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Use of Lipoprotein(A) in Clinical Practice: a Biomarker Whose Time Has Come

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Use of Lipoprotein(A) in Clinical Practice: a Biomarker Whose Time Has Come Journal of Clinical Lipidology (2019) -, -–- Original Research Use of lipoprotein(a) in clinical practice: A biomarker whose time has come. A scientific statement from the National Lipid Association. Don P. Wilson, MD, on behalf of the Writing group Don P. Wilson, MD*, Terry A. Jacobson, MD, Peter H. Jones, MD, Marlys L. Koschinsky, PhD, Catherine J. McNeal, MD, PhD, Børge G. Nordestgaard, MD, DMSc, Carl E. Orringer, MD Department of Pediatric Endocrinology and Diabetes, Cook Children’s Medical Center, Fort Worth, TX, USA (Dr Wilson); Department of Medicine, Lipid Clinic and Cardiovascular Risk Reduction Program, Emory University, Atlanta, GA, USA (Dr Jacobson); Department of Medicine, Baylor College of Medicine, Houston, TX, USA (Dr Jones); Robarts Research Institute, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada (Dr Koschinsky); Division of Cardiology, Department of Internal Medicine, Baylor Scott & White Health, Temple, TX, USA (Dr McNeal); Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark (Dr Nordestgaard); and Division of Cardiology, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA (Dr Orringer) KEYWORDS: Abstract: Lipoprotein(a) [Lp(a)] is a well-recognized, independent risk factor for atherosclerotic car- Lipoprotein (a); diovascular disease, with elevated levels estimated to be prevalent in 20% of the population. Observa- Lp(a); tional and genetic evidence strongly support a causal relationship between high plasma concentrations Biomarker; of Lp(a) and increased risk of atherosclerotic cardiovascular disease–related events, such as myocardial Atherosclerotic infarction and stroke, and valvular aortic stenosis. In this scientific statement, we review an array of cardiovascular disease; evidence-based considerations for testing of Lp(a) in clinical practice and the utilization of Lp(a) levels Cutpoints; to inform treatment strategies in primary and secondary prevention. Cardiovascular risk; Ó 2019 National Lipid Association. All rights reserved. Coronary heart disease; Myocardial infarction; Stroke; Calcific valvular aortic disease; Primary prevention; Secondary prevention; Treatment; Lifestyle; Scientific statement E-mail address: [email protected] * Corresponding author. Lipoprotein(a) Scientific Statement Committee, Na- Submitted April 24, 2019. Accepted for publication April 26, 2019. tional Lipid Association, Pediatric Endocrinology and Diabetes, Cook Children’s Medical Center, 1500 Cooper Street, 2nd Floor, Fort Worth, TX, 76104, USA. 1933-2874/Ó 2019 National Lipid Association. All rights reserved. https://doi.org/10.1016/j.jacl.2019.04.010 2 Journal of Clinical Lipidology, Vol -,No-, - 2019 Preamble: In 2014, the National Lipid Association taking into account potential benefits and risks or harms (NLA) convened an expert panel to develop a consensus associated with the test or intervention. For rating the set of recommendations for the Patient-Centered Manage- level (or quality) of the evidence, consideration was given ment of Dyslipidemia (Part 1).1 The evidence base used to obtaining the highest quality evidence to support a was derived from randomized controlled trials (RCTs), recommendation, such as that from RCTs or meta- meta-analyses of results from RCTs, and review of results analysis. from observational, genetic, metabolic, and mechanistic studies. Based on the totality of evidence, the NLA Part 1 Recommendations laid out several core principles and l. Introduction conclusions. One important core principle is that an a. Question: What are the proposed pathophysiologic elevated level of cholesterol carried by circulating apoli- mechanisms supporting a causal link between increased poprotein B–containing lipoproteins (non–high-density li- circulating concentrations of Lp(a) and (1) atheroscle- poprotein cholesterol and low-density lipoprotein rotic cardiovascular disease (ASCVD) and (2) valvular cholesterol, termed atherogenic cholesterol) is a root aortic stenosis (VAS)? cause of atherosclerosis, the key underlying process contributing to most clinical atherosclerotic cardiovascu- Observational and genetic evidence strongly support a lar disease–related events. Another core principle is that causal relationship between high plasma concentrations of providers use a patient-centered approach that accounts lipoprotein(a) [Lp(a)] and increased risk of ASCVD and 6–9 for the circumstances, objectives, and preferences of VAS. Although the precise pathophysiologic mechanism each individual patient. The patient should be an active behind these relationships is not completely clear, the participant in the decision-making