Pulmonary Arterial Hypertension Improvement With Nutrition and Exercise (PHINE)

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.

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