Aerobic Exercise in Patients With Pulmonary Hypertension

We propose a randomized trial to determine the safety and effectiveness of aerobic exercise
for patients who have primary pulmonary hypertension (PH) or PH secondary to interstitial
lung disease (ILD). This project will be the first in a series of studies aimed at
establishing exercise prescription and general rehabilitation guidelines for patients who
have advanced lung diseases.

An essential treatment for almost all cardiovascular and pulmonary disorders is aerobic
exercise training. The effectiveness of exercise rehabilitation has been established and
exercise rehabilitation has become a standard of care for patients with chronic obstructive
pulmonary disease (COPD). However, fundamental information about the mechanisms underlying
exercise training and its therapeutic benefits remains lacking for patients who have advanced
lung disease in general and specifically for those with PH.

Subjects will be over the age of 21 years. The patients will be enrolled from sites within a
reasonable travel distance from the greater Washington area and will receive their exercise
training at Inova Fairfax Hospital or at the National Institutes of Health (NIH) main campus.
Exercise-based rehabilitation is already common for patients who have PH at the Inova Fairfax
Hospital. Their pulmonary rehabilitation program is well established, and their staff is
experienced in providing exercise therapy for patients with PH and advanced lung diseases.
The Rehabilitation Medicine Department (RMD) at The NIH Clinical Center has established a
pulmonary rehabilitation program for this protocol as well as to provide rehabilitation
services for NIH clinic patients.

There will be two primary treatment arms. Patients with PH will be randomized to either
aerobic exercise training plus education (AET) or education only (Ed-only) treatments. A
comparison group of patients with ILD who do not have secondary PH (ILD-only) will also
undergo the AET arm. Exercise training will consist of a 10-week regimen of supervised
treadmill or over ground walking three times a week. Exercise session duration will be 30
minutes and will progress to 45 minutes per session over the 10 weeks. The intensity of the
exercise will be between 70 and 80% of the heart rate reserve.

There will also be two secondary studies. First, the subjects with PH initially randomized to
the education only arm will complete an aerobic exercise training program after participation
in education. In addition, we will also compare baseline tests among patients with PH,
patients with ILD-only and healthy controls.

The study outcome measures will be assessed at NIH, RMD. These will include pre- and
post-exercise training comparisons of symptom limited treadmill exercise tests to assess
heart rate, pulse oximetry, EKG, maximum oxygen consumption, bioelectrical impedance
cardiography, and near infrared spectroscopy measurements of muscle oxygenation. We will also
assess accelerometry based activity, 6-minute walk distance, and a number of other quality of
life and functional measures questionnaires including: International Physical Activity
Questionnaire, Fatigue Severity Scale, SF-36v2 Health Survey, Human Activity Profile, Stages
of Exercise Change, Exercise Self-Efficacy, Profile of Mood States, Cambridge Pulmonary
Hypertension Outcome Review.

This study represents a unique opportunity to assess the effects of exercise on patients with
advanced lung disease and may open up valuable new treatment options for these patients.

- INCLUSION CRITERIA:

PH and ILD-only Groups: Subjects of this study will include individuals with ILD and PH who
are referred for Pulmonary Rehabilitation. Patients with ILD, PH or PH comorbid with ILD
will be included. The following list provides more specific inclusion criteria:

- Between age 21-82 years

- WHO functional class II or III, will accept WHO functional class I and IV based on 6
minute walk test results (less than or equal to 400 meters for Class I and greater
than or equal to 50 meters for Class IV)

- No recent syncope or significant chest pain

- No prior Pulmonary Rehabilitation received within the last 6 months.

- Physically inactive, no participation in a structured exercise program 3 or more days
a week for over 30 minutes at each session including pulmonary rehabilitation
maintenance within the last 6 months.

- Patients may qualify if they have any one of the following conditions:

- PAH diagnosed by right heart catheterization defined as resting pulmonary mean
arterial pressure equal to or higher than 25 mmHg

- Interstitial lung disease, including idiopathic pulmonary fibrosis (IPF),
non-specific pulmonary fibrosis (NSPF), sarcoidosis or other form of chronic lung
fibrosis will be based on clinical context via clinic note from primary
pulmonologist and an echo within one year of enrollment showing an RVSP <40mmHg.

1. If RVSP is lower than 40mmHg patients with interstitial lung disease will be
enrolled without the need for a right heart catheterization.

2. If RVSP is indeterminate on an echo procedure performed within a year of
enrollment, the patient will undergo another echo test at The National
Institutes of Health, Echocardiogram Laboratory.

3. Only if RVSP is unable to be estimated on an echo at NIH, the absence of the
following abnormalities on echo will be used: right ventricular enlargement,
right ventricular hypertrophy, paradoxical movement of interventricular
septum and/or altered pulmonary flow velocity. If RVSP is unable to be
estimated and these abnormalities are absent on echo, the patient will be
enrolled as an ILD-only patient. If any of these echocardiographic
abnormalities are present the patient will not be enrolled until the results
of a right heart catheterization can be obtained to verify the absence of
pulmonary hypertension.

Healthy Controls: The controls will include individuals who have never been diagnosed with
primary or secondary PH and are apparently healthy. Controls will be matched to the PH
cohort for age, gender, and body mass.

- Between 21 82 years

- Physically inactive, no participation in a structured exercise program 3 or more days
a week for over 30 minutes at each session.

- No cardiorespiratory or pulmonary disease

- No other diseases of the neurological, metabolic, renal, or musculoskeletal system

- No medications that would influence aerobic capacity or treadmill performance

EXCLUSION CRITERIA FOR PATIENTS WITH PH, ILD-ONLY AND HEALTHY CONTROLS:

Since the goal is to examine exercise responses and adaptations as affected by PH, patients
will have no other (except the primary disease in those with secondary PH) medical
conditions that would impair aerobic capacity or the ability to engage in physical
activity. These conditions would include any of those affecting the cardiovascular,
pulmonary, metabolic, neurological, or musculoskeletal systems. Specific exclusion criteria
for the PH and control cohorts are:

- Significant Restrictive or Obstructive Lung Disease with a FEV1/FVC ratio less than or
equal to 65 percent

- Diagnosis of ischemic heart disease

- Left ventricular dysfunction with the ejection fraction less than 40 or a documented
pulmonary capillary wedge pressure greater than or equal to 18 mmHg.

- Acute cor pulmonale

- Dilated or hypertrophic cardiomyopathy

- Non-idiopathic cardiomyopathy

- Significant hepatic or renal dysfunction

- Metastatic cancer with a life expectance of less than 6 months

- Disabling stroke

- Active substance abuse

- Severe psychiatric disease

- Patients on Antiretroviral Therapy

- Uncontrolled diabetes mellitus with a history of DKA

- Mitochondrial disease

- Pregnancy

- Ongoing tobacco use

- Children: Individuals younger than 21 years will not be included in the protocol
because reference ranges for normative aerobic capacity and aerobic fitness have not
been established for these age ranges.