Right Heart-Pulmonary Vascular Interactions in Bronchopulmonary Dysplasia

Summary

Principal Investigator: Marlowe Eldridge
Abstract: DESCRIPTION (provided by applicant): Premature birth is a major health care problem, affecting approximately 12% of all births and contributing to more than 85% of all perinatal complications and deaths. Survival of very low birth weight (VLBW) infants has increased, however, these infants remain at risk for long-term medical problems including neurocognitive impairment and bronchopulmonary dysplasia (BPD). Each year 15,000 newborns develop BPD, a chronic lung disease that affects VLBW infants (<1500 grams) who need long-term mechanical ventilation and oxygen therapy. The subsequent lung injuries impair the growth and development of the airways and pulmonary vasculature, leading to a decrease in the air exchanging units of the lung and fewer blood vessels that can participate in exchanging CO2 and O2. Unfortunately, little is known about the long-term cardiopulmonary consequences of BPD. We postulate that a compromised lung vasculature, present in newborns with BPD, will persist to some extent as these patients age. We expect that children and adults with a history of BPD will have abnormal pulmonary vascular function, particularly when the lungs are challenged, which will place excess stress on the right heart. We anticipate that abnormal pulmonary vascular-right heart interactions in BPD will cause right heart dysfunction and increase the potential for right heart failure in adults with a history of BPD. In this grant we am to determine the impact of BPD on 1) the pulmonary vasculature, 2) right heart function, and 3) the efficiency with which the right heart and pulmonary vasculature interact. To accomplish these aims, we will study humans with and without a history of BPD as well as a rat BPD model. We have access to two unique human cohorts (born in 1988-1991 and 2003) of serially followed VLBW infants, which will allow us to assess the impact of prematurity and early life events on the progression of right heart and pulmonary vascular dysfunction into childhood and early adulthood. To answer our questions, we propose to use a combination of state-of-the-art MR imaging, right heart catheterization, 3D echocardiography and exercise to reveal any abnormalities in the pulmonary vasculature, right heart, and their interactions in our BPD cohort compared to healthy, controls. In our animal model, we will assess the hemodynamic impact of BPD in both intact rats and isolated rat lungs. Furthermore, we will determine at cellular and molecular levels how BPD affects the contractility of the right heart, through length- tension experiments and protein analysis. We expect that our findings will be exciting to clinicians who care for the growing population of those with BPD, biomedical engineers interested in novel diagnostic and prognostic indicators based on cardiopulmonary hemodynamics, and scientists investigating the causes and consequences of right ventricular failure in chronic lung diseases. PUBLIC HEALTH RELEVANCE: A too frequent consequence of premature birth is a chronic lung disease known as bronchopulmonary dysplasia (BPD). A group of well-studied very low birth weight infants (1-3 pounds), including those who did and did not develop BPD, are now reaching adulthood. We have a unique and important opportunity to investigate the consequences of BPD on lung and right heart function in this population, which will inform treatment strategies and predictions of disease progression in the future.
Funding Period: 2012-09-01 - 2017-06-30
more information: NIH RePORT

Top Publications

  1. pmc Ventilatory control in infants, children, and adults with bronchopulmonary dysplasia
    Melissa L Bates
    Department of Pediatrics, Division of Critical Care, University of Wisconsin, Madison, WI, USA John Rankin Laboratory of Pulmonary Medicine, University of Wisconsin, Madison, WI, USA Electronic address
    Respir Physiol Neurobiol 189:329-37. 2013

Detail Information

Publications1

  1. pmc Ventilatory control in infants, children, and adults with bronchopulmonary dysplasia
    Melissa L Bates
    Department of Pediatrics, Division of Critical Care, University of Wisconsin, Madison, WI, USA John Rankin Laboratory of Pulmonary Medicine, University of Wisconsin, Madison, WI, USA Electronic address
    Respir Physiol Neurobiol 189:329-37. 2013
    ..As a secondary goal, we also identify three key areas of future research and describe the benefits and challenges of longitudinal human studies using well-defined patient cohorts...

