Carnitine Consumption and Augmentation in Pulmonary Arterial Hypertension
Condition: Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Primary Pulmonary Hypertension; Lung Diseases; Carnitine Nutritional Deficiency
MeSH terms: Lung Diseases; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension; Malnutrition
Study type: Interventional
Phase: Phase 1

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.
    

Intervention name(s): L-carnitine
Intervention type(s): Dietary Supplement
Intervention description(s): supplement provided twice a day for 2 weeks
Other intervention name(s): Carnitine; Carnitor
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Intervention 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)
Primary purpose: Other