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dc.contributor.authorWare, James S.
dc.contributor.authorAmor-Salamanca, Almudena
dc.contributor.authorTayal, Upasana
dc.contributor.authorGovind, Risha
dc.contributor.authorSerrano, Isabel
dc.contributor.authorSalazar-Mendiguchia, Joel
dc.contributor.authorManuel Garcia-Pinilla, Jose
dc.contributor.authorPascual-Figal, Domingo A 
dc.contributor.authorNunez, Julio
dc.contributor.authorGuzzo-Merello, Gonzalo
dc.contributor.authorGonzalez-Vioque, Emiliano
dc.contributor.authorBardaji, Alfredo
dc.contributor.authorManito, Nicolas
dc.contributor.authorLopez-Garrido, Miguel A.
dc.contributor.authorPadron-Barthe, Laura 
dc.contributor.authorEdwards, Elizabeth
dc.contributor.authorWhiffin, Nicola
dc.contributor.authorWalsh, Roddy
dc.contributor.authorBuchan, Rachel J.
dc.contributor.authorMidwinter, William
dc.contributor.authorWilk, Alicja
dc.contributor.authorPrasad, Sanjay
dc.contributor.authorPantazis, Antonis
dc.contributor.authorBaski, John
dc.contributor.authorO'Regan, Declan P.
dc.contributor.authorAlonso-Pulpon, Luis
dc.contributor.authorCook, Stuart A.
dc.contributor.authorLara-Pezzi, Enrique 
dc.contributor.authorBarton, Paul J.
dc.contributor.authorGarcia-Pavia, Pablo
dc.identifier.citationJ Am Coll Cardiol. 2018; 71(20):2293-2302
dc.description.abstractBACKGROUND Alcoholic cardiomyopathy (ACM) is defined by a dilated and impaired left ventricle due to chronic excess alcohol consumption. It is largely unknown which factors determine cardiac toxicity on exposure to alcohol. OBJECTIVES This study sought to evaluate the role of variation in cardiomyopathy-associated genes in the pathophysiology of ACM, and to examine the effects of alcohol intake and genotype on dilated cardiomyopathy (DCM) severity. METHODS The authors characterized 141 ACM cases, 716 DCM cases, and 445 healthy volunteers. The authors compared the prevalence of rare, protein-altering variants in 9 genes associated with inherited DCM. They evaluated the effect of genotype and alcohol consumption on phenotype in DCM. RESULTS Variants in well-characterized DCM-causing genes were more prevalent in patients with ACM than control subjects (13.5\% vs. 2.9\%; p = 1.2 x10(-5)), but similar between patients with ACM and DCM (19.4\%; p = 0.12) and with a predominant burden of titin truncating variants (TTNtv) (9.9\%). Separately, we identified an interaction between TTN genotype and excess alcohol consumption in a cohort of DCM patients not meeting ACM criteria. On multivariate analysis, DCM patients with a TTNtv who consumed excess alcohol had an 8.7\% absolute reduction in ejection fraction (95\% confidence interval: -2.3\% to -15.1\%; p < 0.007) compared with those without TTNtv and excess alcohol consumption. The presence of TTNtv did not predict phenotype, outcome, or functional recovery on treatment in ACM patients. CONCLUSIONS TTNtv represent a prevalent genetic predisposition for ACM, and are also associated with a worse left ventricular ejection fraction in DCM patients who consume alcohol above recommended levels. Familial evaluation and genetic testing should be considered in patients presenting with ACM.(C)2018 The Authors.
dc.description.sponsorshipThis work was supported by the Instituto de Salud Carlos III (ISCIII) (PI15/01551), the Spanish Ministry of Economy and Competitiveness (SAF2015-71863-REDT), the Wellcome Trust (107469/Z/15/Z), the British Heart Foundation (SP/10/10/28431), the Medical Research Council, the National Institute for Health Research (NIHR) Cardiovascular Biomedical Research Unit based at Royal Brompton \& Harefield NHS Foundation Trust and Imperial College London, the NIHR Biomedical Research Centre based at Imperial College London Healthcare NHS Trust and Imperial College London, the Fondation Leducq (11 CVD-01), and a Health Innovation Challenge Fund award from the Wellcome Trust and Department of Health, United Kingdom (HICF-R6-373). The CNIC is supported by the Ministry of Economy, Industry and Competitiveness and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). Grants from ISCIII and the Spanish Ministry of Economy and Competitiveness are supported by the Plan Estatal de I+D+I 2013-2016-European Regional Development Fund (FEDER) ``Away of making Europe.´´ The Hospital Universitario Puerta de Hierro Majadahonda and Hospital Virgen de la Arrixaca are members of the European Reference Network for rare, low-prevalence, and complex diseases of the heart (ERN GUARD-Heart). The funders played no role in the design, collection, analysis, or interpretation of the data or in the decision to submit the manuscript for publication. Prof. Cook is cofounder and a shareholder of Enleofen Bio. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
dc.relation.isversionofPublisher's version
dc.subjectdilated cardiomyopathy
dc.titleGenetic Etiology for Alcohol-Induced Cardiac Toxicity
dc.rights.licenseAtribución 4.0 Internacional*
dc.contributor.funderInstituto de Salud Carlos III - ISCIII
dc.contributor.funderMinisterio de Economía y Competitividad (España)
dc.contributor.funderWellcome Trust
dc.contributor.funderBritish Heart Foundation
dc.contributor.funderMedical Research Council (United Kingdom)
dc.contributor.funderNational Institute for Health Research (United Kingdom)
dc.contributor.funderMinisterio de Economía, Industria y Competitividad (España)
dc.contributor.funderFundación ProCNIC
dc.contributor.funderEuropean Regional Development Fund (ERDF/FEDER)
dc.identifier.journalJournal of the American College of Cardiology
dc.repisalud.orgCNICCNIC::Grupos de investigación::Regulación Molecular de la Insuficiencia Cardiaca

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