This study aims to investigate therapies for exercise induced pulmonary hypertension (EiPH). This is a condition that effects the blood vessels in the lungs and causes shortness of breath with activity. Currently, there are very limited treatment options for this condition. Inhaled treprostinil, also known as Tyvaso, is a medication used to treat other forms of lung disease and is safe and well tolerated. This study will measure the ability of Tyvaso to improve symptoms related to EiPH and improve performance on exercise testing.

Exercise-induced pulmonary hypertension (EiPH) is defined by the presence of normal resting pulmonary hemodynamics with an abnormal elevation in mean pulmonary artery pressure (mPAP) for a given cardiac output with exercise. EiPH is typically characterized by exertional dyspnea, with the absence of other features of resting pulmonary arterial hypertension (PAH) such as elevated right atrial pressure at rest or lower extremity peripheral edema. Since patients with EiPH have normal resting echocardiograms, the disease is often underdiagnosed. Exercise right-heart catheterization remains the gold standard in diagnosing EiPH.

Aside from subjective markers of clinical improvement with therapy, assessment for physiological improvement is challenging since most measures of PAH severity, including echocardiograms, biomarkers and risk calculators, are normal at baseline in this population with EiPH. The investigators have pioneered the use of non-invasive cardiopulmonary exercise testing (CPET) to assess patients with cardiopulmonary limitations during exercise. Changes in oxygen pulse (O2 pulse) during exercise on CPET have previously been validated as an accurate predictor of stroke volume augmentation, which is an important physiological adaptation to exercise, and may serve as an objective marker of improvement in patients with EiPH.

While the guidelines agree that EiPH is real and under-diagnosed, there is no consensus on the management since these patients have not been included in high-quality clinical trials for PAH treatment. Given the lack of treatment guidelines for EiPH, many providers use PAH-targeted therapy off-label in EiPH. Specifically, generic phosphodiesterase-5 inhibitors are the typical first line agent due to insurance barriers to accessing other therapies. Inhaled treprostinil (Tyvaso DPI) would be an ideal medication for this population. Tyvaso DPI is a convenient, inhaled medication with quick onset. The favorable pharmacokinetic profile raises the potential of this medication for dosing prior to exertion for patients with EiPH.

Inclusion Criteria:

• Provision of signed and dated informed consent form

• Stated willingness to comply with all study procedures and availability for the duration of the study

• Persons, aged 18 years of older

• Established diagnosis of exercise induced pulmonary hypertension defined by the following:

  1. Invasive cardiopulmonary exercise testing demonstrating a mean pulmonary artery pressure to cardiac output (P/Q slope) greater than 3 mmHg/L/min
  2. Symptoms of exertional dyspnea

• Ability to perform non-invasive cardiopulmonary exercise testing, either on upright bicycle or treadmill

• If childbearing age, patient must agree to use of effective contraception during the trial

Exclusion Criteria:

• Diagnosis of pulmonary hypertension as defined by resting mean pulmonary arterial pressure of ≥ 20 mmHg, PVR > 3
• Severe underlying chronic lung disease (e.g. COPD, interstitial lung disease)
• Underlying chronic left ventricular disease (e.g. heart failure with reduced ejection fraction)
• Chronic thromboembolic disease
• Pregnancy
• Acute infectious symptoms including fevers within the last week
• Inability or unwillingness to discontinue any phosphodiesterase 5 inhibitors or other off-label
• Known allergic reactions to inhaled treprostinil
• Inability to comply with study protocols

Patients name, phone number, and medical record number will be stored with associated information regarding baseline diagnostic testing, cardiopulmonary exercise testing results, PAH-Sympact scores, and adverse event reporting

IPD and supporting information will be available from trial start date (previously specified) until two years after study completion date (previously specified)

IPD will be stored on a password protected RedCap database and analyzed on password protected and encrypted devices belonging to the University of California, San Diego or the study team. Only members of the study team will be able to access IPD. Any other dissemination of IPD will be shared in a manner that is de-identified. Publication of individual results may occur but this will be presented in a de-identified manner (ie through individual data points on a spaghetti plot).