The National Heart, Lung, and Blood Institute (NHLBI) convened a workshop on September 7-8, 2010 in Bethesda, Maryland titled: Defining Molecular Pathways and Mechanisms that Predict Cardiovascular Disease (CVD) Risk Associated with Sleep Disordered Breathing (SDB). The goals of the workshop were to: 1) identify opportunities and new strategies to advance interdisciplinary research on the role of sleep apnea and short sleep duration on antecedents and progression of cardiometabolic disease (CMD) during early and middle adulthood focused on the molecular and systemic pathways associated with inflammation and oxidative stress; 2) stimulate the cross-fertilization of science between traditionally distinct research communities, (i.e., cardiology, pulmonary sleep, circadian, and endocrine); 3) accelerate the identification of novel translational approaches to elucidate mechanisms linking SDB and cardiovascular disease (CVD) risk.
Sleep, Circadian and Neuroendocrine Mechanisms of Energy Metabolism
Recent studies clearly demonstrate that insufficient and poor quality sleep and circadian misalignment increase risk of cardiometabolic disease and disease pathogenesis including, glycemic control, hyperlipidemia and overweight. The risk of cardiometabolic disease may be mediated by abnormalities in circadian-coupled genomic regulation in virtually all body systems including the liver, kidney, endothelium and heart. There appear to be co-regulatory and feedback systems among the clock genes and the suprachiasmatic nucleus (the central circadian pacemaker), that contribute to energy metabolism, adipose, lipid and endocrine signaling. These mechanisms may partially account for the CVD and cardiometabolic risk that has been associated with SDB, sleep disruption, and circadian misalignment in shift work.
- Develop animal-human translational models for proof of concept studies.
- Prioritize Sleep and Circadian (SaC) independent variables (e.g., circadian misalignment, sleep disruption, sleep restriction, intermittent hypoxemia) and develop models related to human disorders.
- Elucidate intermediate and surrogate markers associated with SaC disregulation and the effect sizes associated with CVD and CMD (e.g., inflammatory markers, lipid).
- Develop disease relevant models to study central and peripheral cross talk in clock gene transcription.
Cardiovascular and SDB Pathophysiology
Multiple lines of evidence associate SDB with CVD and an increased risk of incident CVD events. However, the specific contributions of SaC disruptions to mechanisms of CVD pathogenesis, and particularly high risk phenotypes, and vulnerable periods have only recently been the focus of research. A key interim step to the development of these models requires selection of the most salient mechanisms of CVD progression that are have hypothesized links to SDB and circadian misalignment.
- Focus scientific investigations on key variables that are candidates for linking SDB, sleep disruption, and circadian misalignment to CVD pathogenesis: the inflammatory reflex, intermittent hypoxemia, autonomic instability, central and peripheral hypertension, arterial stiffness.
- Define individual protective and high risk factors that account for CVD pathogenesis and are relevant to SaC disturbances.
Intermediate Molecular Markers of CVD and SDB
Selection of biomarkers linking SaC disruption to CVD is a critical step in the development of models of CVD and CMD pathophysiology and methodology for clinical trials. While there are numerous candidates, models of disease pathogenesis and clinical trial design may be the key factors that will guide and organize approaches to prioritizing biomarkers in basic, epigenetic clinical research.
- Particularly high priority areas include the evaluation of markers of: cardiac structure, autonomic function, inflammation, vascular injury, platelet aggregation.
- Define effect sizes for markers of CVD (from lab-based molecules to clinical measures) that are modifiable through SDB treatment modalities.
- In SaC science, two of the highest priority areas of focus are intermittent hypoxia and the interaction of sleep disruption and the function of clock genes in central and peripheral tissue.
Additional discussion of the barriers to multidisciplinary collaboration pointed toward the need for training and re-specialization opportunities for established investigators in sleep and circadian biology.
Working Group Members
- Atul Malhotra, M.D., Harvard University
- Muredach P. Reilly, MBBCH, MSCE, University of Pennsylvania
- Craig S. Anderson, M.D., University of Sydney
- Alan D. Attie, Ph.D., University of Wisconsin-Madison
- Ferran Barbe, M.D., Hospital Univ. Arnau de Vilanova
- Doug Bradley, M.D., Toronto General Hospital
- David A. Calhoun, M.D., University of Alabama Hospital
- Eve Van Cauter, M.D., University of Chicago
- Julio A. Chirinos, M.D., Hospital of the University of Pennsylvania
- Giovanni Cizza, Ph.D., National Institute of Diabetes, Digestive and Kidney Diseases
- Sonya Craig, MRCP, Churchill Hospital
- Christiane Ferran, M.D., Ph.D., Harvard Medical School
- Kathy Taylor Griendling, Ph.D., Emory University
- Martica Hall, Ph.D., Western Psychiatric Institute and Clinic
- John Hogenesch, Ph.D., University of Pennsylvania School of Medicine
- Sanja Jelic, M.D., Columbia University
- Suraj Kapa. M.D., Hospital of the University of Pennsylvania
- Brendan Keating, Ph.D., University of Pennsylvania
- Samuel T. Kuna, M.D., University of Pennsylvania Medical Center
- Clete A. Kushida, M.D., Ph.D., Stanford Sleep Medicine Center
- Doug McEvoy, M.D., Repatriation General Hospital
- Alan D. Michelson, M.D., Harvard Medical School
- Allan I. Pack, M.B.Ch.B., Ph.D., University of Pennsylvania
- Mac A. Pfeffer, M.D., Ph.D, F.A.C.C., Harvard Medical School
- Vsevolod Y. Polotsky, M.D., The Johns Hopkins Outpatient Center
- Naresh M. Punjabi, M.D., Ph.D., Johns Hopkins University School of Medicine
- Susan Redline, M.D., MPH, Harvard Medical School
- Thomas Rice, M.D., University of Pittsburgh Medical Center
- R. Daniel Rudic, Ph.D., Medical College of Georgia
- Philipp E. Scherer, Ph.D., University of Texas Southwestern Medical Center
- Frank A.J.L. Scheer, Ph.D., Harvard Medical School
- Lawrence I. Sinoway, M.D., Penn State Milton S. Hershey Medical Center
- Virend Somers, M.D., Mayo Clinic
- Kevin J. Tracey, M.D., The Feinstein Institute for Medical Research
- Sigrid C. Veasey, M.D., DABSM, University of Pennsylvania
- James Kiley, Ph.D., MS., Director, Division of Lung Diseases
- Michael S. Lauer, MD, FACC, FAHA, Director, Division of Cardiovascular Sciences
- Daniel Lewin, Ph.D., Director Sleep Disorders Medicine, DLD
Last Updated April 2011