Aromatase Inhibitors in Pulmonary Vascular Complications of Liver Disease

Summary

Principal Investigator: Steven M Kawut
Abstract: Steven M. Kawut, MD, MS is an Associate Professor of Medicine and Epidemiology at the University of Pennsylvania School of Medicine (Penn) who has committed his career to the research and care of patients with pulmonary vascular disease (PVD). His interest in this area began early in his training and has guided his development since then. He heads a federally-funded research program based on the epidemiology and treatment of PVD and right ventricular dysfunction. He has also mentored more than twenty-nine trainees to success in patient-oriented research (POR), resulting in publications and funding as they develop towards their own independence. Dr. Kawut[unreadable]s recent recruitment to Penn to direct the Pulmonary Vascular Disease Program has created a significant opportunity to expand his research program as well as to train and mentor young investigators. There are outstanding resources at Penn housed in the Cardiovascular Institute, the Pulmonary, Allergy, and Critical Care Division, and the Center for Clinical Epidemiology and Biostatistics available to the candidate and his trainees. These include state-of-the-art clinical research and laboratory resources. The candidate[unreadable]s immediate- and long-term career goals during this award center on acquiring skills in performing clinical trials in rare PVDs and developing his mentorship abilities. The environment at Penn is ideal to develop the applicant as a mentor and to foster the academic growth of mentees in these areas. Pulmonary arterial hypertension occurs in 4-8% of patients with portal hypertension (termed portopulmonary hypertension (PPHTN)). PPHTN has no known disease mechanism, limited, non-specific therapies, and may greatly complicate, delay, or prevent liver transplantation. Hepatopulmonary syndrome (HPS) is characterized by pulmonary microvascular dilations and impaired gas exchange and is found in up to 30% of patients being evaluated for liver transplantation. The mechanism for the development of HPS is similarly cryptic. Dr. Kawut recently performed a NIH-funded study focused on the clinical and genetic determinants of PPHTN and HPS. These studies showed that 1) female gender was a strong risk factor for PPHTN, 2) genetic variation in estrogen receptor βwas associated with the occurrence of HPS , and 3) genetic variation in aromatase was associated with both higher plasma estradiol (E2) levels and a higher risk of PPHTN. These data strongly suggest estrogen as a potential therapeutic target in treatment and prevention of these pulmonary vascular sequelae of portal hypertension. Anastrozole (AN) is an FDA-approved aromatase inhibitor which dramatically decreases peripheral estrogen production in men and post-menopausal women. We therefore propose to conduct two [unreadable]proof-ofprinciple[unreadable] randomized clinical trials (RCTs) to begin the study of estrogen inhibition with AN for the treatment of PPHTN and HPS. We aim: 1) To determine the effects of AN versus placebo over three months in patients with PPHTN and 2) To determine the effects of AN versus placebo over three months in patients with HPS. End points will include E2 levels, transthoracic echocardiology measures, alveolar-arterial oxygen gradient, functional status, safety, and tolerability. If suggestive of benefit, the results could be used to plan and power multicenter Phase II or III RCTs of AN in one or both of these PVDs. This research would provide the ideal training ground for young investigators interested in POR in PVD who wish to study novel therapeutics for [unreadable]orphan[unreadable] diseases.
Funding Period: 2011-05-01 - 2016-04-30
more information: NIH RePORT

