Pulmonary arterial hypertension (PAH) is a deadly disease, partially treated with pulmonary vasodilators. Emerging data suggest a potential role for insulin resistance in PAH. Both conditions are linked to chronic low- grade inflammation and monocyte (MNC) activation. However, direct measurements of insulin resistance in PAH patients have not been performed to date. Furthermore, the extent to which exercise and diet may improve PAH through the modulation of insulin sensitivity and inflammation has not been investigated. Our central hypothesis is that insulin resistance is a mediator of the disease process in PAH. We will test this hypothesis by pursuing the following Specific Aims: 1) Quantitate insulin sensitivity and body composition in PAH, and correlate with PAH severity. Indices of insulin sensitivity will be calculated using an oral glucose tolerance test (OGTT), and body composition will be measured by means of dual energy x-ray absorptiometry. These data will be correlated with PAH severity and mortality during a 2-3-year follow up. 2) Measure the inflammatory response of PAH-MNCs to hyperglycemia. Our working hypothesis is that insulin resistance elicits an enhanced inflammatory response in PAH. We will test this hypothesis by measuring the release of interleukin 6 and tumor necrosis-alpha by peripheral MNCs, both in the fasting state and after an oral glucose load.
Aims 1 and 2 will include age-, gender-, and BMI-matched healthy controls. 3) Determine the extent to which improvements in insulin resistance via diet and exercise impact PAH. The working hypothesis is that improvement in insulin sensitivity might lead to improvements in PAH parameters through blunting of the inflammatory response. We will assess the impact of a 12-week exercise and low glycemic index Mediterranean type diet program compared to standard of care on insulin resistance, PAH indices of severity (echo estimated pulmonary pressure and right ventricular function) and monocyte- derived inflammatory cytokines, and in a proof-of-concept randomized study. The candidate has a strong clinical background in PAH, a track record of successful research endeavors with publications in major pulmonary journals, and a clear commitment and passion for patient-oriented research. The proposal's feasibility and success are predicated upon the large PAH population followed at the Cleveland Clinic; the one on one mentoring by Dr. Dweik, a PAH expert, and Dr. Kirwan, an insulin resistance expert; the collaboration with Dr. Barkoukis, an expert in diet interventions; and the CTSA Clinical Research Unit where the metabolic testing, diet counseling and exercise training will take place. The career plan includes didactic courses and guidance from a Mentoring Committee. The ultimate goal is to expand the applicant's research skills to allow a future career as an independent investigator able to conduct research that will directly benefit PAH patients.

Public Health Relevance

Pulmonary hypertension is a disabling incurable condition of unknown cause characterized by narrowing of the small arteries that carry blood through the lungs, resulting in damage to the heart. The current proposal will investigate the link between abnormalities in the metabolism of blood sugar and inflammation to this deadly disease, and the extent to which it may be improved by diet and exercise. As a sedentary lifestyle and poor diet choices are a problem of epidemic proportions in the US and potentially easily reversible, this proposal may have a significant impact in the way care is delivered to people suffering from pulmonary hypertension.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Mentored Patient-Oriented Research Career Development Award (K23)
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Special Emphasis Panel (ZHL1-CSR-X (O1))
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Colombini-Hatch, Sandra
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Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
United States
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Heresi, Gustavo A; Love, Thomas E; Tonelli, Adriano R et al. (2018) Choice of Initial Oral Therapy for Pulmonary Arterial Hypertension: Age and Long-Term Survival. Am J Respir Crit Care Med 198:1090-1093
Rahaghi, Farbod Nicholas; Minhas, Jasleen Kaur; Heresi, Gustavo A (2018) Diagnosis of Deep Venous Thrombosis and Pulmonary Embolism: New Imaging Tools and Modalities. Clin Chest Med 39:493-504
Khirfan, Ghaleb; Tejwani, Vickram; Wang, Xiaofeng et al. (2018) Plasma levels of high density lipoprotein cholesterol and outcomes in chronic thromboembolic pulmonary hypertension. PLoS One 13:e0197700
Heresi, Gustavo A; Malin, Steven K; Barnes, Jarrod W et al. (2017) Abnormal Glucose Metabolism and High-Energy Expenditure in Idiopathic Pulmonary Arterial Hypertension. Ann Am Thorac Soc 14:190-199