process, and shared de- mechanism likely involves either or both components of cisions should be based on the objectives of therapy, po- Lp(a), that is, the low-density lipoprotein (LDL)-like parti- tential risks, and side effects, as well as benefits and cle and the apolipoprotein(a) [apo(a)] attached to apolipo- costs. In 2015, the NLA Part 2 Recommendations for Pa- protein B (apoB) via a disulfide bridge (Fig. 1). The tient-Centered Management of Dyslipidemia were pub- apo(a) protein has homology with plasminogen and in vitro, lished to expand on the NLA Part 1 Recommendations as well as in some animal models, inhibits fibrino- 2,10,11 in areas where clinicians needed additional guidance, lysis. Historically, it has been suggested that high con- particularly where the evidence base was less robust or centrations of circulating Lp(a) could have provided a 12,13 where RCT evidence was lacking to guide clinical deci- survival benefit by facilitating wound healing, reduce 4,6 sion-making.2 The current 2019 NLA Position Statement bleeding, and aiding hemostasis during childbirth. on Lp(a) builds on the NLA Recommendations Part 1 Both ASCVD and VAS share elements of stenosis as and Part 2 and updates a previous NLA expert panel state- well as cholesterol deposition in the arterial intima and ment on the clinical utility of advanced lipoprotein aortic valve leaflets, respectively. In susceptible individ- testing.3 The current statement was developed by a diverse uals, Lp(a) mediated promotion of thrombosis in vulner- and international panel of experts. The process began with able plaques of coronary arteries or at sites of stenosis the appointment of an Executive Steering Committee by may increase risk of myocardial infarction (MI), and the Chair of the NLA Scientific Publications Committee. thrombotic emboli may increaseriskofischemicstroke 4 The Executive Steering Committee then selected expert (Fig. 1). panel members and appointed a Scientific Chair. The The cholesterol content of the LDL portion of Lp(a) may Chair and Executive Steering Committee initially drafted promote cholesterol deposition in the arterial intima and at a set of key clinical questions to be addressed that were aortic valve leaflets, leading, respectively, to symptomatic later revised with input from the expert panel members. atherosclerosis resulting in MI and ischemic stroke, and Once the key clinical questions were agreed on, writing VAS (Fig. 1). However, even at very high Lp(a) concentra- assignments were determined based on expertise. After tions such as 100 mg/dL, the cholesterol content of Lp(a) 14 grading the quality and strength of the evidence, final rec- would only amount to 33 mg/dL, which is unlikely to ommendations were drafted that required a consensus of cause substantial deposition of cholesterol in tissues. 60% of the expert panel before being presented to the Although ASCVD and VAS are distinct clinical entities, NLA board for approval. The NLA expert panel graded they have several risk factors in common and similar the recommendations using the American College of Car- pathological processes. Evidence suggests that oxidized diology/American Heart Association Evidence-Based phospholipids (oxPL), which modify Lp(a) primarily by Grading System (Table 1).4 This is the same grading sys- covalent binding to its unique apo(a) component, might tem that was used in the 2018 American College of Cardi- hold the key to Lp(a) pathogenicity and provide a ology/American Heart Association Multisociety Guideline mechanistic link between ASCVD and VAS. Oxidized on Cholesterol Management that was endorsed by the phospholipids co-localize with apo(a)-Lp(a) in arterial NLA.5 In rating the class (or strength) of the recommenda- and aortic valve lesions and may directly participate in tion, consideration was given to the ‘‘net benefit’’ after the pathogenesis of these disorders by promoting Wilson et al Lipoprotein(a)—Scientific Statement 3 Table 1 endothelial dysfunction, lipid deposition, inflammation and patients (70.3 years 6 9.9 years) with VAS found that osteogenic differentiation in valvular interstitial cells higher Lp(a) and oxPL levels significantly increased (VIC)15,16 leading to calcification. Genetic evidence for a markers of disease progression, assessed by multimodal im- contribution of oxPL has been presented,17 and associations aging methods, including the risk for aortic valve replace- between elevated oxPL on Lp(a) and risk for coronary heart ment and death. In vitro studies demonstrated that disease disease (CHD) and valvular aortic stenosis have been de- was mediated by Lp(a)-associated oxPL osteogenic differ- tected.10,18 A recent prospective study of 145 elderly entiation of VIC and further showed that this effect was 4 Journal of Clinical Lipidology, Vol
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