Browsing by Author "Mukamal, Kenneth J."

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    Higher usual alcohol consumption was associated with a lower 41-y mortality risk from coronary artery disease in men independent of genetic and common environmental factors: the prospective NHLBI Twin Study
    (American Society for Nutrition, 2015-07) Dai, Jun; Mukamal, Kenneth J.; Krasnow, Ruth E.; Swan, Gary E.; Reed, Terry; Department of Medical and Molecular Genetics, IU School of Medicine
    BACKGROUND: Evidence that alcohol consumption is inversely associated with long-term coronary artery disease (CAD) mortality independent of genetic and early life environmental factors is lacking. OBJECTIVE: We evaluated whether alcohol consumption was prospectively associated with CAD mortality risk independent of familial factors. DESIGN: In total, 843 male twins (396 pairs and 51 unpaired twins) aged 42-55 y (mean: 48 y) without baseline CAD reported beer, wine, and spirits consumption at baseline (1969-1973) and were followed up to 2010 in the prospective National Heart, Lung, and Blood Institute Twin Study. Data on usual alcohol consumption over the past year were collected. Outcome was time to event, where the primary event was death from CAD and secondary events were death from cardiovascular disease and all causes. HRs were estimated by using frailty survival models, both overall and within-pair. RESULTS: There were 129 CAD deaths and 219 cardiovascular deaths during 41 y of follow-up. In the whole cohort, after adjustment for caloric intake and cardiovascular disease risk factors, overall HRs per 10-g increment in alcohol intake were 0.94 (95% CI: 0.89, 0.98) for CAD and 0.97 (95% CI: 0.93, 1.00) for cardiovascular mortality. The within-pair adjusted HRs for a twin with 10-g higher daily alcohol consumption than his co-twin were 0.90 (95% CI: 0.84, 0.97) for CAD and 0.95 (95% CI: 0.90, 1.00) for cardiovascular disease mortality in the cohort pooled by zygosity, which remained similar among monozygotic twins. All 3 beverage types tended to be associated with lower CAD mortality risk within-pair to a similar degree. Alcohol consumption was not associated with total mortality risk overall or within-pair. CONCLUSION: Higher usual alcohol consumption is associated with lower CAD mortality risk, independent of germline and early life environment and adulthood experience shared among twins, supporting a possible causal role of alcohol consumption in lowering CAD death risk. This trial was registered at clinicaltrials.gov as NCT00005124.
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    Lipoprotein Z, a hepatotoxic lipoprotein, predicts outcome in alcohol-associated hepatitis
    (Wiley, 2022) Hu, Kunpeng; Perez-Matos, Maria C.; Argemi, Josepmaria; Vilar-Gomez, Eduardo; Shalaurova, Irina; Bullitt, Esther; Landeen, Lee; Sugahara, Go; Deng, Huiyan; Mathur, Karan; Tran, Stephanie; Cai, Huimei; He, Hanchang; Yalcin, Yusuf; Barbosa, Joana Vieira; Ventura-Cots, Meritxell; Marx, Katherine; Gad, Aniket P.; Niezen, Sebastian; Barba, Sofia Izunza; Ang, Lay-Hong; Popov, Yury V.; Fricker, Zachary; Lai, Michelle; Curry, Michael; Afdhal, Nezam; Szabo, Gyongyi; Mukamal, Kenneth J.; Sanyal, Arun J.; Otvos, James D.; Malik, Raza; Saito, Takeshi; Connelly, Margery A.; Chalasani, Naga P.; Bataller, Ramon; Jiang, Z. Gordon; Medicine, School of Medicine
