King's College London

TY - JOUR

T1 - Genetic Etiology for Alcohol-Induced Cardiac Toxicity

AU - Ware, James S.

AU - Amor-Salamanca, Almudena

AU - Tayal, Upasana

AU - Govind, Risha

AU - Serrano, Isabel

AU - Salazar-Mendiguchía, Joel

AU - García-Pinilla, Jose Manuel

AU - Pascual-Figal, Domingo A.

AU - Nuñez, Julio

AU - Guzzo-Merello, Gonzalo

AU - Gonzalez-Vioque, Emiliano

AU - Bardaji, Alfredo

AU - Manito, Nicolas

AU - López-Garrido, Miguel A.

AU - Padron-Barthe, Laura

AU - Edwards, Elizabeth

AU - Whiffin, Nicola

AU - Walsh, Roddy

AU - Buchan, Rachel J.

AU - Midwinter, William

AU - Wilk, Alicja

AU - Prasad, Sanjay

AU - Pantazis, Antonis

AU - Baski, John

AU - O’Regan, Declan P.

AU - Alonso-Pulpon, Luis

AU - Cook, Stuart A.

AU - Lara-Pezzi, Enrique

AU - Barton, Paul J.

AU - Garcia-Pavia, Pablo

PY - 2018/5/22

Y1 - 2018/5/22

N2 - 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.

AB - 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.

KW - alcohol

KW - dilated cardiomyopathy

KW - genetics

KW - titin

KW - variant

U2 - 10.1016/j.jacc.2018.03.462

DO - 10.1016/j.jacc.2018.03.462

M3 - Article

VL - 71

SP - 2293

EP - 2302

JO - Journal of the American College of Cardiology

JF - Journal of the American College of Cardiology

SN - 0735-1097

IS - 20

ER -