Pulmonary Arterial Hypertension Improvement With Nutrition and Exercise (PHINE)

Study Overview
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Brief Summary
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The purpose of this study is to investigate the extent to which diet and exercise may improve PAH through the modulation of insulin sensitivity. The central hypothesis is that dysregulated glucose metabolism elicits a response in PAH patients that can be modified by exercise and diet, thereby leading to improvements in pulmonary vascular disease.

Detailed Description
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Pulmonary arterial hypertension (PAH) leads to premature death as a consequence of increased pulmonary vascular resistance and right heart failure. PAH-targeted therapies developed over the past 20 years target excessive vasoconstriction. However, the pathobiology of PAH is more complicated, and includes dysregulated vascular cell proliferation, cellular metabolic abnormalities, and inflammation. Even with modern PAH therapies, current outcomes remain poor, with an estimated 3-year survival rate of only 55%. Thus, there is a clear need for more effective therapies, based on better understanding of the pathobiology of the disease. Insulin resistance has emerged as a potential new mechanism in PAH. Animal models of insulin resistance are associated with PAH, which reverses with the administration of insulin sensitizing drugs. Over the past decade there has been an epidemiologic shift in PAH, where the disease is increasingly observed in older, obese, and diabetic subjects. Low levels of high-density lipoprotein cholesterol in PAH, a feature of insulin resistance, have been observed and found to be a strong independent predictor of PAH mortality. Elevated glycosylated hemoglobin (HbA1c) also correlates with PAH diagnosis and severity. As measured by the OGTT, idiopathic PAH patients have not only insulin resistance, but also an inability to mount an appropriate insulin response to a glucose challenge. These data point to dysfunction in the pancreatic beta cells of PAH patients. It is known that an exercise and low glycemic index diet intervention improves insulin sensitivity in pre-diabetic subjects.

Official Title
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Pulmonary Arterial Hypertension Improvement With Nutrition and Exercise (PHINE) A Randomized Controlled Trial

Conditions
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Pulmonary Arterial Hypertension, Insulin Resistance

Intervention / Treatment
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* Behavioral: Nutrition and Exercise


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age range between 18-75 years old Group 1 PAH, including idiopathic, heritable, drugs and toxin induced, and PAH associated with connective tissue disease, HIV infection and congenital heart disease NYHA Class II or III ≥ 1 PAH-targeted therapy with a stable dose for ≥ 2 months Stable dose of diuretics and rate of supplemental oxygen for the preceding 2 months Exclusion Criteria: Decompensated Right Heart Failure NYHA Class IV Syncope within the previous 3 months Cardiac Arrhythmia (except for controlled atrial fibrillation or flutter) Baseline supplemental O2 > 4 LPM Portal Hypertension Pulmonary hypertension due to Lung Disease and Hypoxia Pulmonary Hypertension due to Left Heart Disease Chronic Thromboembolic Pulmonary Hypertension Pulmonary Hypertension associated with systemic diseases such as hematological disorders and sarcoidosis Type 2 Diabetes Evidence of cardiac ischemia on a graded exercise test

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nutrition and Exercise<br>5 days a week of moderate exercise and biweekly diet counseling on Low Glycemic Index/ Mediterranean Diet for 12 weeks. | Behavioral: Nutrition and Exercise<br>* 5 times a week exercise training and biweekly diet counseling for 12 weeks.<br>|
| No Intervention: Standard of Care<br>Counseling at baseline on diet as recommended by USDA and on the benefits of regular aerobic exercise. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin Sensitivity | Assessed by the frequently-sampled intravenous glucose tolerance test. Units of assessment in min/uU*mL | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Right Ventricular Global Peak Longitudinal Strain | Assessed by the Doppler Echocardiography 2D longitudinal speckle tracking. Units of assessment in percent. | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Glucose, Insulin Resistance, Inflammation, Right Ventricular Function, Metabolism