Hormonal, Metabolic, and Signaling Interactions in PAH

Official title

Hormonal, Metabolic, and Signaling Interaction in Pulmonary Arterial Hypertension

Overview

Our hypothesis is that optimal treatment of the dysfunctional metabolic pathways which underlie PAH will improve pulmonary vascular function and consequences of the disease.

Detailed description

Project 1: This project will work to understand why women are affected by pulmonary arterial hypertension (PAH) so much more often than men. This observation is true in heritable, idiopathic and associated forms of PAH. While males and females have some similar hormone levels, certain hormones exist at higher levels in each gender. For example, estrogen levels are much higher in females, and thus seemed the most sensible place to start looking for differences that may be affecting disease. In a small, early study of our heritable patients, we found differences in how patients break down estrogens as compared to healthy control subjects. Now, we want to confirm that what we found is true in a much larger group of patients that includes idiopathic and associated forms of PAH. We will also look to see if testosterone and other androgenic hormones are somehow protective for males. If the observation holds true in the larger group of patients, then we may try to "fix" the hormone imbalance in a mouse model of PAH with a drug therapy, and see if it helps improve the mouse pulmonary hypertension without bad side effects to the animals. If the animal drug studies work, then we may be able to try this drug in patients to see if it will work as a human treatment.

Project 2: Despite major advances in understanding PAH in recent decades, safe, effective and tolerable therapies remain elusive. The metabolic syndrome (central obesity, insulin resistance, high blood pressure and hyperlipidemia-fats in the blood) has been implicated in PAH. Treating the downstream consequences of insulin resistance in the pulmonary vasculature is a new approach to effective intervention against this highly mortal disease. This project will study the role of insulin resistance in pulmonary arterial hypertension and determine if therapies to treat insulin resistance will improve pulmonary arterial hypertension.

Project 3: In Project 3, we are working on the theory that PAH can be treated by fixing cell-cell junctions in blood vessels with a drug called recombinant ACE2(angiotensin converting enzyme 2). This is the only approach so far that has worked to reverse disease in mouse models of heritable PAH, but we need to better understand how it is working and make sure it has long term safety in animal models before starting human trials, hopefully within a few years. Definition: Cell-cell junctions-all of our organs and body structures are made from cells. Normally, these cells (think of a balloon filled with water) line up right next to each other so that the cell membranes touch each other. Materials can flow from one cell to the next. In PAH patients it is believed that the cells in the linings of the small arteries are not able to line up together as they should.

Primary outcome measures

• Ratio of sex hormone metabolites [Time frame: 5 years]
• Evaluation of insulin resistance in pulmonary arterial hypertension patients/Clinical trial of Metformin in Pulmonary Arterial Hypertension [Time frame: 5 years]
• Mechanism, safety, and efficacy of ACE-2 (Angiotensin Converting Enzyme 2) in the treatment of PAH. [Time frame: 5 years]
• Clinical Trial of Metformin in Pulmonary Arterial Hypertension [Time frame: 3 years]

Secondary outcome measures (2)

• Mechanism, safety, and efficacy of ACE-2 in the treatment of PAH. [Time frame: 5-year]
• Clinical Trial of Metformin in Pulmonary Arterial Hypertension [Time frame: 3 years]

Eligibility criteria

Inclusion criteria

Project 1

Inclusion:

• Diagnosis of IPAH (idiopathic pulmonary arterial hypertension), HPAH (heritable pulmonary arterial hypertension), or APAH (associated pulmonary arterial hypertension), family members of affected persons
• Age 0-90, age 12-90 for skin biopsy

Exclusion:

• Other diagnosis
• Age greater than 90, age less than 12 or greater than 90 for skin biopsy

Project 2

Inclusion:

• Diagnosis of IPAH, HPAH, or APAH, family members of affected persons
• 0-90
• Subjects with reasonably easy access to clinic for blood collection and other testing
• Subject able to tolerate fasting state prior to sample collection and EndoPAT (endothelial function assessment) testing

Exclusion:

