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?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?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 ?proof-ofprinciple? 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 ?orphan? diseases.

Public Health Relevance

Pulmonary arterial hypertension (high blood pressure in the lungs) and hepatopulmonary syndrome (dilations of lung vessels with abnormal oxygen levels) affect patients with liver disease with significant morbidity and mortality. We will study the use of anastrozole, which lowers estrogen levels, in patients with these conditions. Studying the impact of anastrozole on patients with pulmonary hypertension and hepatopulmonary syndrome may help us treat patients with these conditions in the future.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Midcareer Investigator Award in Patient-Oriented Research (K24)
Project #
5K24HL103844-02
Application #
8258295
Study Section
Special Emphasis Panel (ZHL1-CSR-X (F1))
Program Officer
Colombini-Hatch, Sandra
Project Start
2011-05-01
Project End
2016-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
2
Fiscal Year
2012
Total Cost
$193,758
Indirect Cost
$14,352
Name
University of Pennsylvania
Department
Biostatistics & Other Math Sci
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Ventetuolo, Corey E; Baird, Grayson L; Barr, R Graham et al. (2016) Higher Estradiol and Lower Dehydroepiandrosterone-Sulfate Levels Are Associated with Pulmonary Arterial Hypertension in Men. Am J Respir Crit Care Med 193:1168-75
Matura, Lea Ann; Shou, Haochang; Fritz, Jason S et al. (2016) Physical Activity and Symptoms in Pulmonary Arterial Hypertension. Chest 150:46-56
Diamond, Joshua M; Porteous, Mary K; Jackson Roberts 2nd, L et al. (2016) The relationship between plasma lipid peroxidation products and primary graft dysfunction after lung transplantation is modified by donor smoking and reperfusion hyperoxia. J Heart Lung Transplant 35:500-7
Porteous, Mary K; Ky, Bonnie; Kirkpatrick, James N et al. (2016) Diastolic Dysfunction Increases the Risk of Primary Graft Dysfunction after Lung Transplant. Am J Respir Crit Care Med 193:1392-400
Sanges, Sébastien; Launay, David; Rhee, Rennie L et al. (2016) A prospective study of the 6 min walk test as a surrogate marker for haemodynamics in two independent cohorts of treatment-naïve systemic sclerosis-associated pulmonary arterial hypertension. Ann Rheum Dis 75:1457-65
O'Byrne, Michael L; Rome, Jonathan J; Kawut, Steven J (2016) Reply: The Need for Comprehensive Cardiac Catheterization in Children With Pulmonary Hypertension: To "Cath" or Not in Pediatric Pulmonary Hypertension? J Am Coll Cardiol 67:1011-2
Aaron, Carrie P; Chervona, Yana; Kawut, Steven M et al. (2016) Particulate Matter Exposure and Cardiopulmonary Differences in the Multi-Ethnic Study of Atherosclerosis. Environ Health Perspect 124:1166-73
Ventetuolo, Corey E; Mitra, Nandita; Wan, Fei et al. (2016) Oestradiol metabolism and androgen receptor genotypes are associated with right ventricular function. Eur Respir J 47:553-63
Al-Naamani, Nadine; Palevsky, Harold I; Lederer, David J et al. (2016) Prognostic Significance of Biomarkers in Pulmonary Arterial Hypertension. Ann Am Thorac Soc 13:25-30
Oelsner, Elizabeth C; Lima, Joao A C; Kawut, Steven M et al. (2015) Noninvasive tests for the diagnostic evaluation of dyspnea among outpatients: the Multi-Ethnic Study of Atherosclerosis lung study. Am J Med 128:171-180.e5

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