Lipoprotein(a) in cardiovascular disease with focus on peripheral arterial disease, major adverse limb events, abdominal aortic aneurysms and interaction with low-grade inflammation

Lipoprotein(a) is an established risk factor for atherosclerotic cardiovascular disease (ASCVD), with strong evidence of causality from genetic and epidemiological studies. This recognition has led to the development of multiple potent lipoprotein(a)-lowering therapies, four of which are currently in phase 3 cardiovascular outcomes trials. Despite this progress, several critical knowledge gaps remain. Notably, the potential role of high lipoprotein(a) in non-coronary vascular diseases, specifically peripheral arterial disease, major adverse limb events, and abdominal aortic aneurysms, has not been adequately investigated, despite the considerable morbidity and mortality associated with these conditions. Furthermore, recent findings suggest that systemic low-grade inflammation, as measured by high-sensitivity C-reactive protein (hsCRP), may modify the ASCVD risk attributable to high lipoprotein(a). This raises the possibility that future lipoprotein(a)-lowering therapies may only benefit individuals with concomitantly elevated hsCRP. This review summarizes the current knowledge of lipoprotein(a) as a risk factor for cardiovascular disease and aortic valve stenosis, outlines the emerging evidence linking lipoprotein(a) with peripheral arterial disease, major adverse limb events, and abdominal aortic aneurysms, and examines whether high lipoprotein(a) independently predicts the risk of ASCVD and aortic valve stenosis regardless of the presence or absence of systemic low-grade inflammation. By placing recent studies within a broader scientific landscape, we will thus attempt to clarify the vascular relevance of high lipoprotein(a) beyond coronary disease and inform precision targeting of future lipoprotein(a)-lowering therapies.