• Other diagnosis
• 0-90
• Subjects with difficulty reaching clinic for blood collection and other testing
• Subjects unable to tolerate fasting state

Project 3

Inclusion:

• Diagnosis of IPAH, HPAH, or APAH, family members of affected persons
• 7-90

Exclusion:

• Other diagnosis
• Age less than 7 or greater than 90

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Exclusion criteria

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Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Observational model

Cohort

Study locations

United States · 1 center

• Vanderbilt University Medical Center — Nashville

Publications

• Austin ED, Cogan JD, West JD, Hedges LK, Hamid R, Dawson EP, Wheeler LA, Parl FF, Loyd JE, Phillips JA 3rd. Alterations in oestrogen metabolism: implications for higher penetrance of familial pulmonary arterial hypertension in females. Eur Respir J. 2009 Nov;34(5):1093-9. doi: 10.1183/09031936.00010409. Epub 2009 Apr 8. PMID 19357154
• Robbins IM, Newman JH, Johnson RF, Hemnes AR, Fremont RD, Piana RN, Zhao DX, Byrne DW. Association of the metabolic syndrome with pulmonary venous hypertension. Chest. 2009 Jul;136(1):31-36. doi: 10.1378/chest.08-2008. Epub 2009 Feb 2. PMID 19188551
• Ferreira AJ, Shenoy V, Yamazato Y, Sriramula S, Francis J, Yuan L, Castellano RK, Ostrov DA, Oh SP, Katovich MJ, Raizada MK. Evidence for angiotensin-converting enzyme 2 as a therapeutic target for the prevention of pulmonary hypertension. Am J Respir Crit Care Med. 2009 Jun 1;179(11):1048-54. doi: 10.1164/rccm.200811-1678OC. Epub 2009 Feb 26. PMID 19246717
• Pugh ME, Robbins IM, Rice TW, West J, Newman JH, Hemnes AR. Unrecognized glucose intolerance is common in pulmonary arterial hypertension. J Heart Lung Transplant. 2011 Aug;30(8):904-11. doi: 10.1016/j.healun.2011.02.016. Epub 2011 Apr 13. PMID 21493097
• West J. Cross talk between Smad, MAPK, and actin in the etiology of pulmonary arterial hypertension. Adv Exp Med Biol. 2010;661:265-78. doi: 10.1007/978-1-60761-500-2_17. PMID 20204736
• Brittain EL, Niswender K, Agrawal V, Chen X, Fan R, Pugh ME, Rice TW, Robbins IM, Song H, Thompson C, Ye F, Yu C, Zhu H, West J, Newman JH, Hemnes AR. Mechanistic Phase II Clinical Trial of Metformin in Pulmonary Arterial Hypertension. J Am Heart Assoc. 2020 Nov 17;9(22):e018349. doi: 10.1161/JAHA.120.018349. Epub 2020 Nov 10. PMID 33167773
• Hemnes AR, Rathinasabapathy A, Austin EA, Brittain EL, Carrier EJ, Chen X, Fessel JP, Fike CD, Fong P, Fortune N, Gerszten RE, Johnson JA, Kaplowitz M, Newman JH, Piana R, Pugh ME, Rice TW, Robbins IM, Wheeler L, Yu C, Loyd JE, West J. A potential therapeutic role for angiotensin-converting enzyme 2 in human pulmonary arterial hypertension. Eur Respir J. 2018 Jun 21;51(6):1702638. doi: 10.1183/139 PMID 29903860
• Shenoy V, Kwon KC, Rathinasabapathy A, Lin S, Jin G, Song C, Shil P, Nair A, Qi Y, Li Q, Francis J, Katovich MJ, Daniell H, Raizada MK. Oral delivery of Angiotensin-converting enzyme 2 and Angiotensin-(1-7) bioencapsulated in plant cells attenuates pulmonary hypertension. Hypertension. 2014 Dec;64(6):1248-59. doi: 10.1161/HYPERTENSIONAHA.114.03871. Epub 2014 Sep 15. PMID 25225206

Identifiers

NCT: NCT01884051 · 9401

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