Abstract Body: Introduction: Hepatic de novo lipogenesis (DNL) is the biological process of fatty acids synthesis from non-lipid precursors of glycolysis. Elevated DNL has been implicated in metabolic dysregulation, potentially contributing to fatty liver disease (FLD), cardiovascular disease (CVD), and impaired kidney function. Little is known about DNL and cardiometabolic endpoints in patients with a history of a myocardial infarction (MI).

Methods: We included 4305 patients from the Alpha Omega Cohort, aged 60-80 y, with an MI <10 y prior to enrollment. DNL was assessed at baseline (2002-2006) using the lipogenic index, for which we calculated the ratio of palmitic acid (C16:0) and linoleic acid (C18:2n-6) in plasma cholesterol esters. Prevalent FLD was defined as the upper sex-specific tertile of the Fatty Liver Index (FLI), based on BMI, waist circumference, serum triglycerides and gamma-glutamyl transferase. The estimated glomerular filtration rate (eGFR; CKD-EPI equation) was monitored from baseline through 2009 (median follow-up: 3.4 y). CVD mortality risk was monitored through 2022 (median follow-up: 14.5 y). Prevalence ratios (PR) for FLD and hazard ratios (HR) with 95% confidence intervals (CI) for CVD mortality in quintiles of the lipogenic index (Q1, reference) were obtained from Cox models. Betas (95%CI) for annual eGFR change were obtained from linear regression models. Multivariable models included demographics, anthropometrics, lifestyle, and cardiovascular risk factors.

Results: Patients (79% male) had a mean (SD) age of 69 (6) y and a BMI of 27.7 (3.8) kg/m². Of the cohort, 24% were obese, 17% were smokers, and 86% were on lipid lowering medication. Baseline FLI was 65 (23) and eGFR was 81 (21) mL/min/1.73m², with 15% having eGFR <60. The annual eGFR change was -1.7 (3.8) during short-term follow-up. The number of deaths was 305 (138 from CVD) during short-term follow-up and 2827 (1096 from CVD) during long-term follow-up. The lipogenic index (Q5 vs Q1) was associated with a higher FLD prevalence (PR: 1.67; 95%CI: 1.40 to 2.00), more annual kidney function decline (beta: -0.76; -1.32 to -0.20), and an increased CVD mortality risk (short-term HR: 1.83; 1.06 to 3.15; long-term HR: 1.38; 1.14 to 1.68).

Conclusion: Elevated DNL in post-MI patients is associated with FLD, kidney function decline, and CVD mortality risk. An abnormal hepatic fatty acid synthesis may represent a common pathophysiological pathway in cardiometabolic diseases.