Clinical trial NCT03288025: Pulmonary Arterial Hypertension Improvement With Nutrition and Exercise (PHINE)
Official title: Pulmonary Arterial Hypertension Improvement With Nutrition and Exercise (PHINE) A Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Pulmonary Arterial Hypertension
Insulin Resistance
Keywords: Insulin Resistance
Inflammation
Right Ventricular Function
Metabolism
Glucose
Lead sponsor: The Cleveland Clinic
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2017-09-19
Enrollment: 34
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Insulin Sensitivity
timeFrame: 5 years
Secondary outcomes:
measure: Right Ventricular Global Peak Longitudinal Strain
timeFrame: 5 years
Other outcomes:
Locations:
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
Study officials:
affiliation: The Cleveland Clinic
name: Raed Dweik, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: The Cleveland Clinic
name: Gustavo Heresi, MD
role: PRINCIPAL_INVESTIGATOR
References: