NHLBI Working Group
Future Directions in High-density Lipoprotein Research

Executive Summary

The National Heart, Lung, and Blood Institute convened a working group (WG) of expert scientists on April 27-28, 2009 in Bethesda, Maryland, to assess our current understanding of the therapeutic role of altering high density lipoprotein (HDL) and to recommend the direction of future NHLBI supported research in this area.

Discussion

A series of talks were presented:

• Cholesterol Efflux and ABC transporters
• In vivo Reverse Cholesterol Transport (RCT) and HDL Function
• HDL and Atherosclerosis Regression
• Proteomics and Lipidomics of HDL
• Structure and Function of HDL
• Novel Functions and Dysfunctional HDL
• Genome wide association studies
• Apolipoprotein-mimetic Peptides
• Emerging HDL Therapies
• Current Evidence of Clinical Benefit from Raising HDL

A number of challenges and barriers to progress in better understanding HDL specifically, and lipoprotein research generally, were identified.  These included: 1) the topic is considered somewhat scientifically unfashionable and fewer promising young investigators are likely to enter the field;  2) despite extensive epidemiological data showing an inverse relationship between HDL levels and coronary heart disease (CHD), the association of genetic predictors of HDL level do not consistently correlate with CHD events; 3) the failure of torcetrapib (in the ILLUMINATE study) underscores a previously unrecognized complexity to gaining the expected benefit from raising HDL.  Further progress is likely to rest on an improved understanding of the molecular biology of HDL particles.

Based upon its deliberations, the WG reached a consensus on the urgent need for a better understanding of the biology and pathophysiology of HDL, particularly in regard to the relationship of HDL to atherogenesis. The deliberation of the WG also made clear the importance of  accessibility of available biological samples from existing NHLBI-supported clinical trials.

The extensive discussions led to the following recommendations.

Recommendations:

Encourage multidisciplinary and collaborative research approaches to the study of HDL and its role in atherogenesis and develop and evaluate HDL therapies. These studies should include studies that:

• Elucidate HDL functions
  • Define the relative importance of different cellular cholesterol efflux pathways and  their roles in different cell types at various stages of atherogenesis
  • Develop, validate, and standardize reliable and reproducible assays to measure:
    • human serum cholesterol efflux capacity
    • in vivo RCT, particularly in humans
    • “pro-inflammatory” HDL or “dysfunctional” HDL
  • Understand the effect of HDL on monocyte-macrophage trafficking in lesions
  • Investigate cellular and molecular mechanisms linking HDL to other athero-protective properties of HDL such as anti-inflammatory, antioxidant, antiapoptotic, antithrombotic, and vasodilating abilities in endothelial cell, T cells, and other cells
  • Identify proteins in HDL that could serve as biomarkers for CVD using proteomics strategy such as mass spectrometry, protein arrays, and other quantitative techniques.
• Evaluate genetic determinants of HDL and its significance in clinical atherosclerotic disease
  • Define causal genes by deep sequencing in humans and/or by systematic study of novel HDL genes in model organisms and elucidate the mechanisms by which the novel genes affect HDL metabolism
  • Identify genes that are related to plasma HDL-C conferring risk for CVD  in population-based and case-control studies
  • Establish newer HDL-related biomarkers based on genetic variants
  • Map new genes related to HDL function (not only plasma HDL-C) such as RCT
• Establish HDL as a therapeutic target and assess its effectiveness
  • Develop reliable methods for production of both mutant and wild-type apoA-I, with administration either by itself or in lipidated particles
  • Understand the impact of transcriptional factors on apolipoproteins, additional proteins and remodelling factors involved in RCT
  • Explore the therapeutic potential of oral delivery or parenteral administration of protein, mimetic peptide or lipidated particles
  • Evaluate modulators of HDL functionality and their roles in atherogenesis
  • Develop methods of assessing HDL therapeutics such as optimal use of arterial imaging and RCT in humans

Publication Plans:

The working group meeting summary is planned for publication in a peer-reviewed journal.

NHLBI Contacts:

Lijuan Liu, Ph.D., NHLBI, NIH
lliu@mail.nih.gov

Michael J. Domanski, M.D., NHLBI, NIH
domanskimj@mail.nih.gov

Working Group Members:

Chair:
Alan Tall, M.D., Columbia University

Members:

• G.M. Anantharamaiah, Ph.D., University of Alabama at Birmingham
• Bruce Gregory Brown, M.D., Ph.D., University of Washington
• Edward Fisher, M.D., Ph.D., New York University
• Jay Heinecke, M.D., University of Washington
• Sekar Kathiresan, M.D., Massachusetts General Hospital
• Stephen Nicholls, MBBS, Ph.D., Cleveland Clinic
• Daniel Rader, M.D., University of Pennsylvania
• Mary Sorci-Thomas, Ph.D., Wake Forest University

Last updated: October 5, 2009