Introduction

Promoting cardiovascular health across the lifespan is a priority of the NHLBI. In 2016, NHLBI unveiled its Strategic Vision after engaging nearly 4,500 diverse scientists and stakeholders from across the U.S. and 42 countries around the globe. The unprecedented number of ideas resulted in 4 research goals and 8 objectives, with each objective having critical research questions and challenges that collectively formed the Strategic Vision. Information on the NHLBI Strategic Vision is in this link: https://www.nhlbi.nih.gov/about/strategic-vision

Discussions

After brief introductions and charge, the workshop focused on three main discussion topics:

1. What are the biological underpinnings (i.e. genetic, epigenetic, and environmental (e.g. social, physical, home) and factors that predict cardiovascular health (CVH) or that influence the emergence of a clinical phenotype of children who go on to get cardiovascular disease (CVD)?
2. What are the predictors of cardiovascular health and social determinants indicators (including vulnerable populations) that should be included in interventions in early childhood?
3. What research opportunities should we stimulate that would integrate basic, population and clinical research for the promotion of cardiovascular health in childhood?

Structure of the Workshop

The program was structured to address each of these questions from the perspectives of the 3 research domains. General discussions followed each set of presentations. Together, this process generated a rich array of ideas, highlighted here:

Basic science:  Participants discussed the state of the science, research gaps and future research recommendations related to environmental exposures, genetic and epigenetic factors and microbiota changes in childhood and adolescence. Presenters noted lack of, or limited evidence about, these factors in childhood and adolescence and their contributions to cardiovascular health. Biomarkers including novel inflammatory markers were discussed, as well as the effects on cardiovascular health of the timing of sleep and sleep duration, night light exposures, diet, early life stressors, alteration in the biological clock and human circadian systems. The evidence linking vitamin D and cardiovascular health, particularly in African American children, was discussed as a case example. The need to examine racial disparities and the causal relationships among vitamin D, other nutrients and cardiovascular health was emphasized.

Clinical science: Participants discussed implementation research and interventions that should be considered in early childhood and in the transitions through adolescence. Presentations were on the application of positive cardiovascular health, behavioral approaches to health promotion, adaptive interventions, policy and environmental factors, sleep factors in cardiometabolic health, home visitation by nurses to improve health of mothers and children, and community-based interventions.  Research recommendations include the need to match interventions with individual needs and account for developmental factors including sensitive periods of adversity exposures and stress. Research gaps included limited knowledge on long-term effects of sleep abnormalities on cardiometabolic health and the mechanisms underlying pediatric sleep-cardiovascular risk relationships. Other gaps are limited knowledge of the influence of policy and environmental factors on cardiovascular health.

Population science:  Participants discussed evidence-based association and predictors of cardiovascular health that should be included in interventions in early childhood and noted research gaps. Discussions focused on prenatal, paternal and maternal influences; challenges in promoting ideal cardiovascular health in children; emerging technologies; and social determinants of health and childhood adversities. It was emphasized that prenatal factors are related to offspring outcomes, although effects vary by exposures and there are research gaps related to inter- and trans-generational influences and their effects on cardiovascular health. Primordial prevention, which emphasizes the need to promote and preserve cardiovascular health from the beginning of life was discussed as was a novel approach to addressing cardiovascular health by integrating cardiovascular health and positive psychology (positive cardiovascular health).  Participants emphasized the need to study the potential benefits of integrating cardiovascular health and brain health early in life to help preserve ideal cardiovascular health in children from birth forward. This includes assessment of neurodevelopment and fostering healthy lifestyle and coping techniques.   Participants also emphasized the importance of considering novel technologies, ecological momentary sampling techniques, or artificial intelligence to study the effects of adverse childhood experiences and other stressors on cardiovascular health. Research gaps identified include the need to consider these factors as well as research that focuses on positive cardiovascular health and on preserving ideal cardiovascular health from early life through adulthood.

Integration and synergy:

In addition to the 3 distinct research domains, participants discussed their integration to achieve an integrated and synergistic approach to promoting cardiovascular health in childhood and adolescence. This would require innovative approaches to training and career development with the goal of establishing a new generation of researchers in basic, population, and clinical sciences research.

