Association of apolipoprotein C-III with atherosclerotic cardiovascular disease and the effectiveness of simulated interventions

Despite effective control of low-density lipoprotein cholesterol, the residual risk of atherosclerotic cardiovascular disease (ASCVD) remains substantial, underscoring the urgent need to identify novel targets to further reduce ASCVD risk. This study aimed to investigate the association between apolipoprotein C-III (APOC3) levels and ASCVD, and further explore the potential impact of APOC3 intervention for reducing ASCVD risk.

We leveraged the 20-year longitudinal data from the Chinese Multi-provincial Cohort Study–Proteomics Project, obtained totaling 5308 APOC3 measurements from 2550 participants, with up to four repeated measurements per participant. The intensity model was employed to estimate the association between time-varying APOC3 and ASCVD, accounting for time-varying potential confounders. The target trial emulation framework was used to emulate the effectiveness of various APOC3-targeted hypothetical interventions on ASCVD risk, with a guideline-directed low-density lipoprotein cholesterol-lowering strategy serving as a positive control.

Of 2550 participants aged 57.5 ± 7.9 years at baseline, and 56% of participants were females. The median level of APOC3 was 5554.8 (interquartile range: 3936.5-7913.8) Relative Fluorescence Units. The level of time-varying APOC3 level were associated with an increased risk of incident ASCVD, and a stronger association was observed in populations with metabolic abnormalities. Furthermore, more intensive reductions in APOC3 produced progressively larger decreases in ASCVD risk, with a maximum estimated reduction of 9.3% observed at a 90% APOC3 reduction.

Our findings suggest that APOC3 may play an important role in ASCVD incidence and that targeting APOC3 may offer additional cardiovascular benefits beyond conventional lipid-lowering strategies.