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Risk Factors Identified for Cardiovascular Disease in Individuals With Hepatic Steatosis

Key findings

  • This study analyzed 959 participants in the PROMISE trial who had hepatic stenosis as well as suspected coronary artery disease (CAD); the goal was to assess determinants of cardiovascular disease risk in patients with hepatic stenosis
  • Male sex, atherosclerotic CVD (ASCVD) risk score, and N-terminal proB-type natriuretic peptide (NT-proBNP) were among the factors associated with prevalent obstructive CAD
  • Male sex and ASCVD risk were also associated, among other factors, with atherosclerotic plaque burden and severity at baseline
  • ASCVD risk score, NT-proBNP, and sedentary lifestyle were the only independent risk factors for incident major adverse cardiovascular events
  • Clinicians should estimate the ASCVD score of adults with nonalcoholic fatty liver disease and recommend intervention as necessary; the benefit of measuring NT-proBNP requires more study

Hepatic steatosis can progress to cirrhosis and hepatocellular carcinoma, but cardiovascular disease (CVD) is the leading cause of mortality. Substantial evidence has accumulated that hepatic steatosis is an independent risk factor for CVD and major adverse cardiovascular events (MACE).

Massachusetts General Hospital researchers recently conducted the first study of MACE in a large population of patients with hepatic steatosis who had a comprehensive evaluation of baseline risk factors, baseline atherosclerotic burden, and prospective determination of outcomes.

Kathleen E. Corey, MD, MPH, MMSc, director of the Mass General Fatty Liver Program, Júlia Karády, MD, an instructor in the Department of Radiology and a researcher in the Cardiovascular Imaging Research Center, and colleagues report outcomes and risk factors in Hepatology Communications.


The team designed a cohort study nested within the multicenter PROMISE trial, which compared noninvasive functional testing against anatomical testing with cardiac computed tomography angiography (CTA) for reducing the risk of incident MACE in adults with suspected coronary artery disease (CAD).

Of all 10,003 participants, 3,756 were randomized to the anatomical testing arm. 959 were found to have hepatic steatosis (55% male, mean age 59) and were included in this analysis.

Prevalent Obstructive CAD

The primary endpoint, prevalent obstructive CAD (≥50% stenosis in one or more coronary arteries), was present in 15% of the patients. In multivariate analysis, risk factors directly and significantly associated with obstructive CAD were:

  • Male sex: OR, 1.83
  • Atherosclerotic CVD (ASCVD) risk score: OR, 1.05 for every 1-point increase*
  • Total cholesterol: OR, 1.48
  • LDL cholesterol: OR, 1.44
  • Triglycerides: OR, 1.33
  • Triglycerides/HDL cholesterol ratio: OR, 1.36
  • Non-HDL cholesterol: OR, 1.52
  • Apolipoprotein B: OR, 1.47
  • Branched-chain amino acids (BCAA): OR, 1.48
  • N-terminal proB-type natriuretic peptide (NT-proBNP): OR, 1.90

*10-year risk was calculated as specified in the 2013 American College of Cardiology/American Heart Association guideline

Galectin-3 levels were inversely associated with obstructive CAD (OR, 0.64; P= 0.01).

In a sensitivity analysis, the risk factors were similar when a more stringent definition of obstructive CAD was used (≥70% stenosis in any epicardial artery or ≥50% in the left main branch).

Coronary Plaque Burden

The median Leaman score of plaque burden and severity, calculated from the CTA images at baseline, was 4.6 (IQR, 0–9.1). On multivariate analysis, direct and significant risk factors were:

  • Male sex: β, 0.58
  • ASCVD risk score: β, 0.02
  • Triglycerides: β, 0.17
  • Triglyceride/HDL cholesterol ratio: β, 1.31
  • BCAA: β, 0.58

Leaman score was inversely associated with:

  • HDL cholesterol: β, −0.67
  • ApoA-1: β, −0.93
  • Creatinine: β, −1.54
  • Adiponectin: β, −0.27


4.3% of participants experienced MACE (hospitalization for unstable angina, nonfatal myocardial infarction, or death for any reason) over the median follow-up period of 25 months. Significant independent predictors were:

  • Sedentary lifestyle: HR, 2.53
  • ASCVD risk score: HR, 1.03 for each percentage point increase
  • NT-proBNP: HR, 1.05 for each 1-SD increase

Individuals with a 10-year ASCVD risk score ≥12.3% had significantly higher rates of MACE than those with lower scores (P=0.002).

Recommendations for Clinicians

ASCVD score estimation should improve the clinician's ability to risk-stratify and modify CVD risk in adults with nonalcoholic fatty liver disease; the benefit of measuring NT-proBNP requires more study. A sedentary lifestyle is a modifiable risk factor and could be targeted to decrease the risk of major CV events.

higher risk of major cardiovascular events in adults with hepatic steatosis for every percentage point increase in atherosclerotic cardiovascular disease risk score

higher risk of major cardiovascular events in adults with hepatic steatosis for every 1 standard deviation increase in N-terminal proB-type natriuretic peptide

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