Author + information
- Received January 5, 2018
- Revision received February 14, 2018
- Accepted March 1, 2018
- Published online May 14, 2018.
- James S. Ware, MRCP, PhDa,b,c,∗,
- Almudena Amor-Salamanca, MDd,∗,
- Upasana Tayal, MRCP, PhDa,b,∗,
- Risha Govind, MSca,b,e,∗,
- Isabel Serrano, MDf,
- Joel Salazar-Mendiguchía, MDg,h,
- Jose Manuel García-Pinilla, MD, PhDi,j,
- Domingo A. Pascual-Figal, MD, PhDi,k,
- Julio Nuñez, MD, PhDi,l,
- Gonzalo Guzzo-Merello, MD, PhDd,
- Emiliano Gonzalez-Vioque, PhDm,
- Alfredo Bardaji, MD, PhDf,
- Nicolas Manito, MD, PhDg,
- Miguel A. López-Garrido, MDi,j,
- Laura Padron-Barthe, PhDd,i,
- Elizabeth Edwards, PhDa,b,
- Nicola Whiffin, PhDa,b,c,
- Roddy Walsh, MSc, PhDa,b,
- Rachel J. Buchan, MSca,b,
- William Midwinter, BSca,b,
- Alicja Wilk, BSca,b,
- Sanjay Prasad, MDa,b,
- Antonis Pantazis, MDb,
- John Baski, MRCP, PhDb,
- Declan P. O’Regan, MRCP, PhDc,
- Luis Alonso-Pulpon, MD, PhDd,i,
- Stuart A. Cook, MRCP, PhDa,c,n,o,
- Enrique Lara-Pezzi, PhDi,p,
- Paul J. Barton, PhDa,b,∗∗∗ ( and )
- Pablo Garcia-Pavia, MD, PhDd,i,q,∗∗ ()
- aNational Heart and Lung Institute, Imperial College London, London, United Kingdom
- bCardiovascular Research Centre, Royal Brompton and Harefield NHS Foundation Trust London, London, United Kingdom
- cMRC London Institute of Medical Sciences, Imperial College London, London, United Kingdom
- dHeart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, Madrid, Spain
- eInstitute of Psychiatry, Psychology and Neuroscience, Social Genetic and Developmental Psychiatry Centre, King's College London, London, United Kingdom
- fDepartment of Cardiology, Hospital Universitario de Tarragona Joan XXIII, IISPV, Rovira Virgili University, Tarragona, Spain
- gInherited Cardiac Diseases Unit, Department of Cardiology, Hospital Bellvitge, Barcelona, Spain
- hGenetics Department, Universidad Autónoma de Barcelona, Barcelona, Spain
- iCIBER in Cardiovascular Diseases, Madrid, Spain
- jHeart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Virgen de la Victoria, IBIMA, Málaga, Spain
- kDepartment of Cardiology, Hospital Universitario Virgen de la Arrixaca, IMIB-Arrixaca, University of Murcia, Murcia, Spain
- lCardiology Department, Hospital Clínico Universitario, INCLIVA Universitat de Valencia, Valencia, Spain
- mDepartment of Biochemistry, Hospital Universitario Puerta de Hierro, Madrid, Spain
- nNational Heart Research Institute Singapore, National Heart Centre Singapore, Singapore
- oDivision of Cardiovascular & Metabolic Disorders, Duke-National University of Singapore, Singapore
- pMyocardial Biology Programme, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- qUniversity Francisco de Vitoria (UFV), Pozuelo de Alarcón, Madrid, Spain
- ↵∗Address for correspondence:
Dr. Pablo Garcia-Pavia, Department of Cardiology, Hospital Universitario Puerta de Hierro, Manuel de Falla 2, Majadahonda, Madrid 28222, Spain.
- ↵∗∗Dr. Paul J. Barton, Cardiovascular Research Centre, Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, London SW3 6NP, United Kingdom.
Background 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 ×10−5), 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.
↵∗ Drs. Ware, Amor-Salamanca, Tayal, Govind, Barton, and Garcia-Pavia contributed equally to this work.
This 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) “A way 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.
- Received January 5, 2018.
- Revision received February 14, 2018.
- Accepted March 1, 2018.
- 2018 The Authors