Pulmonary hypertension in children is a critical determinant of morbidity and mortality in various pediatric diseases. Despite advances in therapies, long-term outcome in many settings remain poor. Although reasons for this are multi-factorial, one critical component is the relative lack of disease-defining knowledge regarding the functional impact of the disease on the right heart and coupled pulmonary vasculature. In fact, clinically, pulmonary arterial hypertension continues to be evaluated predominantly as a distal vascular phenomenon, and only limited recognition is given to the fact that the pulmonary arterial system (PA) is intimately coupled with right ventricular function in health and disease. Functionally speaking, RV-PA coupling is driven by the principles of hydrodynamic and mechanical energy transfer and is thus not markedly dependent on the biological heterogeneity of the pediatric PH population. Over the last 7 years, our group using a reverse bedside-to-bench approach have developed novel markers of RV afterload using vascular input impedance principles, and have shown on studies of over 250 pediatric subjects with pulmonary hypertension that PVR does not represent the sole metric of RV afterload, that PA stiffness increases dramatically in pediatric pulmonary hypertension patients and consequently loads the RV to a proportionally greater level, and that inclusion of impedance and PA stiffness measures improves prediction of 1-year outcomes. These clinical studies generated a series of mechanistic studies to understand how the upstream pulmonary vessels stiffen, which have led to novel and interesting hypotheses regarding the role of extracellular matrix proteins in upstream vascular remodeling, mechanisms of healthy versus maladaptive remodeling, and differences in the developing versus the fully developed RV-PA system. These are currently being tested by our group and others through parallel efforts. In this project, we intend to complete the RV-PA axis picture by extending our clinical studies on evaluating RV afterload to include pump function from global and local viewpoints and thereby develop and test clinically usable methods to functionally phenotype the pediatric PH patient. In parallel and since biological maladaptation of the RV may precede discernable functional maladaptation, we will biologically phenotype these patients using an established circulating marker of cardiac failure (BNP and NTproBNP) and emerging circulating biomarkers of cardiac failure (micro RNAs). Together these studies will test our hypotheses that RV decompensation in pediatric PH is significantly correlated to deteriorating RV-PA coupling, and that comprehensive functional and biological phenotyping of the RV-PA axis in pediatric PH provides significantly greater prediction of 1- and 2-year clinical outcomes. Through the coordinated, multidisciplinary approach proposed here, which involves experts in bioengineering, imaging, pediatric heart failure, pediatric pulmonary hypertension, and micro RNAs, we should: 1) gain greater understanding of precisely how the human, pediatric RV compensates or decompensates under hypertensive load; 2) generate novel yet clinically usable techniques for the routine evaluation of the RV-PA function; 3) identity the combination of functional and biological phenotypes that best predict outcomes in this complex disease population; and 4) advance our understanding of the functional relationship between RV-PA coupling and RV health. 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.

Public Health Relevance

Pulmonary arterial hypertension (PAH) is a fatal disease in children and adults in which progressive increases in load on the right ventricle (RV) ultimately lead to heart failure and death. Current clinical assessment of the disease involves invasive collection of pulmonary vascular resistance (PVR), which is believed to represent RV load, and thus a primary determinant of heart failure. Studies at our institution and others have already shown pulmonary vascular input impedance better characterizes RV load, and in turn, better predicts PAH outcome. We believe that combining impedance with new mechanical and biological measures of RV function will further improve our understanding of the pulmonary system, and in turn further improve prediction of PAH outcomes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL114753-04
Application #
8890190
Study Section
Special Emphasis Panel ()
Program Officer
Xiao, Lei
Project Start
2012-08-15
Project End
2017-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
4
Fiscal Year
2015
Total Cost
$545,069
Indirect Cost
$155,604
Name
University of Colorado Denver
Department
Pediatrics
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Gates, Phillip E; Gurung, Arati; Mazzaro, Luciano et al. (2018) Measurement of Wall Shear Stress Exerted by Flowing Blood in the Human Carotid Artery: Ultrasound Doppler Velocimetry and Echo Particle Image Velocimetry. Ultrasound Med Biol 44:1392-1401
Zhu, Na; Gonzaga-Jauregui, Claudia; Welch, Carrie L et al. (2018) Exome Sequencing in Children With Pulmonary Arterial Hypertension Demonstrates Differences Compared With Adults. Circ Genom Precis Med 11:e001887
Liptzin, Deborah R; Abman, Steven H; Giesenhagen, Ann et al. (2018) An Approach to Children with Pulmonary Edema at High Altitude. High Alt Med Biol 19:91-98
Kheyfets, Vitaly O; Sucharov, Carmen C; Truong, Uyen et al. (2017) Circulating miRNAs in Pediatric Pulmonary Hypertension Show Promise as Biomarkers of Vascular Function. Oxid Med Cell Longev 2017:4957147
Parker, Donna K; Shen, Shuijie; Zheng, Jiang et al. (2017) Inhaled Treprostinil Drug Delivery During Mechanical Ventilation and Spontaneous Breathing Using Two Different Nebulizers. Pediatr Crit Care Med 18:e253-e260
Peña, Brisa; Bosi, Susanna; Aguado, Brian A et al. (2017) Injectable Carbon Nanotube-Functionalized Reverse Thermal Gel Promotes Cardiomyocytes Survival and Maturation. ACS Appl Mater Interfaces 9:31645-31656
Schäfer, Michal; Ivy, D Dunbar; Abman, Steven H et al. (2017) Apparent Aortic Stiffness in Children With Pulmonary Arterial Hypertension: Existence of Vascular Interdependency? Circ Cardiovasc Imaging 10:
Gurung, Arati; Gates, Phillip E; Mazzaro, Luciano et al. (2017) Echo Particle Image Velocimetry for Estimation of Carotid Artery Wall Shear Stress: Repeatability, Reproducibility and Comparison with Phase-Contrast Magnetic Resonance Imaging. Ultrasound Med Biol 43:1618-1627
Kim, John S; McSweeney, Julia; Lee, Joanne et al. (2016) Pediatric Cardiac Intensive Care Society 2014 Consensus Statement: Pharmacotherapies in Cardiac Critical Care Pulmonary Hypertension. Pediatr Crit Care Med 17:S89-100
Burkett, Dale A; Slorach, Cameron; Patel, Sonali S et al. (2016) Impact of Pulmonary Hemodynamics and Ventricular Interdependence on Left Ventricular Diastolic Function in Children With Pulmonary Hypertension. Circ Cardiovasc Imaging 9:

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