resulting in the improvement of anemia in all patients from a hemoglobin concentration of 7.5 1.0 g/dl preoperatively to 12.4 1.3 g/dl postoperatively (p 0.0001). Conclusions: Acquired von Willebrand syndrome may be a differential diagnosis in patients with AS with anemia. The prevalence of AS-associated acquired von Willebrand syndrome is higher than anticipated.

Background-Observational

espite recent improvements in survival, the 5-year mortality rate for patients with congestive heart failure (CHF) ranges between 40% and 60%. 1,2 The discovery of risk markers for CHF and their appropriate use have contributed to improved screening, prevention, diagnosis and treatment of CHF. Because the pathophysiology of CHF is complex, a variety of markers associated with different pathophysiologic conditions may be used in the management of CHF.Adiponectin is an insulin-sensitizing adipocytokine that regulates energy metabolism by increasing free fatty acid oxidation in skeletal myocytes and gluconeogenesis in the liver. [3][4][5] In addition to its beneficial effects on both lipid and glucose metabolism, adiponectin has antiinflammatory properties. 6 It reduces the endothelial expression of cell adhesion molecules and the monocyte/macrophage production of inflammatory cytokines; however, it induces antiinflammatory cytokines. 7-10 Moreover, in a mouse model of pressure overload adiponectin had antihypertrophic effects on cardiac myocytes, and its deficiency exacerbated CHF. 11,12 Myocardial expression of adiponectin receptor 1 and adiponectin receptor 2 suggest possible effects of Circulation Journal Vol.71, May 2007adiponectin on cardiac myocytes. 13,14 Adiponectin can also inhibit growth factor-mediated fibroblast proliferation and prevent fibrosis. 15 Because these factors, namely, myocardial inflammation, hypertrophy and fibrosis, and dysregulation of myocardial lipid/glucose metabolisms can either cause or exacerbate CHF, 16,17 adiponectin may play a protective role in CHF.Increased levels of circulating adiponectin and the prognostic potential of adiponectin have been reported in Caucasian CHF patients 18,19 and very recently, an increase in the circulating adiponectin level and an association of this with the severity of CHF have been shown in Japanese CHF patients. 20 Nevertheless, it remains uncertain whether adiponectin has prognostic potential in Asians, and the difference in the circulating adiponectin levels of Caucasian and Asian patients suggests that the prognostic potential of Circ J 2007; 71: 623 -630 (Received June 26, 2006; revised manuscript received January 29, 2007; accepted February 9, 2007 Background Congestive heart failure (CHF) is associated with altered energy homeostasis and myocardial inflammation, hypertrophy, and fibrosis. Adiponectin, an insulin-sensitizing adipocytokine, may affect these pathogenic factors, and the circulating adiponectin level may serve as a biological marker of CHF. This study aimed to assess the significance of serum adiponectin as a prognostic marker for Japanese CHF patients. Methods and ResultsThe serum adiponectin levels were compared between 54 (24 ischemic and 30 nonischemic) CHF patients with left ventricular systolic dysfunction and 55 age-and gender-matched control subjects. The CHF patients also underwent simultaneous clinical assessment and measurements for brain natriuretic peptide (BNP) and parameters of lipid or glucose metabolism. Com...

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