NHLBI Workshop
Pediatric Sleep Disturbances and their Contribution to Developmental Pathophysiology of Cardiometabolic Risk

Executive Summary

Introduction

The National Heart, Lung, and Blood Institute (NHLBI) convened a working group on September 9, 2010 in Bethesda, Maryland titled: Pediatric Sleep Disturbances and their Contribution to Developmental Pathophysiology of Cardiometabolic Risk. The goals of the workshop were to: 1) identify opportunities and new strategies to advance interdisciplinary research on the role of sleep disordered breathing (SDB), short sleep duration and circadian disruption on the development and progression of cardiovascular disease (CVD) and cardiometabolic disease (CMD) during childhood; 2) stimulate the cross-fertilization of science between traditionally distinct research communities, (i.e., pediatric cardiology, pediatric pulmonology, sleep medicine, circadian biology and pediatric endocrinology); 3) accelerate the identification of novel translational approaches to elucidate mechanisms linking SDB, short sleep duration and circadian disruption in childhood to increased cardiometabolic and cardiovascular disease risk; 4) define high risk phenotypes and developmental critical periods for poor CVD and CMD outcomes; and 5) prioritization of intermediate markers and biomarkers of CVD and CMD in children that should be the focus of future research.

Summary and Overview


Sleep Disordered Breathing (SDB)

Children experience insufficient sleep, circadian disruption and SDB, of which the latter may pose the greatest and most immediate risk to health. There are diverse physiological effects of SDB including;swings in intrathoracic pressure, intermittent hypoxia, rapid changes in autonomic tone, and recurrent arousals that, in adults, are associated with increased risk of cardiovascular and cardiometabolic disease. In adults, these sleep-related derangements are associated with pathological changes in autonomic function, endothelial function, blood pressure regulation, obesity, and metabolism, but currently there is scant evidence of their contribution to adverse outcomes during childhood or to disease pathogenesis throughout the life span.

Sleep Health: Sleep Duration and Timing

Sleep duration and circadian regulation change across development and there appear to be individual differences in both sleep need and the timing of sleep that may play a critical role in development and are markers of maturation. There is evidence that adults who fall at the extremes of sleep duration or spend many years as shift workers may have higher risk of morbidity. The effects of deficient sleep on children are not known, but are a major concern because of a broad national trend for children to obtain inadequate sleep. A prime example of a disturbance in sleep duration and timing occurs during adolescence when there is a biologically mediated delay in the sleep period that conflicts with early school start times. Given evidence of the prevalence of deficient sleep and poor sleep health among youth, there is an urgent need to better characterize the environmental and biological determinants of short sleep, to define optimal sleep needs (both timing and duration) across the pediatric age range, and to design and test interventions aimed at improving sleep in children, especially those at high risk for obesity and cardiometabolic dysfunction. Special consideration may be given to health disparities, socio-cultural and environmental factors genetic and intrinsic biological differences.

Recommendations


Sleep Disordered Breathing Cardiovascular and Cardiometabolic Pathophysiology:

  • Links between SDB, deficient sleep and CVD risk factors are well established in adults, yet there is scant evidence for these associations in children. Research is needed to define the contribution of SDB to cardiovascular pathophysiology. Because some pathological mechanisms leading to CVD become less reversible over time, special consideration of development, critical periods and phenotypes at high risk are important for future planning of prevention and treatment trials.
  • There are established cardiovascular biomarkers of CVD risk in childhood. Research is needed to validate cardiovascular biomarkers as surrogate endpoints for subsequent clinically significant disease in children with OSA. Establishing effect sizes and prioritizing biomarkers will establish the basis for future studies including clinical trials and epidemiology studies
  • Specific pathophysiological mechanisms such as chronic intermittent hypoxia, while well-studied in adults, remain poorly understood during infancy, childhood, and adolescence. Research is needed in animal to human translation models and in infants and children to define the mechanisms that lead to CVD disease pathophysiology.
  • The metabolic consequences of SDB in children remain poorly understood and there are multiple fundamental areas of needed scientific investigation. Research is needed to define the mechanistic links and test the direction of the causal association between SDB effects (e.g., intermittent hypoxia, autonomic disregulation, and arousal, and inflammation) on pathological mechanisms of CMD.
  • Research is needed to determine whether SDB plays a causal role in the development and severity of type 2 diabetes and/or complicates management of type 1 diabetes. In particular, future studies must carefully consider the confounding effects of central obesity in examining the link between SDB and alterations in glucose metabolism.
  • Other related research directions include, studying the effects of SDB associated with the development of steatohepatitis, insulin resistance and fatty liver.
  • Research is needed to define the impact of deficient sleep and poor sleep health associated with alterations in the 24 hour variation in leptin, ghrelin, adiponectin and other biochemical regulators of energy metabolism (e.g., hunger, glucose regulation, and adipose deposition). Are there specific sensitive periods in development and individual vulnerabilities (overweight, family history of diabetes, etc.) that account for these alterations and are there associated alterations in markers of cardiometabolic risk?

Short Sleep Duration and Circadian Disorders of Childhood:

  • Given the significant changes in sleep and circadian regulation from conception through adolescence, research is needed to evaluate developmental changes in sleep duration and timing from conception through adolescence and their links to a variety of pediatric health outcomes. Selection of sleep and circadian linked biomarkers, intermediate mechanisms, and definitions of at-risk phenotypes are needed to establish the foundation for future studies of normal development and pathological conditions.
    • Examples of research that have ecological validity and some precedent in adult populations include: studying extremes of sleep duration and timing of sleep on decrements in health and neurobehavioral function in children and adolescents; or protocols utilizing optimized or “healthy sleep” as a complementary intervention to traditional interventions in health promotion/disease prevention programs geared to infants, children and adolescents.
    • Fundamental questions about the interplay between development and circadian biology remain unanswered. Research is needed to understand the developmental trajectory of circadian regulation from the contributions of molecular clocks in cells to the broader regulatory function of the central circadian pacemaker. Specifically, how circadian and clock functions are related to other aspects of cell, tissue or systems development.

Workshop Roster


Co-Chairs

  • John L. Carroll, M.D., University of Arkansas for Medical Sciences
  • Sonia Caprio, M.D., Yale University

Participants

  • Raouf S. Amin, M.D., Cincinnati Children’s Hospital
  • Fred C. Davis, Ph.D., North Eastern University
  • Bonita Falkner, M.D., Thomas Jefferson University Medical School
  • Matthew W. Gillman, M.D., Harvard University School of Medicine
  • Steven Lipschultz, M.D.,  University of Miami, School of Medicine
  • Atul Malhotra, M.D., Brigham and Women’s Hospital, Harvard Medical School
  • Usha Raj, M.D., University of Illinois, Chicago
  • Susan Redline, M.D., M.P.H., Harvard University, School of Medicine
  • Alexander  Vgontzas, M.D., Penn State, Hershey Medical Center

NHLBI Staff

  • Daniel Lewin, Ph.D., Division of Lung Diseases


Last Updated July 2011

 

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