Recommendations:

To identify a priority set of cross-cutting research topics, organizers assigned each participant to one of 3 interdisciplinary discussion groups. In a breakout session, each group identified three top areas for research; in joint discussion, topics emerged that were common across the groups. These concerned metrics, mechanisms, and means of improving cardiovascular health equity, including overcoming disparities related to race/ethnicity, poverty, or adverse childhood experiences. (A more detailed discussion of research recommendations is expected to be published in a peer-reviewed journal.)​​​​

1. What are basic ideal cardiovascular health metrics for different age groups?
   1. Basic- novel biomarkers and their trajectories
      1. Identify novel biomarkers and their trajectories in childhood through adolescence and conduct research to investigate the influence of early life environmental exposures and microbiome on CVD risk factors.
      2. Conduct research to investigate the influence of early life environmental exposures and microbiome on risk factors for cardiovascular disease and factors to maintain cardiovascular health in childhood and adolescence.
   2. Population- predictors of cardiovascular health
      1. Examine the relationships among diet, physical activity, food environment, and built environment and their contributions to ideal cardiovascular health promotion.
      2. Conduct research that addresses appropriateness of current recommended cutoffs of ideal health metrics [plus new measures] to better understand cardiovascular health trajectories in childhood and adolescence and identify the appropriate measures from birth through adulthood. Optimize and validate ideal cardiovascular health metrics from the beginning of life through early childhood and beyond.
   3. Clinical – Implementation science research
      1. Conduct studies that emphasize implementation science research and include cost effectiveness and cost benefits of maintaining ideal cardiovascular health.
      2. Conduct clinical and community trials and demonstrations to test short-term improvements in CVH metrics in children and adolescents.
2. What are the mechanisms of maintenance/loss of cardiovascular health
   1. Basic – Functional genomics, omics and vascular research
      1. Determine the mechanisms underlying the pediatric sleep-cardiovascular risk relationships and how sleep and disordered breathing affect central cardiovascular control.
      2. Identify functional pathways with altered genetics/epigenetics in children that go on to develop disease to better understand etiology and inform interventions.
   2. Population – Critical leverage points, gene-environment, and public health implication
      1. Gene-environment interactions identified for adult cardiovascular disease should be considered for investigation in children and adolescents.
      2. Explore the role of other nutrients (i.e. anti-oxidants), diet and physical activity on cellular and humoral phenotypes of adiposity and their relevance of cardiovascular health promotion.
   3. Clinical – New treatments and how to translate into clinical practice
      1. Conduct studies to test whether non-obstructive sleep apnea, and sleep disorders affect children’s cardiovascular risk and to determine whether the effect of sleep on cardiovascular risk is modified by other factors (e.g. genetic, environment).
      2. Test interventions that examine the beneficial effects of diet that are tailored based on weight, lipids, blood pressure or blood glucose and determine which diets are most acceptable and sustainable, culturally, by age and by socio-economic status.
      3. Conduct studies that would integrate family, school and clinic efforts to improve diet in childhood through adolescence.
3. How does adversity in early life influence cardiovascular health equity then and later in the life course?
   1. Basic – normative data on biomarkers and adversity at different life stages/ages
      1. Studies that use large data sources consisting of diverse racial/ethnic minorities or low SES populations to better understand measures of stress and mechanisms related to stress and cardiovascular health in children and adolescents.
      2. Conduct studies on the mechanisms of Early Life Adversity (ELA) and impact on cardiovascular health.
   2. Population – differential response to environment by adversity
      1. Longitudinal studies that examine the impact of pubertal development, various theoretical models (timing, mechanisms), within-vulnerable populations, ELA, epigenetics and cardiovascular health.
   3. Clinical – interventions that narrow the health equity gap, consider adversity
      1. Test interventions to determine what level of intervention is needed such as home visiting, peer coaching, videos, etc. and to match the intervention to need.
      2. Conduct interventions that: a) account for developmental factors, sensitive periods of stress/adversity exposure, and models individual child differences (including biology), b) are sustainable, and c) engages vulnerable and under-resourced parents to foster intergenerational health and well-being.

Overarching themes

• Consistent with the purpose of the Workshop, attention was given to the value of interdisciplinary communication, as exemplified by the Workshop itself and to interdisciplinary training, to bridge basic, clinical, and population research within novel research program design.  There is a need for experiential research training opportunities for high school students and higher education institutions for postdoctoral training including training of medical students, and residents in lifestyle medicine, behavior change, prevention, diet, and physical activity.

