Functional and Biological Phenotyping of Pediatric PH

Summary

Principal Investigator: Robin Shandas
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 2012-08-15 - 2017-06-30
more information: NIH RePORT

Top Publications

  1. pmc Plasma proteomics of differential outcome to long-term therapy in children with idiopathic pulmonary arterial hypertension
    Michael E Yeager
    Department of Pediatric Critical Care, University of Colorado Denver, Denver, CO 80045, USA
    Proteomics Clin Appl 6:257-67. 2012
  2. pmc The design and fabrication of two portal vein flow phantoms by different methods
    Bryan E Yunker
    Department of Bioengineering, University of Colorado Denver Anschutz, 12700 East 19th Avenue, MS 8607, Aurora, Colorado 80045
    Med Phys 41:023701. 2014
  3. pmc Drug treatment of pulmonary hypertension in children
    Erika E Vorhies
    Division of Pediatric Cardiology, Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, C S Mott Children s Hospital, Ann Arbor, MI, USA
    Paediatr Drugs 16:43-65. 2014
  4. pmc Evaluation of circulating proteins and hemodynamics towards predicting mortality in children with pulmonary arterial hypertension
    Brandie D Wagner
    Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Denver, Aurora, Colorado, United States of America
    PLoS ONE 8:e80235. 2013
  5. pmc Influence of distal resistance and proximal stiffness on hemodynamics and RV afterload in progression and treatments of pulmonary hypertension: a computational study with validation using animal models
    Zhenbi Su
    Department of Mechanical Engineering, University of Colorado at Boulder, Boulder, CO 80309, USA
    Comput Math Methods Med 2013:618326. 2013
  6. pmc Ventilatory efficiency slope correlates with functional capacity, outcomes, and disease severity in pediatric patients with pulmonary hypertension
    Christopher M Rausch
    University of Colorado School of Medicine, Department of Pediatrics CO, USA Children s Hospital Colorado, Division of Pediatric Cardiology, CO, USA Electronic address
    Int J Cardiol 169:445-8. 2013
  7. pmc The hemodynamic response to dexmedetomidine loading dose in children with and without pulmonary hypertension
    Robert H Friesen
    Department of Anesthesiology, Children s Hospital Colorado, University of Colorado, 13123 E 16th Ave, Aurora, CO 80045
    Anesth Analg 117:953-9. 2013
  8. pmc Current challenges in pediatric pulmonary hypertension
    Shinichi Takatsuki
    Department of Pediatrics, University of Colorado School of Medicine, Children s Hospital Colorado, Aurora, Colorado
    Semin Respir Crit Care Med 34:627-44. 2013
  9. pmc Wall shear stress measured by phase contrast cardiovascular magnetic resonance in children and adolescents with pulmonary arterial hypertension
    Uyen Truong
    Department for Bioengineering, University of Colorado, 13123 E, 16th Avenue B100, Aurora, CO 80045, USA
    J Cardiovasc Magn Reson 15:81. 2013
  10. ncbi Diagnostic evaluation of paediatric pulmonary hypertension in current clinical practice
    Maurice Beghetti
    Paediatric Cardiology Unit, University Hospital, Geneva, Switzerland
    Eur Respir J 42:689-700. 2013

