When Lowering LDL Is Not Enough: Confronting Residual Inflammatory Risk After Myocardial Infarction

Numerous strategies have been studied to improve clinical outcomes after acute myocardial infarction (AMI), and the most firmly established is low-density lipoprotein (LDL) cholesterol-lowering therapy.Contemporary dyslipidemia guidelines therefore recommend intensive LDL-lowering after AMI, with an European Society of Cardiology/European Atherosclerosis Society and American College of Cardiology/American Heart Association goal of below 55 mg/dL together with at least a 50% reduction from baseline in very-high-risk patients.1)2) Yet despite aggressive LDL lowering, cardiovascular event continue to occur, and considerable effort is now directed at identifying and treating the residual risk that remains once lipid targets are met.Inflammation has long been implicated in the prognosis of patients with AMI.The inflammatory hypothesis of atherosclerosis moved from association to causation with the CANTOS trial, in which canakinumab-an interleukin (IL)-1β antagonist that lowers IL-6 and C-reactive protein (CRP) without altering lipids-reduced cardiovascular events.3) Low-dose colchicine subsequently reduced ischemic events after myocardial infarction (MI) and in chronic coronary disease, 4)5) whereas methotrexate, which does not lower IL-6 or CRP, was neutral (CIRT)-underscoring that benefit tracks specifically with the IL-6-CRP axis.6) More recently, however, the CLEAR-SYNERGY (OASIS-9) trial did not show a significant reduction in cardiovascular events with colchicine after MI, reminding us that the optimal agent, timing, and target population for anti-inflammatory therapy remain unsettled.7) In this context, the study by Hyun et al. 8) published in the current issue of the Korean Circulation Journal provides timely evidence on whether CRP adequately reflects residual risk after AMI.Among 661 such patients with serial high-sensitivity C-reactive protein (hsCRP) measurements, 19.5% had high residual inflammatory risk (RIR), defined as an hsCRP level >2 mg/L at 1 year.During a median follow-up of 5.3 years, high RIR was independently associated with a more than 4-fold higher risk of all-cause mortality (adjusted hazard ratio [HR], 3.41) and a 3-fold higher risk of major adverse cardiac and cerebrovascular event (adjusted HR, 3.08).Importantly, these associations remained consistent in the subgroup with LDL cholesterol <55 mg/dL.