• Above all, the Workshop pointed the way to advance science, policy, and practice to achieve improved cardiovascular health for all within the next generation.

Selected References

1. Becher H, Palm F, Aigner A, Safer A, Urbanek C, Buggle F, Grond-Ginsbach C, Grau AJ. Socioeconomic Conditions in Childhood, Adolescence, and Adulthood and the Risk of Ischemic Stroke. Stroke. 2016;47:173-179. DOI: 10.1161/STROKEAHA.115.011523. (CONCLUSIONS: This study supports the hypothesis that unfavorable childhood socioeconomic conditions are related to ischemic stroke risk, independent of established risk factors and socioeconomic status in adulthood, and fosters the idea that stroke prevention needs to begin early in life.).

2. Eckenrode J, Campa M, Luckey DW, Henderson CR, Cole R…Olds D. Long-term Effects of Prenatal and Infancy Nurse Home Visitation on the Life Course of Youths 19-Year Follow-up of a Randomized Trial. Arch Pediatr Adolesc Med. 2010;164(1):9-15. (CONCLUSIONS: Prenatal and infancy home visitation reduced the proportion of girls entering the criminal justice system. For girls born to high-risk mothers, there were additional positive program effects consistent with results from earlier phases of this trial. There were few program effects for boys).

3. Rajakumar K, de las Heras J, Chen TC, Lee S, Holick MF, Arslanian SA. Vitamin D status, adiposity, and lipids in black American and Caucasian children. J Clin Endocrinol Metab 2011;96:1560-7.

4. Labarthe D, Kubzansky LD, Boehm JK, Lloyd-Jones D, Berry JD, Seligman MEP. Positive cardiovascular health: A timely convergence. JACC 68 (8), 860-867, 2016.

5. Laitinen TT, Pahkala TJ, Magnussen CJ, Oikonen M, Viikari JS, Sabin MA, Daniels SA, et al. Lifetime measures of ideal cardiovascular health and their association with subclinical atherosclerosis: The Cardiovascular Risk in Young Finns Study. International Journal of Cardiology 185 (2015) 186–191. (CONCLUSIONS: The results show that ideal cardiovascular health (ICH) can be lost and regained, and importantly that regaining of ICH has a beneficial effect on cardiometabolic health. Health care providers should work to improve health behaviors especially in those who have lost ICH).

6. Steinberger J, Daniels SR, Hagberg N, Isasi CR, Kelly AS, Lloyd-Jones D, Pate RR, Pratt C, Shay CM, Towbin JA, Urbina E, Van Horn LV, Zachariah JP. Cardiovascular Health Promotion in Children: Challenges and Opportunities for 2020 and Beyond: A Scientific Statement From the American Heart Association. Circulation. 2016 Sep 20;134(12):e236-55. doi: 10.1161/CIR.0000000000000441

7. Suglia SF, Koenen KC, Boynton-Jarrett R, Chan PS, Clark CJ, Danese A, Faith MS, Goldstein BI, Hayman L, Isasi C, Pratt CA, Slopen N et al. Childhood and Adolescent Adversity and Cardiometabolic Outcomes: A Scientific Statement from the American Heart Association. Circulation. 2018 Jan 30;137(5):e15-e28. doi:10.1161/CIR.0000000000000536.

Meeting Participants:

Workshop Chair

• Stephen R. Daniels, MD, PhD, Professor and Chair, Department of Pediatrics, University of Colorado School of Medicine, Pediatrician-in-Chief Children’s Hospital of Colorado

Co-Leads

• Cashell Jaquish, PhD, Statistician, NHLBI, Epidemiology Branch
• Brian Kit, MD, MPH, Medical Officer, CDR, United States Public Health Service, NHLBI, Epidemiology Branch
• Charlotte Pratt, PhD, RD, FAHA, Deputy Branch Chief, NHLBI Clinical Applications and Prevention Branch

