Liver Fat and Cardiovascular Events: Bystander or Causative Relationship?

Objective : Non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD) share common metabolic risk factors, and there is a high prevalence of CVD in patients with NAFLD. We aimed to determine if liver fat is an independent risk factor for CVD events.

Methods: We analyzed data from participants in the Dallas Heart Study (a multiethnic sample of the Dallas County adult population) without baseline CVD who underwent liver fat quantification by proton magnetic resonance spectroscopy (N=1932). The primary outcome was the composite of any incident CVD event (CV death, non-fatal myocardial infarction, non-fatal stroke, coronary or peripheral artery revascularization, hospitalization for heart failure, and hospitalization for atrial fibrillation). Secondary outcomes were all atherosclerotic events, all non-atherosclerotic events, and all-cause mortality. Data was analyzed by (1) groups defined by tertile of baseline liver fat content (median for each tertile: 1.6, 3.6, 9.2%), and (2) grouped by BMI (< or ≥30 kg/m2) and liver fat (< or ≥5.5%). Unadjusted and multivariable adjusted (for age, gender, race, BMI, diabetes, HTN, smoking, family history of CVD, statin use, physical activity, alcohol use) Cox regression for liver fat tertiles or BMI/liver fat groups were performed for all outcomes, and further validated by comparisons of restricted mean survival times (RMST), which were restricted to 13.5 years for the primary outcome (the length of the study period).

Results: Mean age was 43 years, 62% were women, and 48% were African-American. A total of 168 participants (8.7%) experienced a primary outcome event. For the primary outcome, the RMSTs were similar at 13.1, 13.0, and 13.1 years for the lowest to highest tertile (p=0.512). In the multivariable analysis, liver fat tertiles were not associated with cardiovascular events for either the middle tertile (HR= 1.06; 95% CI 0.7-1.61) nor for the highest tertile (HR=0.78; 95% CI 0.5-1.22) compared with lowest tertile. Compared with non-obese participants with normal liver fat, obese participants with elevated liver fat had a HR 0.77 (95% Cl 0.42-1.43), obese participants with normal liver fat had a HR 0.78 (95% Cl 0.42-1.43), and non-obese participants with increased liver fat had a HR 0.69 (95% Cl 0.39-1.23) for the primary outcome. None of the secondary outcomes were associated with liver fat content, and no differences were found in the RMSTs for any of the secondary outcomes between groups defined by tertiles of liver fat or BMI/liver fat.

Discussion/Conclusion: NAFLD was not independently associated with cardiovascular events in the multiethnic DHS population. Our findings should be validated in other cohorts, especially in those with documented advanced NAFLD (NASH or cirrhosis).