Research Grants34

  1. The unique role of IkBa in modulating NF-kB activity in the newborn lung.
    CLYDE JASON WRIGHT; Fiscal Year: 2013
    ..Interventions aimed at preventing the development of BPD will reduce the impact of this major public health burden. ..
  2. Rebuilding the Failing Heart
    Piero Anversa; Fiscal Year: 2013
    ..abstract_text> ..
  3. Mechanisms of PMN and Endothelial-Mediated Lung Inflammation and Injury
    Asrar B Malik; Fiscal Year: 2013
    ..abstract_text> ..
  4. INNATE AND ADAPTIVE IMMUNE RESPONSES IN TH2-HIGH ASTHMA
    John V Fahy; Fiscal Year: 2013
    ..Including studies in human biospecimens in a PPG that promises to advance understanding of airway TH2 inflammation in ways that are highly relevant to patients with asthma. ..
  5. Right Ventricular-Pulmonary Vascular Interactions in Pulmonary Hypertension
    Naomi C Chesler; Fiscal Year: 2013
    ..1 ..
  6. Functional and Biological Phenotyping of Pediatric PH
    Robin Shandas; Fiscal Year: 2013
    ..As in prior work, we believe methods, questions and results generated from this study should help guide mechanistic studies to elucidate specific pathways of RV and RV-PA decompensation. ..
  7. Fibroblasts and Mononuclear Fibrogenic Cells Drive Right Ventricular Pulmonary Ar
    Kurt R Stenmark; Fiscal Year: 2013
    ..Collectively, work by this interdisciplinary group will provide insight into abnormalities of RV-pulmonary arterial interactions in the setting of severe pulmonary hypertension and will lay the groundwork for potential new therapies. ..
  8. Host Factors in Regulation of Inflammatory and Fibroproliferative Lung Disease
    PAUL WESLEY NOBLE; Fiscal Year: 2013
    ..Each of these projects shares the common theme that interactions of host factors regulates inflammatory and fibrotic lung diseases. ..
  9. The unique role of B-Raf in murine cardiac development and postnatal function
    Natasha N Chattergoon; Fiscal Year: 2013
    ..We will couple the results of B-Raf disruption to morphological, biochemical, and functional parameters of cardiac performance in the newborn and adult using echocardiographic measures. (End of Abstract) ..
  10. Peptide Therapy for Pulmonary Arterial Hypertension
    Jawaharlal M Patel; Fiscal Year: 2013
    ..Confirmation of the mechanism-based physiological approach for NO releasing PDE5 inhibitor function of this novel peptide in preclinical animal model is innovative for progression towards Phase I clinical trial for treatment of PH. ..
  11. Mechanisms of Health Effects of Exercise in Children
    Dan M Cooper; Fiscal Year: 2013
    ..Collectively, the PPG will promote novel preventive and adjunctive exercise therapies in children with chronic inflammation- therapies grounded in a firm understanding of biological mechanisms. ..
  12. Understanding mechanisms of Fontan failure and key predictors for patient outcome
    Ajit P Yoganathan; Fiscal Year: 2013
    ..Understanding these interconnections will provide the means to develop optimal medical strategies to improve those outcomes. ..
  13. Cardiac Myosin Binding Protein-C: Structure, Function, and Regulation
    David M Warshaw; Fiscal Year: 2013
    ..abstract_text> ..
  14. Immune-Based Interventions Against Infectious Diseases
    Alan L Rothman; Fiscal Year: 2013
    ..3. Recruit promising junior investigators and provide mentoring by established NIH-funded researchers. 4. Support a multidisciplinary research program led by junior investigators in translational infectious diseases immunology. ..
  15. Expanding Excellence in Developmental Biology in Oklahoma
    Linda F Thompson; Fiscal Year: 2013
    ..abstract_text> ..
  16. Brain imaging and developmental follow-up of infants treated with erythropoietin
    Robin K Ohls; Fiscal Year: 2013
    ....
  17. PSYCHOSOCIAL FACTORS AND CARDIOVASCULAR DISEASE
    Joseph E Schwartz; Fiscal Year: 2013
    ..We believe that our findings are likely to have a major impact on the methods used to measure BP routinely in clinical practice. ..
  18. MITOCHONDRIAL ENCEPHALOMYOPATHIES AND MENTAL RETARDATION
    Salvatore DiMauro; Fiscal Year: 2013
    ....
  19. A Bifunctional Katp Channel Activator and Redox Mimetic for BPD
    Kanneganti Murthy; Fiscal Year: 2013
    ....
  20. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
    ..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..
  21. PPG - Mechanisms of Cardiovascular Protection and Disease
    Donald D Heistad; Fiscal Year: 2013
    ..abstract_text> ..
  22. MULTIDISCIPLINARY STRUCTURES AT VASCULAR CELL SURFACES
    Timothy A Springer; Fiscal Year: 2013
    ..Administrative (Springer) and Protein Expression (Lu) Cores enhance efficiency of the PPG. (End of Abstract) ..