Speakers

• P. Babu Balagopal, PhD, Nemours Children’s Clinic, Mayo Clinic College of Medicine
• Dean W. Beebe, PhD, Professor of Pediatrics, University of Cincinnati College of Medicine,  Cincinnati Children’s Hospital Medical Center
• Bettina M. Beech, Dr PH, MPH, Dean, John D. Bower School of Population Health, Executive Director, Myrlie Evers-William Institute for the Elimination of Health Disparities, University of Mississippi Medical Center
• Deborah A. Cohen, MD, MPH, RAND Corporation
• Glenn H. Dillon, PhD, Director, Research Operations, Office of Science Operations, American Heart Association National Center
• W. Timothy Garvey, MD, Butterworth Professor and Chair, Department of Nutrition Sciences, GRECC Investigator & Staff Physician
• Matthew W. Gillman, MD, SM, Program Director, Environmental Influences on Child Health Outcomes (ECHO)
• Jaclyn Goodrich, PhD, Research Assistant Professor Department of Environmental Health Sciences, University of Michigan School of Public Health
• William Heerman, MD, MPH Assistant Professor of Pediatrics, Vanderbilt University Medical Center
• Emily B. Hollister, PhD, VP, Information Technology & Analytics, Diversigen, Inc.
• Michael Knudtson, MS, Research Associate/Biostatistician, Director, Biostatistics and Data Operations, Prevention Research Center for Family and Child Health
• Darwin Labarthe, MD, PhD, MPH, Professor of Preventative Medicine, Northwestern Medicine Feinberg School of Medicine
• Alison L Miller, PhD, Associate Professor, Health Behavior & Health Education, Research Associate Professor, Center for Human Growth and Development, University of Michigan School of Public Health
• David Olds, PhD, Professor of Pediatrics and Director, Prevention Research Center for Family and Child Health
• Emily Oken, MD, MPH, Professor of Population Medicine at Harvard Pilgrim Health Care Inc.
• Voula Osganian, MD, ScD, MPH, Pediatric Clinical Obesity Program Director, Division of Digestive Diseases Nutrition
• Kumaravel Rajakumar, MD, MS, Associate Professor of Pediatrics, Children’s Hospital of Pittsburgh, Division of General Academic Pediatrics, University of Pittsburgh School of Medicine
• Nancy E. Sherwood, PhD, University of Minnesota, School of Public Health and Senior Investigator, Director of Scientific Development, Research, Health Partners Institute
• Donna Spruijt-Metz, MFA, PhD, Director, USC mHealth Collaboratory Center for Economic and Social Research, Research Professor Psychology and Preventative Medicine
• Julia Steinberger, MD, Pediatric Cardiologist, University of Minnesota
• Shakira F Suglia, ScD, Emory University Rollins School of Public Health, Department of Epidemiology
• Perdita Taylor-Zapata, MD, Pediatric Medical Officer, Obstetric and Pediatric Pharmacology and Therapeutics Branch, NICHD, NIH
• Susan Teitelbaum, PhD, Professor, Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai
• Elaine M. Urbina, MD, MS, Director, Preventative Cardiology, Cincinnati Children’s Hospital Medical Center, Cincinnati Children’s
• Linda Van Horn, PhD, RD, Professor of Preventative Medicine, Associate Dean for Faculty Development, Department of Preventative Medicine Northwestern University
• Dianne Ward, PhD, University of North Carolina, Chapel Hill
• Martin E. Young, PhD, Professor of Medicine, University of Alabama At Birmingham

NIH Staff

• Sonia Arteaga, PhD, Program Director, NHLBI Clinical Applications and Prevention Branch
• Josephine Boyington, PhD, Health Scientist Administrator, NHLBI, Clinical Applications and Prevention Branch
• Kristin Burns, MD, Medical Officer, NHLBI, Heart Development and Structural Disease Branch
• Rebecca Campo, Health Scientist Administrator, NHLBI, Clinical Applications and Prevention Branch
• Shu Chen, PhD, Scientific Program Specialist, NHLBI, Program in Prevention and Population Sciences
• Lawrence J. Fine, MD, DrPH, Branch Chief, NHLBI Clinical Applications and Prevention Branch
• David Goff, MD, PhD, Director, Division of Cardiovascular Sciences, NHLBI
• John Kunz, Scientific Program Analyst, NHLBI, Epidemiology Branch
• Huiqing Li, MD, PhD, Program Fellow, NHLBI Advanced Technology and Surgery Branch
• Charlene Schramm, PhD, Health Scientist Administrator, NHLBI Heart Development Structural Diseases Branch
• Jenelle Walker, PhD, MS, CTRIS, Office of the Director
• Gina Wei, MD, Associate Director, NHLBI Division of Cardiovascular Sciences
• Ye Yan, PhD, Research Fellow, NHLBI Laboratory of Molecular Biology
• Carol Blaisdell, MD, Program Director, ECHO