The Apolipoprotein A2/Apolipoprotein C3 ratio predicts future cardiovascular events after percutaneous coronary intervention in patients receiving LDL-cholesterol-lowering therapy

Background/Introduction Low-density lipoprotein cholesterol (LDL-C) lowering therapy with statins is effective for secondary prevention in patients with cardiovascular disease after percutaneous coronary intervention (PCI). Epidemiological studies have shown that serum apolipoproteins (Apos) (A1, A2, B, C2, C3, and E) are associated with atherosclerosis risk, but their role in secondary prevention remains unclear, as statins strongly influence their levels. Our preliminary study showed that single apolipoprotein levels were insufficient to evaluate residual risk under statin therapy. Based on the pathological role of each apolipoprotein and our previous findings on apolipoprotein A2 (Apo A2), we hypothesized that combining Apo A2 and apolipoprotein C3 (Apo C3) may help identify high-risk patients for future cardiovascular events. Purpose We aimed to evaluate whether Apo A2 and Apo C3 levels predict major cardiovascular events (MACEs) in post-PCI patients on statins. Methods We analyzed 649 patients who underwent PCI for acute coronary syndrome (ACS) or chronic coronary syndrome (CCS), had serum apolipoprotein A1, A2, B, C2, C3, and E measured, and were on statin therapy between 2016 and 2022. Based on median values of Apo A2 and Apo C3, we defined lower Apo A2 (<24.2 mg/dL) or higher Apo C3 (>8.3 mg/dL) as potential risk factors. Patients were categorized into three groups: 1) L–A2 and H–C3 group (both low–Apo A2 and high–Apo C3), 2) L–A2 or H–C3 group (either low–Apo A2 or high–Apo C3), and 3) H–A2 and L–C3 group (both high–Apo A2 and low–Apo C3). Moreover, patients were categorized into two groups using a receiver operating characteristic curve based on the Apo A2/Apo C3 ratio and the incidence of MACEs, yielding an optimal cut–off ratio of 2.418. The primary endpoint was MACEs, which included cardiovascular death, non-fatal ACS, ischemic stroke, heart failure hospitalization, and any repeat revascularization. Results During a median follow-up of 622 days, 124 patients (19.0%) experienced MACEs. Kaplan-Meier analysis revealed that both the L-A2 and H-C3 group and the low Apo A2/Apo C3 ratio group had a significantly higher MACE incidence than the other groups, respectively (L–A2 and H–C3: 51.5% vs L–A2 or H–C3: 34.7% vs H–A2 and L–C3: 22.3%, log-rank test, p = 0.030; 54.0% vs 27.4%, log-rank test, p = 0.001, Figure 1). Multivariable Cox proportional hazard analysis indicated the L–A2 and H–C3 group as an independent predictor of MACEs (hazard ratio [HR] 1.59, 95% confidence interval [CI] 1.06–2.38, p =0.025). Analysis of the Apo A2/Apo C3 ratio as a continuous variable indicated that a higher ratio was associated with a lower HR for MACE (Wald test, p = 0.02, Figure 2). Conclusion Patients with low Apo A2 and high Apo C3 levels remain at a high cardiovascular risk despite statin therapy. The Apo A2/Apo C3 ratio may serve as a novel marker for residual cardiovascular risk stratification beyond LDL-cholesterol.