Top Publications

  1. pmc Brachial artery diameter and the right ventricle: the Multi-Ethnic Study of Atherosclerosis-right ventricle study
    Christopher T Dibble
    Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
    Chest 142:1399-405. 2012
  2. pmc Pulmonary hyperinflation and left ventricular mass: the Multi-Ethnic Study of Atherosclerosis COPD Study
    Benjamin M Smith
    Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
    Circulation 127:1503-11, 1511e1-6. 2013
  3. ncbi Tricuspid annular plane systolic excursion in the assessment of right ventricular function in children and adolescents after repair of tetralogy of Fallot
    Laura Mercer-Rosa
    Division of Cardiology, Department of Pediatrics, The Children s Hospital of Philadelphia and the Perelman School of Medicine, Philadelphia, Pennsylvania Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania Electronic address
    J Am Soc Echocardiogr 26:1322-9. 2013
  4. pmc Relationship of CRP, IL-6, and fibrinogen with right ventricular structure and function: the MESA-Right Ventricle Study
    Michael O Harhay
    Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
    Int J Cardiol 168:3818-24. 2013
  5. ncbi Sex and haemodynamics in pulmonary arterial hypertension
    Corey E Ventetuolo
    Alpert Medical School of Brown University, Providence, RI
    Eur Respir J 43:523-30. 2014
  6. pmc The prospective association of Chlamydia pneumoniae and four other pathogens with development of coronary artery calcium: the multi-ethnic study of atherosclerosis (MESA)
    Babray Laek
    Department of Epidemiology, Johns Hopkins University, 615 North Wolfe Street, Baltimore, MD 21205, USA Netherlands Institute for Health Sciences, Erasmus University, Dr Molewaterplein 60, 3015 GJ Rotterdam, The Netherlands Electronic address
    Atherosclerosis 230:268-74. 2013
  7. pmc Validity of the surface electrocardiogram criteria for right ventricular hypertrophy: the MESA-RV Study (Multi-Ethnic Study of Atherosclerosis-Right Ventricle)
    Isaac R Whitman
    Department of Medicine, Division of Cardiology, University of California, San Francisco, California
    J Am Coll Cardiol 63:672-81. 2014
  8. pmc Mammalian target of rapamycin complex 2 (mTORC2) coordinates pulmonary artery smooth muscle cell metabolism, proliferation, and survival in pulmonary arterial hypertension
    Dmitry A Goncharov
    Pulmonary, Allergy and Critical Care Division D A G, T V K, H Z, H D, V P K, S M K, E A G, Department of Pathology and Laboratory Medicine K I S, Pulmonary Vascular Disease Program K I S, H D, V P K, S M K, E A G, Center for Clinical Epidemiology and Biostatistics S M K, and Abramson Cancer Center V P K, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver, Aurora, CO R M T and Division of Pulmonary, Allergy and Critical Care Medicine, Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA D A G, T V K Dr Goncharova s current affiliation is the Division of Pulmonary, Allergy and Critical Care Medicine, Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA
    Circulation 129:864-74. 2014
  9. pmc Percent emphysema and right ventricular structure and function: the Multi-Ethnic Study of Atherosclerosis-Lung and Multi-Ethnic Study of Atherosclerosis-Right Ventricle Studies
    Maria Grau
    Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA
    Chest 144:136-44. 2013
  10. pmc Early plasma soluble receptor for advanced glycation end-product levels are associated with bronchiolitis obliterans syndrome
    R J Shah
    Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
    Am J Transplant 13:754-9. 2013

