Lipoprotein(a) as a Risk Factor for Cardiovascular Diseases: Pathophysiology and Treatment Perspectives

Abstract

Cardiovascular disease (CVD) is still a leading cause of morbidity and mortality, despite all the progress achieved as regards to both prevention and treatment. Having high levels of lipoprotein(a) [Lp(a)] is a risk factor for cardiovascular disease that operates independently. It can increase the risk of developing cardiovascular disease even when LDL cholesterol (LDL-C) levels are within the recommended range, which is referred to as residual cardiovascular risk. Lp(a) is an LDL-like particle present in human plasma, in which a large plasminogen-like glycoprotein, apolipoprotein(a) [Apo(a)], is covalently bound to Apo B100 via one disulfide bridge. Apo(a) contains one plasminogen-like kringle V structure, a variable number of plasminogen-like kringle IV structures (types 1–10), and one inactive protease region. There is a large inter-individual variation of plasma concentrations of Lp(a), mainly ascribable to genetic variants in the Lp(a) gene: in the general po-pulation, Lp(a) levels can range from <1 mg/dL to >1000 mg/dL. Concentrations also vary between different ethnicities. Lp(a) has been established as one of the risk factors that play an important role in the development of atherosclerotic plaque. Indeed, high concentrations of Lp(a) have been related to a greater risk of ischemic CVD, aortic valve stenosis, and heart failure. The threshold value has been set at 50 mg/dL, but the risk may increase already at levels above 30 mg/dL. Although there is a well-established and strong link between high Lp(a) levels and coronary as well as cerebrovascular disease, the evidence regarding incident peripheral arterial disease and carotid atherosclerosis is not as conclusive. Because lifestyle changes and standard lipid-lowering treatments, such as statins, niacin, and cholesteryl ester transfer protein inhibitors, are not highly effective in reducing Lp(a) levels, there is increased interest in developing new drugs that can address this issue. PCSK9 inhibitors seem to be capable of reducing Lp(a) levels by 25–30%. Mipomersen decreases Lp(a) levels by 25–40%, but its use is burdened with important side effects. At the current time, the most effective and tolerated treatment for patients with a high Lp(a) plasma level is apheresis, while antisense oligonucleotides, small interfering RNAs, and microRNAs, which reduce Lp(a) levels by targeting RNA molecules and regulating gene expression as well as protein production levels, are the most widely explored and promising perspectives. The aim of this review is to provide an update on the current state of the art with regard to Lp(a) pathophysiological mechanisms, focusing on the most effective strategies for lowering Lp(a), including new emerging alternative therapies. The purpose of this manuscript is to improve the management of hyperlipoproteinemia(a) in order to achieve better control of the residual cardiovascular risk, which remains unacceptably high.

Predictive model and risk analysis for peripheral vascular disease in type 2 diabetes mellitus patients using machine learning and shapley additive explanation

“…Its serum level is associated with atherosclerotic cardiovascular diseases, including PAD. Previous studies have shown that Lp-a is a significant independent risk factor for PVD and is also associated with more severe forms of PVD in specific populations ( 57 – 59 ). Our study also indicated that LP-a is an important risk factor of PVD in T2DM, which is consistent with the aforementioned studies.…”

Association of Apolipoprotein E Gene Polymorphisms with Risk of Coronary Artery Disease in a Han Chinese Population at Middle and High Altitude in China

“…In predicting the onset and progression of heart disease, Apo-B/Apo-A1 has a greater predictive value than Apo-B or Apo-A1 alone [21]. In addition, elevated Lp(a) is an IRF for CAD and can increase the risk of cardiovascular events even in the presence of effective control of LDL-C [22]. APOE gene polymorphisms are markedly linked with lipid levels [23].…”

Lipoprotein(a)'s Role in Atherosclerosis and Aortic Stenosis: A Contemporary Literature Review

“…Significant scientific findings have elucidated Lp(a)'s role in the pathogenesis of aortic stenosis [9]. Enhanced Lp(a) levels are believed to be responsible for quicker aortic progression to stenosis, as reported by Tsimikas et al and Vinci et al, whose studies established clinically measurable parameters such as stenotic valve area and trans-valvular gradients [17]. Studies have also proven that Lp(a) plays an essential role in the onset of CAVD, which is one of the first steps in aortic stenosis formation [9,18].…”

“…Research specifically addresses Lp(a) in relation to CVDs, especially aortic valve stenosis [17]. However, elevated Lp(a) is directly related to clinical parameters such as stenotic valve area and transvalvular gradients, which are involved in the progression of aortic stenosis.…”

“…The research showed that Lp(a) is involved with the development of CAVD, which is an initial stage in the development of aortic stenosis. Greater awareness of the role of Lp(a) in cardiovascular diseases means that new strategies for treating conditions that cause high Lp(a) are being sought [17]. Because elevated Lp(a) levels are largely genetic and have been linked to the process of atherosclerosis formation, coronary artery disease, ischemic stroke, and higher rates of heart failure, therapies designed to lower Lp(a) levels could have important implications in preventative treatment plans.…”