Carnitine Consumption and Augmentation in Pulmonary Arterial Hypertension

Phase 1

Completed

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

Interventions: Dietary Supplement: L-carnitine

Registration Number: NCT04908397

Lead Sponsor: Vanderbilt University Medical Center

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 10

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Supplement	L-carnitine	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

Primary Outcome Measures

Name	Time	Method
Plasma Carnitine Concentration	2 weeks of intervention	Change in plasma Carnitine concentration from Visit 2 (Week 12) to Visit 4 (Week 14).

Secondary Outcome Measures

Name	Time	Method
Patient Reported Side Effects	2 weeks- between visit 2 and visit 4	Markers of tolerability of Carnitine supplement including presence of side effects, adverse events, and serious adverse events. Side effects to be reported beginning Visit 2, at carnitine start, and ended at Visit 4.
Echocardiography Measurements of TAPSE and RV Fractional Area	14 weeks	Correlation of change in plasma Carnitine with change in markers of RV function including TAPSE and RV fractional area change
Stability of Plasma Carnitine	12 weeks- change from visit 1(week 1) to visit 2(week 12)	Change in plasma carnitine from visit 1 to visit 2
Prevalence of Carnitine Supplement Use	12 weeks	Quantify the prevalence of Carnitine supplement use of Carnitine in PAH patients by evaluating the number of study participants that report use of a daily carnitine supplement in baseline dietary reporting.
Carnitine Ingestion Use Through Food	Reported week 1 (3 days leading up to visit 1) and week 12 (3 days leading up to visit 2).	Measure oral ingestion of Carnitine in PAH patients by assessing food intake recorded by diary. Reports lacking meat, fish, and/or eggs are deemed "no ingestion by diet".
Six-minute Walk	14 weeks	Correlation of Carnitine ingestion with six-minute walk distance
WHO Functional Class	14 weeks	Correlation of Carnitine ingestion with WHO functional class