Atherosclerotic plaque stabilization and regression: a review of clinical evidence

Atherosclerotic plaque results from a complex interplay between lipid deposition, inflammatory changes, cell migration and arterial wall injury. Over the past two decades, clinical trials utilizing invasive arterial imaging modalities, such as intravascular ultrasonography, have shown that reducing levels of atherogenic lipoproteins, mainly serum LDL-cholesterol (LDL-C), to very low levels can safely reduce overall atherosclerotic plaque burden and favourably modify plaque composition. Classically, this outcome has been achieved with intensive statin therapy. Since 2016, newer and potent lipid-lowering strategies, such as proprotein convertase subtilisin-kexin type 9 inhibition, have shown incremental effects on plaque regression and risk of clinical events. Despite maximal reduction in plasma LDL-C levels, considerable residual cardiovascular risk remains in some patients. Therefore, there is a need to study therapeutic approaches that address residual risk beyond LDL-C reduction to promote plaque stabilization or regression. Contemporary imaging modalities, such as coronary computed tomography angiography, enable non-invasive assessment of the overall atherosclerotic plaque burden as well as of certain local plaque characteristics. This technology could allow further study of plaque stabilization and regression using novel therapeutic approaches. Non-invasive plaque assessment might also offer the potential to guide personalized management strategies if validated for this purpose. In this Review, Sarraju and Nissen summarize the clinical trial evidence for coronary atherosclerotic plaque stabilization and regression with plasma LDL-cholesterol-lowering therapy and other treatments. Invasive and non-invasive imaging modalities used to assess plaque burden and composition are discussed. Intravascular ultrasonography is the traditionally favoured imaging technique to evaluate plaque burden and morphology in clinical trials; newer and promising invasive techniques include optical coherence tomography and near-infrared spectroscopy.Non-invasive plaque assessment is feasible with coronary computed tomography angiography, including the evaluation of plaque distribution and burden across all epicardial coronary arteries and the identification of high-risk plaque features.The strongest evidence for plaque regression and stabilization comes from clinical trials of intensive reductions of plasma LDL-cholesterol (LDL-C) with statin therapy and the use of intravascular ultrasonography to track coronary atherosclerosis over time.Emerging evidence has shown that plasma LDL-C reduction with proprotein convertase subtilisin-kexin type 9 inhibitors leads to additional plaque regression.Evidence to support non-LDL-C and non-lipid targeting to promote additional plaque regression is inconsistent and less robust than for LDL-C reduction.Future trials should leverage non-invasive plaque assessment through coronary computed tomography angiography and focus on achieving residual risk reduction through effects on plaque regression and stabilization by modifying other targets such as plasma lipoprotein(a) levels.