Detail Information

Publications20

  1. pmc Brachial artery diameter and the right ventricle: the Multi-Ethnic Study of Atherosclerosis-right ventricle study
    Christopher T Dibble
    Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
    Chest 142:1399-405. 2012
    ....
  2. pmc Pulmonary hyperinflation and left ventricular mass: the Multi-Ethnic Study of Atherosclerosis COPD Study
    Benjamin M Smith
    Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
    Circulation 127:1503-11, 1511e1-6. 2013
    ..We therefore hypothesized that residual lung volume in COPD would be associated with greater LV mass...
  3. ncbi Tricuspid annular plane systolic excursion in the assessment of right ventricular function in children and adolescents after repair of tetralogy of Fallot
    Laura Mercer-Rosa
    Division of Cardiology, Department of Pediatrics, The Children s Hospital of Philadelphia and the Perelman School of Medicine, Philadelphia, Pennsylvania Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania Electronic address
    J Am Soc Echocardiogr 26:1322-9. 2013
    ..The aim of this study was to investigate the reliability and validity of tricuspid annular plane systolic excursion (TAPSE) against cardiac magnetic resonance imaging measures and cardiopulmonary exercise testing...
  4. pmc Relationship of CRP, IL-6, and fibrinogen with right ventricular structure and function: the MESA-Right Ventricle Study
    Michael O Harhay
    Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
    Int J Cardiol 168:3818-24. 2013
    ..Inflammation contributes to the pathogenesis of disease associated with the left ventricle (LV); yet, our understanding of the effect of inflammation on the right ventricle (RV) is quite limited...
  5. ncbi Sex and haemodynamics in pulmonary arterial hypertension
    Corey E Ventetuolo
    Alpert Medical School of Brown University, Providence, RI
    Eur Respir J 43:523-30. 2014
    ..In the subgroup of connective tissue disease-associated PAH, males may have had higher right atrial pressure. These findings implicate age as a modifier and provide further evidence of sexual dimorphism in PAH...
  6. pmc The prospective association of Chlamydia pneumoniae and four other pathogens with development of coronary artery calcium: the multi-ethnic study of atherosclerosis (MESA)
    Babray Laek
    Department of Epidemiology, Johns Hopkins University, 615 North Wolfe Street, Baltimore, MD 21205, USA Netherlands Institute for Health Sciences, Erasmus University, Dr Molewaterplein 60, 3015 GJ Rotterdam, The Netherlands Electronic address
    Atherosclerosis 230:268-74. 2013
    ..The aim of this study is to prospectively evaluate this association in a population-based cohort...
  7. pmc Validity of the surface electrocardiogram criteria for right ventricular hypertrophy: the MESA-RV Study (Multi-Ethnic Study of Atherosclerosis-Right Ventricle)
    Isaac R Whitman
    Department of Medicine, Division of Cardiology, University of California, San Francisco, California
    J Am Coll Cardiol 63:672-81. 2014
    ..The study aimed to assess the diagnostic properties of electrocardiographic (ECG) criteria for right ventricular hypertrophy (RVH) measured by cardiac magnetic resonance imaging (cMRI) in adults without clinical cardiovascular disease...
  8. pmc Mammalian target of rapamycin complex 2 (mTORC2) coordinates pulmonary artery smooth muscle cell metabolism, proliferation, and survival in pulmonary arterial hypertension
    Dmitry A Goncharov
    Pulmonary, Allergy and Critical Care Division D A G, T V K, H Z, H D, V P K, S M K, E A G, Department of Pathology and Laboratory Medicine K I S, Pulmonary Vascular Disease Program K I S, H D, V P K, S M K, E A G, Center for Clinical Epidemiology and Biostatistics S M K, and Abramson Cancer Center V P K, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver, Aurora, CO R M T and Division of Pulmonary, Allergy and Critical Care Medicine, Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA D A G, T V K Dr Goncharova s current affiliation is the Division of Pulmonary, Allergy and Critical Care Medicine, Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA
    Circulation 129:864-74. 2014
    ..The role of the distinct mammalian target of rapamycin (mTOR) complexes mTORC1 (mTOR-Raptor) and mTORC2 (mTOR-Rictor) in PAVSMC proliferation and survival in PAH and their therapeutic relevance are unknown...
  9. pmc Percent emphysema and right ventricular structure and function: the Multi-Ethnic Study of Atherosclerosis-Lung and Multi-Ethnic Study of Atherosclerosis-Right Ventricle Studies
    Maria Grau
    Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA
    Chest 144:136-44. 2013
    ..We evaluated whether emphysema and airflow obstruction would be associated with changes in right ventricular (RV) structure and function and whether these associations would differ by smoking status...
  10. pmc Early plasma soluble receptor for advanced glycation end-product levels are associated with bronchiolitis obliterans syndrome
    R J Shah
    Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
    Am J Transplant 13:754-9. 2013
    ..Elevated plasma sRAGE levels measured in the immediate postoperative period are associated with the development of BOS. Early epithelial injury after transplantation may contribute to the development of fibrosis in BOS...
  11. pmc Validation of 6-minute walk distance as a surrogate end point in pulmonary arterial hypertension trials
    Nicole B Gabler
    Center for Clinical Epidemiology and Biostatistics, Philadelphia, PA, USA
    Circulation 126:349-56. 2012
    ..We aimed to validate the difference in Δ6MWD against the probability of a clinical event in pulmonary arterial hypertension trials...
  12. pmc Variation in PTX3 is associated with primary graft dysfunction after lung transplantation
    Joshua M Diamond
    Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania School of Medicine, 3400 Spruce St, 8 West Gates, Philadelphia, PA 19104, USA
    Am J Respir Crit Care Med 186:546-52. 2012
    ..Elevated long pentraxin-3 (PTX3) levels are associated with the development of primary graft dysfunction (PGD) after lung transplantation. Abnormalities in innate immunity, mediated by PTX3 release, may play a role in PGD pathogenesis...
  13. pmc Right ventricular structure is associated with the risk of heart failure and cardiovascular death: the Multi-Ethnic Study of Atherosclerosis (MESA)--right ventricle study
    Steven M Kawut
    Penn Cardiovascular Institute, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia
    Circulation 126:1681-8. 2012
    ..We examined the association of abnormal RV structure and function with the risk of heart failure or cardiovascular death in a population-based multiethnic sample free of clinical cardiovascular disease at baseline...
  14. pmc Von Willebrand factor and the right ventricle (the MESA-Right Ventricle Study)
    Peter J Leary
    Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, Washington, USA
    Am J Cardiol 110:1846-51. 2012
    ..In conclusion, higher vWF activity is associated with lower RV mass, RV end-diastolic volume, and RV stroke volume. These associations are independent of common cardiovascular risk factors and left ventricular morphologic changes...
  15. pmc Pulmonary vascular complications of liver disease
    Jason S Fritz
    Department of Medicine, M S, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
    Am J Respir Crit Care Med 187:133-43. 2013
    ....
  16. pmc Lower socioeconomic status is associated with worse outcomes in pulmonary arterial hypertension
    Wen hui Wu
    Department of Cardio Pulmonary Circulation, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
    Am J Respir Crit Care Med 187:303-10. 2013
    ..Lower socioeconomic status (SES) confers a heightened risk of common cardiovascular and pulmonary diseases and increased mortality. The association of SES with outcomes in patients with pulmonary arterial hypertension (PAH) is less clear...
  17. pmc Cardiovascular risk factors and mitral annular calcification in type 2 diabetes
    Atif N Qasim
    University of California at San Francisco, San Francisco, CA, USA
    Atherosclerosis 226:419-24. 2013
    ..Our goal was to study the risk factors for MAC in a sample of T2DM subjects without renal and cardiac disease...
  18. pmc Elevated plasma angiopoietin-2 levels and primary graft dysfunction after lung transplantation
    Joshua M Diamond
    Pulmonary, Allergy, and Critical Care Division, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
    PLoS ONE 7:e51932. 2012
    ..Angiopoietin-2 serves as a partial antagonist to the Tie-2 receptor and induces increased endothelial permeability. We hypothesized that elevated Ang2 levels would be associated with development of PGD...
  19. pmc Impact of the hepatopulmonary syndrome MELD exception policy on outcomes of patients after liver transplantation: an analysis of the UNOS database
    David S Goldberg
    Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania Clinical Center for Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania Electronic address
    Gastroenterology 146:1256-65.e1. 2014
    ..Patients with hepatopulmonary syndrome (HPS) are prioritized for liver transplantation (given exception points) due to their high pre- and post-transplantation mortality. However, few studies have evaluated the outcomes of these patients...