Detail Information

Publications14

  1. pmc Plasma proteomics of differential outcome to long-term therapy in children with idiopathic pulmonary arterial hypertension
    Michael E Yeager
    Department of Pediatric Critical Care, University of Colorado Denver, Denver, CO 80045, USA
    Proteomics Clin Appl 6:257-67. 2012
    ..The prognosis for children with IPAH unresponsive to therapy is poor. We investigated the plasma proteome for a molecular basis of good versus poor outcome to long-term vasodilator therapy...
  2. pmc The design and fabrication of two portal vein flow phantoms by different methods
    Bryan E Yunker
    Department of Bioengineering, University of Colorado Denver Anschutz, 12700 East 19th Avenue, MS 8607, Aurora, Colorado 80045
    Med Phys 41:023701. 2014
    ..This study outlines the design and fabrication techniques for two portal vein flow phantoms...
  3. pmc Drug treatment of pulmonary hypertension in children
    Erika E Vorhies
    Division of Pediatric Cardiology, Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, C S Mott Children s Hospital, Ann Arbor, MI, USA
    Paediatr Drugs 16:43-65. 2014
    ..This article reviews the current drug therapies and their use in the management of PAH in children. ..
  4. pmc Evaluation of circulating proteins and hemodynamics towards predicting mortality in children with pulmonary arterial hypertension
    Brandie D Wagner
    Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Denver, Aurora, Colorado, United States of America
    PLoS ONE 8:e80235. 2013
    ..The aim of this study was to identify a combination of clinical and molecular predictors of survival in PAH...
  5. pmc Influence of distal resistance and proximal stiffness on hemodynamics and RV afterload in progression and treatments of pulmonary hypertension: a computational study with validation using animal models
    Zhenbi Su
    Department of Mechanical Engineering, University of Colorado at Boulder, Boulder, CO 80309, USA
    Comput Math Methods Med 2013:618326. 2013
    ....
  6. pmc Ventilatory efficiency slope correlates with functional capacity, outcomes, and disease severity in pediatric patients with pulmonary hypertension
    Christopher M Rausch
    University of Colorado School of Medicine, Department of Pediatrics CO, USA Children s Hospital Colorado, Division of Pediatric Cardiology, CO, USA Electronic address
    Int J Cardiol 169:445-8. 2013
    ..The present study sought to evaluate the relationship between ventilatory efficiency slope and functional capacity, outcomes, and disease severity in pediatric patients with pulmonary hypertension...
  7. pmc The hemodynamic response to dexmedetomidine loading dose in children with and without pulmonary hypertension
    Robert H Friesen
    Department of Anesthesiology, Children s Hospital Colorado, University of Colorado, 13123 E 16th Ave, Aurora, CO 80045
    Anesth Analg 117:953-9. 2013
    ..Our primary goal of this prospective, observational study was to quantify the effects of dexmedetomidine initial loading doses on mean pulmonary artery pressure (PAP) in children with and without pulmonary hypertension...
  8. pmc Current challenges in pediatric pulmonary hypertension
    Shinichi Takatsuki
    Department of Pediatrics, University of Colorado School of Medicine, Children s Hospital Colorado, Aurora, Colorado
    Semin Respir Crit Care Med 34:627-44. 2013
    ..A recent randomized clinical trial of sildenafil and its long-term extension has led to disparate recommendations in the United States and Europe. ..
  9. pmc Wall shear stress measured by phase contrast cardiovascular magnetic resonance in children and adolescents with pulmonary arterial hypertension
    Uyen Truong
    Department for Bioengineering, University of Colorado, 13123 E, 16th Avenue B100, Aurora, CO 80045, USA
    J Cardiovasc Magn Reson 15:81. 2013
    ..Given that WSS is known to promote architectural vessel remodeling, it is imperative that the changes of this factor be quantified in the presence of PAH...
  10. ncbi Diagnostic evaluation of paediatric pulmonary hypertension in current clinical practice
    Maurice Beghetti
    Paediatric Cardiology Unit, University Hospital, Geneva, Switzerland
    Eur Respir J 42:689-700. 2013
    ..Most children did not undergo the diagnostic workup currently recommended for adults, which highlights either incomplete awareness of current guidelines and/or challenges their appropriateness for children. ..
  11. pmc An investigation of industrial molding compounds for use in 3D ultrasound, MRI, and CT imaging phantoms
    Bryan E Yunker
    Department of Bioengineering, University of Colorado, Denver, Colorado 80045, USA
    Med Phys 40:052905. 2013
    ..This study investigated the ultrasound, MRI, and CT imaging characteristics of several industrial casting and molding compounds as a precursor to the future development of durable and anatomically correct flow phantoms...
  12. pmc Acute pulmonary vasodilator testing with inhaled treprostinil in children with pulmonary arterial hypertension
    Shinichi Takatsuki
    Pediatric Cardiology, Children s Hospital Colorado, University of Colorado School of Medicine, 13123 East 16th Avenue, B100, Aurora, CO 80045, USA
    Pediatr Cardiol 34:1006-12. 2013
    ..This study report is the first to describe the use of inhaled treprostinil for AVT in children with PAH. In this small pediatric cohort, inhaled treprostinil was effectively delivered and well tolerated and may be useful for AVT...
  13. pmc Effectiveness and safety of inhaled treprostinil for the treatment of pulmonary arterial hypertension in children
    Usha Krishnan
    College of Physicians and Surgeons of Columbia University Medical Center, New York, New York, USA
    Am J Cardiol 110:1704-9. 2012
    ..Based on these early data, further study of inhaled treprostinil appears warranted in pediatric patients with PAH...
  14. pmc Right ventricular to left ventricular diameter ratio at end-systole in evaluating outcomes in children with pulmonary hypertension
    Pei Ni Jone
    Pediatric Cardiology, Children s Hospital Colorado, University of Colorado, Aurora, Colorado Electronic address
    J Am Soc Echocardiogr 27:172-8. 2014
    ....