Genetic Etiology for Alcohol-Induced Cardiac Toxicity

James S. Ware, Almudena Amor-Salamanca, Upasana Tayal, Risha Govind, Isabel Serrano, Joel Salazar-Mendiguchía, Jose Manuel García-Pinilla, Domingo A. Pascual-Figal, Julio Nuñez, Gonzalo Guzzo-Merello, Emiliano Gonzalez-Vioque, Alfredo Bardaji, Nicolas Manito, Miguel A. López-Garrido, Laura Padron-Barthe, Elizabeth Edwards, Nicola Whiffin, Roddy Walsh, Rachel J. Buchan, William MidwinterAlicja Wilk, Sanjay Prasad, Antonis Pantazis, John Baski, Declan P. O’Regan, Luis Alonso-Pulpon, Stuart A. Cook, Enrique Lara-Pezzi, Paul J. Barton, Pablo Garcia-Pavia

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197 Citations (Scopus)
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Abstract

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.
Original languageEnglish
Pages (from-to)2293-2302
Number of pages10
JournalJournal of the American College of Cardiology
Volume71
Issue number20
Early online date14 May 2018
DOIs
Publication statusPublished - 22 May 2018

Keywords

  • alcohol
  • dilated cardiomyopathy
  • genetics
  • titin
  • variant

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