Carnitine Consumption and Augmentation in Pulmonary Arterial Hypertension

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Carnitine Consumption and Augmentation in Pulmonary Arterial Hypertension

Conditions
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Pulmonary Arterial Hypertension, Familial Primary Pulmonary Hypertension, Primary Pulmonary Hypertension, Lung Diseases, Carnitine Nutritional Deficiency

Intervention / Treatment
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* Dietary Supplement: L-carnitine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: This is a single-center, prospective study enrolling 10 PAH patients. All eligible participants will be given carnitine supplements for 2 weeks.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Supplement<br>Form: 500 mg L-carnitine tablet Dosage: Subjects 50-90kg: 3g/day Subjects <50kg or >90kg: 50mg/kg/day Frequency: twice a day for 2 weeks | Dietary Supplement: L-carnitine<br>* supplement provided twice a day for 2 weeks<br>* Other names: Carnitor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Carnitine concentration | Difference in plasma Carnitine concentration from Visit 3 to Visit 4 | 14 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prevalence of Carnitine supplement use | Quantify the prevalence of Carnitine supplement use of Carnitine in PAH patients | 12 weeks | 
| Carnitine ingestion use through food | Measure oral ingestion of Carnitine in PAH patients by assessing food intake recorded by diary | 12 weeks | 
| Six-minute walk | Correlation of Carnitine ingestion with six-minute walk distance | 14 weeks | 
| WHO functional class | Correlation of Carnitine ingestion with WHO functional class | 14 weeks | 
| Patient Reported Side Effects | Markers of tolerability of Carnitine supplement including presence of side effects, adverse events, and serious adverse events | 2 weeks | 
| Echocardiography measurements of TAPSE and RV fractional area | Correlation of change in plasma Carnitine with change in markers of RV function including TAPSE and RV fractional area change | 14 weeks | 
| Stability of plasma carnitine | Change in plasma carnitine from visit 1 to visit 2 | 12 weeks |