Description
The National Heart, Lung, and Blood Institute (NHLBI) convened a working group (WG) on Future Research Directions on Lipoprotein(a) and Cardiovascular Disease in Bethesda, Maryland to evaluate the state of the art of Lipoprotein(a) (Lp(a)) research and the roles of Lp(a) in cardiovascular disease (CVD), to identify research gaps and barriers, and to recommend future research opportunities in Lp(a) research.
Background
Lp(a) is a highly prevalent CVD risk factor with blood levels in the atherothrombotic range affecting >20% of the global population. It is composed of an apolipoprotein B-containing low-density lipoprotein (LDL)-like particle, covalently linked to the plasminogen-like glycoprotein apolipoprotein(a) (apo(a)). Apo(a) is composed of multiple and variable number of structural motifs called ‘kringles’, which give rise to many different Lp(a) isoforms. Lp(a) is subject to tight genetic control, with more than 90% of its variance residing in the LPA gene encoding apo(a). Patients with elevated Lp(a) levels have an increased risk of CVD, including heart attack, stroke and peripheral arterial disease as well as calcific aortic stenosis (AS). The LDL-like component of Lp(a) may promote atherosclerosis through established mechanisms, its content of oxidized phospholipids on both the lipid moiety and apo(a) may promote inflammation, and the plasminogen-like apo(a) particle may potentially promote thrombosis by interfering with fibrinolysis. However, the biological mechanisms underlying its atherogenicity and increased risk of CVD are still poorly understood.
Lp(a) structure is highly complex and the size of the Lp(a) is very heterogeneous due to the variability of apo(a) isoforms. Lp(a) can be measured using a variety of different assays. However, Lp(a) assays are not well standardized and validated across methods and platforms. This hampers comparisons between studies and trials assessing the relationship between Lp(a) and CVD, as well as clinical risk prediction in patients. It can also hamper interpretation of future clinical trials of Lp(a)-lowering agents. Currently a test for Lp(a) is not included in the regular lipid panel, or regularly reimbursed, but it is generally widely available in most hospitals. There is a critical need to standardize Lp(a) assays for uniform reporting and for diagnostic and therapeutic evaluation.
Recent genome-wide association and Mendelian randomization studies indicate that Lp(a) is a causal and independent risk factor for CVD. In addition, the development of selective and potent Lp(a)-lowering agents has re-stimulated interest in Lp(a). Further understanding of Lp(a) pathophysiology and its clinical importance in the treatment of CVD may help reduce the residual risk present following current standard therapy. Lp(a) testing is recommended for those at intermediate or high CVD risk, strong family history, recurrent CVD, premature CVD, and those unresponsive to guideline recommended therapies. The European Society of Cardiology, the European Atherosclerosis Society, the National Lipid Association, and the Canadian lipid guidelines have recommended incorporating Lp(a) measurement as part of clinical care with emerging evidence that Lp(a) enhances clinical risk prediction.