Carnitine Consumption and Augmentation in Pulmonary Arterial Hypertension

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.

Study Overview

• Status: Completed
• Conditions: Lung Diseases; Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Primary Pulmonary Hypertension; Carnitine Nutritional Deficiency
• Intervention / Treatment: Dietary supplement: L-carnitine

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.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Alisha Lindsey, MSHA; Phone Number: (937)638-2416; Email: alisha.lindsey@vumc.org
• Study Contact Backup: Name: Kelly Burke; Phone Number: (865)804-2491; Email: kelly.burke@vumc.org

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Supplement; 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; supplement provided twice a day for 2 weeks; Other Names: Carnitor; Carnitine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma Carnitine concentration	Difference in plasma Carnitine concentration from Visit 2 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

Collaborators and Investigators

• Sponsor: Vanderbilt University Medical Center
• Investigators: Principal Investigator: Anna R Hemnes, Vanderbilt University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): September 29, 2021
• Primary Completion (Actual): June 1, 2023
• Study Completion (Actual): June 30, 2023

Study Registration Dates

• First Submitted: May 17, 2021
• First Submitted That Met QC Criteria: May 25, 2021
• First Posted (Actual): June 1, 2021

Study Record Updates

• Last Update Posted (Actual): February 14, 2024
• Last Update Submitted That Met QC Criteria: February 11, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Nutrition Disorders; Hypertension; Lung Diseases; Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension, Pulmonary; Malnutrition
• Other Study ID Numbers: 210899

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

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.

• IPD Sharing Time Frame: 2 years after study completion.
• IPD Sharing Access Criteria: 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
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No