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Future Research Directions on Lipoprotein(a) and Cardiovascular Disease

Meeting Date(s): March 20, 2017 to March 21, 2017

Executive Summary

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.

Discussions

The WG Presentations and discussions focused on the following areas:

  • Lp(a) metabolism
  • Lp(a) pathophysiology
  • Lp(a) measurement
  • Clinical treatment of high levels of Lp(a)
  • Special populations at risk for CVD with high levels of Lp(a)

The WG identified several important challenges and barriers in better understanding the roles of Lp(a) in CVD:

  • Lack of standardization of Lp(a) assays
  • Lack of access to large bio-repositories for biomarker and clinical research
  • Lack of reliable in vitro cell lines and in vivo animal models
  • Few investigators are performing research on Lp(a), despite the potential large health impact of elevated Lp(a) and the high prevalence of atherogenic level globally

Recommendations

The WG recommended to:

  • Explore mechanisms by which NHLBI could facilitate basic, mechanistic, preclinical, and clinical research on Lp(a)
  • Organize a focused working group comprised of a wide array of stake holders, including regulatory agencies, to standardize Lp(a) measurements and ensure the assays’ accuracy and comparability
  • Foster collaborative research and resource sharing, leverage expertise of different groups and centers with complementary skills, methods, and knowledge, and leverage existing resources such as NHLBI cohorts
  • Educate the public, physicians, regulatory agencies, and funding agencies on the role of Lp(a) in CVD
    • Develop an evidence-based management plan for patients
    • Encourage testing Lp(a) with first lipid panel to identify high risk patients
    • Advocate for an ICD-10 code (an International Classification of Diseases, and its codes hold critical information about epidemiology, managing health, and treating conditions) for Lp(a)

    Future research opportunities:

  • Study normal biological function/physiological roles of Lp(a)
    • Study Lp(a) metabolism, such as turnover studies, quantitative role of various receptors involved in Lp(a) clearance, identification of new Lp(a) receptors, and Lp(a) assembly and secretion
    • Evaluate Lp(a) structure, function, and composition
    • Identify methods to optimally purify and study Lp(a) without other contaminating lipoproteins
  • Investigate Lp(a) pathophysiology, including:
    • Lp(a) contribution to oxidation, inflammation, fibrinolysis, and atherogenesis
    • Role of Lp(a)-associated oxidized phospholipids in mediating inflammation, affecting fibrinolysis and atherothrombosis
    • Development of new model systems such as cell culture and animal models that reflect human Lp(a) metabolism (e.g., mouse and pig models)
    • Relationship between triglyceride (TG) and Lp(a), and mechanisms of Lp(a) in diabetes and TG metabolism
    • Lp(a) pathophysiology in different gender/racial/ethnic groups
    • Apo(a) isoforms and SNPs to further define the pathophysiological role of Lp(a)
  • Explore the value of Lp(a) measurement in population and clinical care
    • Predict clinical risk of patients
    • Set risk and therapy thresholds of Lp(a) in different race/ethnic groups
  • Develop novel selective and specific therapies to reduce Lp(a)-mediated risk and further understand mechanisms of current agents/methods that affect Lp(a) levels
    • Define the potential Lp(a)-raising effect of statins
    • Evaluate lifestyle changes (e.g., exercise and various diets) on Lp(a)
    • Define mechanisms of Lp(a)-lowering by PCSK9 inhibition
    • Identify new targets and novel mechanisms of Lp(a)-lowering
    • Develop new therapeutic agents and test Lp(a)-lowering effects with pilot trials
  • Identify the Lp(a)-mediated risk of CVD and explore the underlying mechanisms in special populations
    • Define the role of Lp(a) in patients with familial hypercholesterolemia
    • Elucidate the mechanisms of Lp(a) elevation and risk in chronic kidney disease
    • Explore the relationship between Lp(a) and stroke, especially in children
    • Investigate the role of Lp(a) and associated molecules in the development and progression of AS
    • Further define the role of elevated Lp(a) in high thrombosis-risk patients
    • Examine the role of apheresis in clinical care of patients with elevated Lp(a) and recurrent events

Publication Plans

The working group plans to prepare a manuscript for publication in a peer-reviewed journal.

NHLBI Contacts:

Lijuan Liu, Ph.D.
Simhan Danthi, Ph.D.
Michelle Olive, Ph.D.

Division of Cardiovascular Sciences
National Heart, Lung, and Blood Institute
National Institutes of Health
Phone: 301-435-0582
Email: lliu@mail.nih.gov

Working Group Participants:

Chair: Sotirios Tsimikas, M.D., University of California San Diego

Members:

  • Sergio Fazio, M.D., Ph.D., Oregon Health & Science University
  • Keith Ferdinand, M.D., Tulane Medical Center
  • Henry Ginsberg, M.D., Columbia University
  • Marlys Koschinsky, Ph.D., Schulich School of Medicine & Dentistry, Canada
  • Santica Marcovina, Ph.D., Sc.D., University of Washington
  • Patrick Moriarty, M.D., University of Kansas Medical Center
  • Daniel Rader, M.D., University of Pennsylvania School of Medicine
  • Alan Remaley, M.D., Ph.D., NHLBI
  • Gissette Reyes-Soffer, M.D., Columbia university medical center
  • Raul Santos, M.D., Ph.D., University of Sao Paulo Medical School Hospital, Brazil
  • George Thanassoulis, M.D., McGill University Health Center, Canada
  • Sandra Revill Tremulis, M.B.A., Lipoprotein(a) Foundation
  • Joseph Witztum, M.D., University of California San Diego

Participants from NHLBI:

  • Yves Rosenberg, M.D., NHLBI
  • Scarlet Shi, Ph.D., NHLBI
  • Emmanuel Peprah, Ph.D., NHLBI
  • Ravi Balijepalli, Ph.D., NHLBI
  • Li-Shin Huang, Ph.D., NHLBI
Last Updated: May 30, 2017