    Background and aims: Lipoprotein Z (LP-Z) is an abnormal free cholesterol (FC)-enriched LDL-like particle discovered from patients with cholestatic liver disease. This study aims to define the diagnostic value of LP-Z in alcohol-associated hepatitis (AH) and interrogate the biology behind its formation. Approach and results: We measured serum levels of LP-Z using nuclear magnetic resonance spectroscopy, a well-established clinical assay. Serum levels of LP-Z were significantly elevated in four AH cohorts compared with control groups, including heavy drinkers and patients with cirrhosis. We defined a Z-index, calculated by the ratio of LP-Z to total apolipoprotein B-containing lipoproteins, representing the degree of deviation from normal VLDL metabolism. A high Z-index was associated with 90-day mortality independent from the Model for End-Stage Liver Disease (MELD) and provided added prognosticative value. Both a Z-index ≤ 0.6 and a decline of Z-index by ≥0.1 in 2 weeks predicted 90-day survival. RNA-sequencing analyses of liver tissues demonstrated an inverse association in the expression of enzymes responsible for the extrahepatic conversion of VLDL to LDL and AH disease severity, which was further confirmed by the measurement of serum enzyme activity. To evaluate whether the FC in LP-Z could contribute to the pathogenesis of AH, we found significantly altered FC levels in liver explant of patients with AH. Furthermore, FC in reconstituted LP-Z particles caused direct toxicity to human hepatocytes in a concentration-dependent manner, supporting a pathogenic role of FC in LP-Z. Conclusions: Impaired lipoprotein metabolism in AH leads to the accumulation of LP-Z in the circulation, which is hepatotoxic from excessive FC. A Z-index ≤ 0.6 predicts 90-day survival independent from conventional biomarkers for disease prognostication.
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    The Moderate Alcohol and Cardiovascular Health Trial (MACH15): Design and methods for a randomized trial of moderate alcohol consumption and cardiometabolic risk
    (Oxford University Press, 2020-12) Spiegelman, Donna; Lovato, Laura C.; Khudyakov, Polyna; Wilkens, Trine L.; Adebamowo, Clement A.; Adebamowo, Sally N.; Appel, Lawrence J.; Beulens, Joline W.J.; Coughlin, Janelle W.; Dragsted, Lars Ove; Edenberg, Howard J.; Eriksen, Jane N.; Estruch, Ramon; Grobbee, Diederick E.; Gulayin, Pablo E.; Irazola, Vilma; Krystal, John H.; Lazo, Mariana; Murray, Margaret M.; Rimm, Eric B.; Schrieks, Ilse C.; Williamson, Jeff D.; Mukamal, Kenneth J.; Biochemistry and Molecular Biology, School of Medicine
    Background: Observational studies have documented lower risks of coronary heart disease and diabetes among moderate alcohol consumers relative to abstainers, but only a randomized clinical trial can provide conclusive evidence for or against these associations. Aim: The purpose of this study was to describe the rationale and design of the Moderate Alcohol and Cardiovascular Health Trial, aimed to assess the cardiometabolic effects of one alcoholic drink daily over an average of six years among adults 50 years or older. Methods: This multicenter, parallel-arm randomized trial was designed to compare the effects of one standard serving (∼11-15 g) daily of a preferred alcoholic beverage to abstention. The trial aimed to enroll 7800 people at high risk of cardiovascular disease. The primary composite endpoint comprised time to the first occurrence of non-fatal myocardial infarction, non-fatal ischemic stroke, hospitalized angina, coronary/carotid revascularization, or total mortality. The trial was designed to provide >80% power to detect a 15% reduction in the risk of the primary outcome. Secondary outcomes included diabetes. Adverse effects of special interest included injuries, congestive heart failure, alcohol use disorders, and cancer. Results: We describe the design, governance, masking issues, and data handling. In three months of field center activity until termination by the funder, the trial randomized 32 participants, successfully screened another 70, and identified ∼400 additional interested individuals. Conclusions: We describe a feasible design for a long-term randomized trial of moderate alcohol consumption. Such a study will provide the highest level of evidence for the effects of moderate alcohol consumption on cardiovascular disease and diabetes, and will directly inform clinical and public health guidelines.