Prognostic impact of total physiologic atherosclerotic burden and residual cholesterol risk in statin-treated patients undergoing PCI

Elevated cholesterol levels and physiologic ischemia are established correlates of cardiovascular risk, particularly non-HDL cholesterol in statin-treated patients. Patients with high total physiologic atherosclerotic burden—quantified as the sum of computational angiography-derived FFR in three vessels (3V-caFFR)—have poorer prognosis compared to those with low burden. In patients adhering to statin therapy, the relative prognostic weight of this total physiologic burden versus residual cholesterol risk remains undefined. This study sought to determine the comparative impact of residual non–high-density lipoprotein cholesterol (non-HDL-c) and 3V-caFFR on long-term outcomes in a statin-treated cohort undergoing percutaneous coronary intervention (PCI). This retrospective cohort study analysed data from 2,167 patients presenting for PCI at our Hospital between 2014 and 2017. Inclusion criteria required consecutive statin use for ≥90 days and cholesterol assessment ≥30 days prior to the index procedure. The cohort was stratified into four risk groups based on the median 3V-caFFR value (2.47; values <2.47 indicate high burden) and the median non-HDL-c level (2.72 mmol/L): (1) Isolated High Physiologic Burden (Low 3V-FFR/Low non-HDL-c); (2) Isolated Residual Cholesterol Risk (High 3V-FFR/High non-HDL-c); (3) Combined Risk; and (4) Low Risk. The primary endpoint was Major Adverse Cardiovascular Events (MACE), defined as a composite of all-cause mortality, myocardial infarction (MI), and heart failure (HF) hospitalization. The study included 615 patients (67.4±9.9 years; 71.1% male). Over a median follow-up of 4.4 years, the highest rate of MACE (25.5%) was observed in patients with isolated high physiologic atherosclerotic burden (low 3V-caFFR/low non-HDL-c), followed by patients with low overall risk, combined risk, and isolated residual cholesterol risk. A significant interaction between non-HDL-c and 3V-caFFR was identified for the endpoint of myocardial infarction (P for interaction=0.006). In multivariable analysis, using patients with isolated residual cholesterol risk as the reference, patients with isolated high physiologic burden were associated with significantly poorer survival outcome, demonstrating a 2.5-fold increase in the risk of all-cause mortality (HR 2.49, 95% CI 1.07–5.82, P=0.035) and a nearly 2-fold increase in MACE (HR 1.96, 95% CI 1.00–3.83, P=0.048). In statin-treated patients undergoing PCI, total physiologic atherosclerotic burden (3V-caFFR) supersedes residual cholesterol risk as the primary driver of long-term clinical outcomes. These findings identify a high-risk phenotype characterized by extensive physiologic disease that portends a poor prognosis regardless of lipid control. Clinical risk stratification should integrate global physiologic burden assessments to identify vulnerable patients who remain at high risk despite optimal lipid control.