In preparation for a future mechanistic study, investigators now propose to test the specific hypothesis that carnitine consumption is not reduced in PAH, that plasma carnitine levels are stable over time in PAH and that carnitine supplementation in PAH can increase plasma carnitine and thereby delivery of carnitine to the RV and possibly improve RV function. Investigators propose three aims in humans to test this mechanistic hypothesis, 1) Measure the oral consumption of carnitine in human PAH. This aim will use food diaries and carnitine supplement use questionnaires in PAH patients to test the hypothesis that carnitine supplementation is uncommon in PAH and food consumption is adequate. Aim 2) Measure the stability over time in plasma carnitine levels in PAH patients. This aim will test the hypothesis that plasma carnitine is not affected by disease severity and is stable over time in PAH patients. Investigators will measure plasma carnitine concentration and markers of fatty acid oxidation at Visit 1 and Visit 2. 3) Perform a mechanistic pilot study using carnitine supplementation to enhance circulating carnitine in PAH. This small pilot study will test the hypothesis that carnitine supplementation increases plasma carnitine (primary endpoint) and will test for physiologic effects using six minute walk testing, echocardiography and plasma markers of lipid metabolism.

Right ventricular (RV) failure is the most common cause of death in pulmonary arterial hypertension (PAH). No RV-specific therapies are available, in part because the underlying mechanisms of RV failure are poorly understood. A growing body of evidence suggests that metabolic abnormalities may underlie RV dysfunction in PAH. Interventions against metabolic dysfunction in PAH may protect against RV failure. Investigators in the PH research group have identified abnormalities in fatty acid (FA) metabolism in PAH that overlap considerably with disorders of carnitine deficiency. Carnitine links to an acyl group, which is required to transport FAs across the mitochondrial membrane to undergo beta-oxidation, the predominate source of ATP production in the human heart. Inborn errors of carnitine metabolism and acquired carnitine deficiency are associated with cardiomyopathy. Acquired deficiency primarily occurs via binding of carnitine to excess circulating fatty acids or renal wasting. Carnitine deficiency and PAH are both associated with insulin resistance, myocardial lipotoxicity, and mitochondrial oxidative stress. Carnitine supplementation in humans and animal models of cardiometabolic dysfunction reverses these abnormalities but has not been studied in PAH. In published work, investigators found that in RV samples from humans with PAH, there is a marked (up to 300-fold) reduction in acylcarnitines along with increased long-chain fatty acids. Investigators also a found a two-fold increase in circulating fatty acids FAs in humans with PAH, indicating increased delivery to the myocardium. As a consequence of unchecked fatty acid accumulation, investigators observed 7-fold higher RV lipid content and markers of lipotoxicity. These observations suggest there is inadequate carnitine substrate to bind fatty acids and facilitate their transport across the mitochondrial membrane in the human PAH RV.

The investigator's overarching hypothesis is that in human PAH, RV function can be improved by augmenting carnitine substrate availability to improve outcomes. In preparation for a future mechanistic study, Vanderbilt PAH research investigators now propose to test the specific hypothesis that carnitine consumption is not reduced in PAH, that plasma carnitine levels are stable over time in PAH and that carnitine supplementation in PAH can increase plasma carnitine and thereby delivery of carnitine to the RV and possibly improve RV function. Investigators propose three aims in humans to test this mechanistic hypothesis, 1) Measure the oral consumption of carnitine in human PAH. This aim will use food diaries and carnitine supplement use questionnaires in PAH patients to test the hypothesis that carnitine supplementation is uncommon in PAH and food consumption is adequate. Aim 2) Measure the stability over time in plasma carnitine levels in PAH patients. This aim will test the hypothesis that plasma carnitine is not affected by disease severity and is stable over time in PAH patients. The study will measure plasma carnitine concentration and markers of fatty acid oxidation at Visit 1 and Visit 2. 3) Perform a mechanistic pilot study using carnitine supplementation to enhance circulating carnitine in PAH. This small pilot study will test the hypothesis that carnitine supplementation increases plasma carnitine (primary endpoint) and will test for physiologic effects using six minute walk testing, echocardiography and plasma markers of lipid metabolism.

Inclusion Criteria:

• Adults aged 18 or older.
• Diagnosed with idiopathic, heritable, simple congenital heart defect, or drug- or toxin-associated pulmonary arterial hypertension (PAH) according to World Health Organization consensus recommendations.
• Stable PAH-specific medication regimen for three months prior to enrollment. Subjects with only a single diuretic adjustment in the prior three months will be included. Adjustments in IV prostacyclin for side effect management are allowed.
• FEV1> or = 60% predicted and no more than mild abnormalities on lung imaging
• WHO Functional Class II-IV
• Ambulatory

Exclusion Criteria:

• Prohibited from normal activity due to wheelchair bound status, bed bound status, reliance on a cane/walker, activity-limiting angina, activity-limiting osteoarthritis, or other condition that limits activity
• Pregnancy
• Diagnosis of PAH etiology other than idiopathic, heritable, simple congenital heart defect, or associated with drugs or toxins
• Drug and toxin associated PAH patients with active drug use
• Prior diagnosis of cirrhosis
• Malignancy
• eGFR by MDRD <60mL/min
• Known allergy to l-carnitine supplements

Since the data that will be produced involves patients with a disease process that is much in need of new treatment options and the investigators agree that data sharing is essential for expedited translation of research results into patient treatment options. A detailed data sharing plan is in place and available upon request. In brief:

It is the investigator's plan to make data available at the time it is accepted for publication of the main findings from the final dataset through the use of a data enclave of our own design that would restrict our Data Analyst from sharing any information that would breach participant confidentiality. Potential researchers will contact the PI to discuss specific needs and how the data will be utilized. A formal approval process is in place to evaluate and complete such requests.

2 years after study completion.

• detailed written description of the project for which the data would be used
• acknowledge in any publication resulting from the data, the source of the data, crediting the program support
• agree to submit all papers or reports submitted for publication to the PI for review prior to submission

Participants were monitored for adverse events for a total of 16 weeks, from Visit 1 until 14 days following the last administration of study treatment.