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Background: Skeletal muscles produce irisin. Growing controversy exists on the association between this myokine and chronic disease risk. On the basis of the potential protective effects that irisin could exert on both vascular function and skeletal muscle mass, we hypothesized that an elevated level of this molecule may contribute to successful aging., Methods: Serum irisin levels were measured using enzyme-linked immunosorbent assay in disease-free centenarians, young healthy controls, and patients with precocious acute myocardial infarction., Results: We found the highest levels of serum irisin in disease-free centenarians (35.3 ± 5.5 ng/mL) compared with young healthy controls (20.7 ± 6.3 ng/mL) and especially with young patients with acute myocardial infarction (15.1 ± 5.4 ng/mL)., Conclusions: Our study demonstrates that healthy centenarians are characterized by increased serum irisin levels, whereas levels of this molecule were found to be significantly lower in young patients with myocardial infarction. Our findings may prompt further research into the role played by irisin not only in vascular disorders but also in life span modulation., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Alterations in coronary vasomotor tone may participate in the pathogenesis of acute myocardial infarction (AMI). Vascular ATP-sensitive K(+) (KATP) channels, formed by Kir6.x/SUR2B, are key regulators of coronary tone and mutations in cardiac (Kir6.2/SUR2A) KATP channels result in heart disease. Here we explore the pathophysiological mechanism of a rare mutation (V734I) found in exon 17 of the ABCC9 gene, estimated to cause a 6.4-fold higher risk of AMI before the age of 60., Methods and Results: Eleven patients carrying the mutation were identified; they presented AMI of vasospastic origin associated with increased plasma levels of endothelin-1 and increased leukocyte ROCK activity. The effects of the mutation on the functional properties of the two splice variants of ABCC9 (SUR2A and SUR2B) were studied using patch-clamp electrophysiology. The mutation reduced the sensitivity to MgATP inhibition of Kir6.2/SUR2B channels but not of Kir6.2/SUR2A and Kir6.1/SUR2B channels. Furthermore, the stimulatory effects of MgNDP (MgADP, MgGDP and MgUDP) were unaltered in mutant Kir6.2/SUR2A and Kir6.1/SUR2B channels. In contrast, mutant channels composed of Kir6.2 and SUR2B were less sensitive to MgNDP activation, assessed in the presence of MgATP. The antianginal drug nicorandil activated Kir6.2/SUR2B-V734I channels, thus substituting for the loss of MgNDP stimulation, suggesting that this drug could be of therapeutic use in the treatment of AMI associated with V734I., Conclusions: The 734I allele in ABCC9 may influence susceptibility to AMI by impairing the response of vascular, but not cardiac, KATP channels to intracellular nucleotides. This is the first human mutation in an ion channel gene to be implicated in AMI., (Crown Copyright © 2013. Published by Elsevier Ireland Ltd. All rights reserved.)

Background: Alterations in coronary vasomotor tone are deemed to play an important role in myocardial infarction (MI), and the ATP-binding cassette transporter C9-ABCC9-may be involved in the regulation of coronary artery vasomotility. We sought to determine whether genetic variations in the coding sequence of ABCC9 gene could be associated with precocious MI (myocardial infarction before the age of 60 years) in humans., Methods: In this study, we screened using PCR-SSCP analysis the entire coding region of the ABCC9 gene in 45 patients with precocious MI and 45 age- and gender-matched controls., Results: A novel missense mutation, Val734Ile in exon 17, was detected in one MI patient. We therefore analyzed by PCR-RFLPs the frequency of this nonsynonymous change in a large Italian cohort of precocious MI patients (n=584) and healthy comparison subjects (n=873). After allowance for the potential confounding effects of age, gender, and established cardiovascular risk factors, multivariate logistic regression analysis revealed that carriers of the rare 734Ile allele would have a 6.40-fold risk of suffering MI before the age of 60 years as compared to controls (95% CI=1.58-25.90, P=0.009)., Conclusions: Taken together, our results provide the first important evidence that the newly discovered 734Ile allele in ABCC9 might influence susceptibility to precocious MI in our population.