The European Union, the UK National Institute for Health Research, the Wellcome Trust, the UK Medical Research Council, Action on Hearing Loss, the UK Biotechnology and Biological Sciences Research Council, the Oak Foundation, the Economic and Social Research Council, Helmholtz Zentrum Munchen, the German Research Center for Environmental Health, the German Federal Ministry of Education and Research, the German Center for Diabetes Research, the Munich Center for Health Sciences, the Ministry of Science and Research of the State of North Rhine-Westphalia, and the German Federal Ministry of Health.

for the RIME Investigators Background-The role of mitral valve repair (MVR) during coronary artery bypass grafting (CABG) in patients with moderate ischemic mitral regurgitation (MR) is uncertain. We conducted a randomized, controlled trial to determine whether repairing the mitral valve during CABG may improve functional capacity and left ventricular reverse remodeling compared with CABG alone. Methods and Results-Seventy-three patients referred for CABG with moderate ischemic MR and an ejection fraction Ͼ30%were randomized to receive CABG plus MVR (34 patients) or CABG only (39 patients). The study was stopped early after review of interim data. At 1 year, there was a greater improvement in the primary end point of peak oxygen consumption in the CABG plus MVR group compared with the CABG group (3.3 mL/kg/min versus 0.8 mL/kg/min; PϽ0.001). There was also a greater improvement in the secondary end points in the CABG plus MVR group compared with the CABG group: left ventricular end-systolic volume index, MR volume, and plasma B-type natriuretic peptide reduction of 22.2 mL/m

No abstract

No abstract

Rationale Disruption in subcellular targeting of Ca2+ signaling complexes secondary to changes in cardiac myocyte structure may contribute to the pathophysiology of a variety of cardiac diseases, including heart failure (HF) and certain arrhythmias. Objective To explore microdomain-targeted remodeling of ventricular L-type Ca2+ channels (LTCCs) in HF. Methods and Results Super-resolution scanning patch-clamp, confocal and fluorescence microscopy were used to explore distribution of single LTCCs in different membrane microdomains of non-failing and failing human and rat ventricular myocytes. Disruption of membrane structure in both species led to re-distribution of functional LTCCs from their canonical location in transversal tubules (T-tubules) to the non-native crest of the sarcolemma, where their open probability (Po) was dramatically increased (0.034±0.011 vs 0.154±0.027, P<0.001). High Po was linked to enhanced calcium-calmodulin kinase II (CaMKII)-mediated phosphorylation in non-native microdomains and resulted in an elevated ICa,L window current which contributed to the development of early afterdepolarizations (EADs). A novel model of LTCC function in HF was developed; following its validation with experimental data, the model was used to ascertain how HF–induced T-tubule loss led to altered LTCC function and EADs. The HF myocyte model was then implemented in a 3D left ventricle model, demonstrating that such EADs can propagate and initiate reentrant arrhythmias. Conclusion Microdomain-targeted remodeling of LTCC properties is an important event in pathways that may contribute to ventricular arrhythmogenesis in the settings of HF-associated remodeling. This extends beyond the classical concept of electrical remodelling in HF and adds a new dimension to cardiovascular disease.

Left ventricular mass (LVM) and cardiac gene expression are complex traits regulated by factors both intrinsic and extrinsic to the heart. To dissect the major determinants of LVM, we combined expression quantitative trait locus1 and quantitative trait transcript2 (QTT) analyses of the cardiac transcriptome in the rat. Using these methods and in vitro functional assays, we identified osteoglycin (Ogn) as a major candidate regulator of rat LVM, with increased Ogn protein expression associated with elevated LVM. We also applied genome-wide QTT analysis to the human heart and observed that, out of ~22,000 transcripts, OGN transcript abundance had the © 2008 Nature Publishing Group Correspondence should be addressed to T.J.A. (t.aitman@csc.mrc.ac.uk) or S.A.C. (stuart.cook@imperial.ac.uk).. 11 These authors contributed equally to this work. AUTHOR CONTRIBUTIONS The study was designed by S.A.C., E.P. and T.J.A.; S.A.C. obtained funding, supervised the study and coordinated the collaborations; R.S. performed PCR-based experiments and genotyping; H.L. and M.K.K. generated rat microarray data; B.S. and Y.M.P. generated human microarray data; M.B. generated immunofluorescence confocal micrographs; R.S. and H.L. performed cell culture and cloning experiments; R.S., B.S. and M.B. performed immunoblotting; P.J.M. and R.S. performed in vivo analyses in Ogn knockout mice; E.S.T., L.M.C., M.D.W. and G.W.C. provided and genotyped the Ogn knockout mice; N.H. and J.F. carried out sequence analysis of Ogn; T.W.K., V.K. and M.P. provided telemetric blood pressure data; P.P.P. provided human tissues for protein studies; S.K.P., D.J.P. and C.K. provided the human cardiac MRI data; E.P. designed, interpreted and supervised all statistical analyses; E.P., I.G. and R.S. performed statistical and bioinformatic analyses and were aided by J.M.; and E.P. and S.A.C. wrote the manuscript.Note: Supplementary information is available on the Nature Genetics website.Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions Europe PMC Funders GroupAuthor Manuscript Nat Genet. Author manuscript; available in PMC 2009 September 11. Elevated indexed LVM is a major cause of morbidity and mortality and is regulated, in part, by hemodynamic indices3. However, only a small proportion of LVM variation is determined by hemodynamic effects4, and it has been proposed that genetic influences may also be important5,6. Many studies have shown that gene expression is heritable and that the genetic control of transcription affects physiological traits and disease phenotypes1,7. We have shown that gene transcription is highly heritable in the rat heart8, which led us to hypothesize that the genetic control of cardiac gene expression may be important in regulating LVM. Here, we used an integrated approach combining correlation of expression quantitative trait loci (eQTL)1 and genome-wide expression profiles with physiological traits, previously designated as quantitative trait transcript (QTT) analysis2, to ide...

Our data show that the mechanisms of myocardial insulin resistance are different between NIDDM and LVD.

Aging leads to increased cellular senescence and is associated with decreased potency of tissue-specific stem/progenitor cells. Here we have done an extensive analysis of cardiac progenitor cells (CPCs) isolated from human subjects with cardiovascular disease (n=119), aged 32-86 years. In aged subjects (>74 years old) over half of CPCs are senescent (p16INK4A, SA-β-gal, DNA damage γH2AX, telomere length, Senescence-Associated Secretory Phenotype (SASP)), unable to replicate, differentiate, regenerate or restore cardiac function following transplantation into the infarcted heart. SASP factors secreted by senescent CPCs renders otherwise healthy CPCs to senescence. Elimination of senescent CPCs using senolytics abrogates the SASP and its debilitative effect in vitro. Global elimination of senescent cells in aged mice (INK-ATTAC or wildtype mice treated with D+Q senolytics) in vivo activates resident CPCs (0.23±0.06% vs. 0.01±0.01% vehicle; p<0.05) and increased the number of small, proliferating Ki67-, EdU-positive cardiomyocytes (0.25±0.07% vs. 0.03±0.03% vehicle; p<0.05). Therapeutic approaches that eliminate senescent cells may alleviate cardiac deterioration with aging and rejuvenate the regenerative capacity of the heart.