Research Grants31

  1. 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. ..
  2. NEW MODALITIES FOR TREATMENT OF PAIN AND DRUG ABUSE
    Victor J Hruby; Fiscal Year: 2013
    ....
  3. Elucidating Risks: From Exposure and Mechanism to Outcome
    James A Swenberg; Fiscal Year: 2013
    ..This Program is highly relevant to Superfund by addressing high-priority chemicals and by focusing on mechanisms underlying health effects, exposure assessment, and remediation to mitigate exposure and toxicity. ..
  4. Semi-volatile PCBs: Sources, Exposures, Toxicities
    Larry W Robertson; Fiscal Year: 2013
    ..These data and dietary studies in the last Aim will provide a scientific basis for risk assessment and advice for stakeholders with the ultimate goal to protect highly-exposed individuals and populations. ..
  5. Estrogen signaling in portopulmonary hypertension
    Steven M Kawut; Fiscal Year: 2013
    ..Finally, downregulation of CEPs by fulvestrant would identify ERalpha blockade as another approach. If these hypotheses are incorrect, we could use the genetic and biomarker data to examine alternative hypotheses. ..
  6. Effect of Spironolactone of Collagen Synthesis in Pulmonary Arterial Hypertension
    Zeenat Safdar; Fiscal Year: 2013
    ..Safdar's development into an independent clinical investigator. Completion of this project will advance our understanding of some of the mechanisms that underlie disease worsening in PAH. ..
  7. Elafin Therapy for Lung Diseases
    Marlene Rabinovitch; Fiscal Year: 2013
    ..The Administrative Core facilitates exchange of information and postdoctoral training in Lung Translational Medicine, and facilitates our strategy to move elafin into clinical trial in the next cycle. ..
  8. Specialized Programs of Translational Research in Acute Stroke at the Partners
    Steven M Greenberg; Fiscal Year: 2013
    ..If our study is successful, we can potentially expand use of lytics to a stroke patient population for whom little acute intervention is currently offered. ..