Precision approach in apoA-I infusion trials: When CSL112 may actually work

In the recent ApoA-I Event Reducing in Ischemic Syndromes II trial, a plasma-derived apolipoprotein A-I (apoA-I) infusion (CSL112) demonstrated no significant reduction in major cardiovascular events in the overall postmyocardial infarction population. However, exploratory analyses revealed benefits in subgroups with both elevated low-density lipoprotein cholesterol (LDL-C) and systemic inflammation, suggesting that biologic context may be critical to therapeutic efficacy. Building on these trial findings, we highlight that the efficacy of CSL112 may depend on the coexistence of elevated LDL-C and systemic inflammation. We integrate ATP-binding cassette transporter A1 (ABCA1) biology with subgroup trial findings to propose a precision-stratification framework for future apoA-I infusion trials. We focus on the interaction of lipid burden and inflammation on ABCA1 transporter function, the impact of statin-induced transporter downregulation, and strategies for patient selection, including ex vivo efflux assays and molecular transporter profiling, and the therapeutic promise of combination therapies (apoA-I infusion with liver X receptor agonists) in patients with impaired transporter function.