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Altered Carnitine Homeostasis in Children With Increased Pulmonary Blood Flow Due to Ventricular Septal Defects

Stephen M Black¹, Aida Field-Ridley, Shruti Sharma

¹1Department of Medicine, University of Arizona, Tucson, AZ. 2Department of Pediatrics, University of California, San Francisco, CA.

Pediatric Critical Care Medicine : a Journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

|July 21, 2017

Insights

Children with congenital heart disease and increased pulmonary blood flow show altered carnitine homeostasis, mitochondrial dysfunction, and increased oxidative stress. These findings in ventricular septal defect patients suggest potential targets for therapeutic intervention.

Area of Science:

Pediatric Cardiology
Biochemistry
Mitochondrial Biology

Background:

Congenital heart disease (CHD) with increased pulmonary blood flow (PBF) leads to progressive pulmonary vascular endothelial dysfunction and perioperative morbidity.
Previous ovine models demonstrated endothelial dysfunction linked to carnitine homeostasis disruption, mitochondrial dysfunction, reduced nitric oxide (NO) signaling, and increased reactive oxygen species (ROS) generation.
Potential alterations in these parameters within human pediatric CHD patients remained uninvestigated.

Purpose of the Study:

To test the hypothesis that children with increased PBF exhibit altered carnitine homeostasis, mitochondrial dysfunction, decreased NO levels, and increased ROS generation.
To investigate biochemical markers of endothelial dysfunction in pediatric patients with CHD.
To compare these markers between patients with and without increased PBF and healthy controls.

Main Methods:

A prospective, single-center cohort study was conducted in a tertiary care cardiac ICU/PICU.
Arterial blood samples were collected from 18 patients with ventricular septal defect (VSD) (increased PBF), 20 with tetralogy of Fallot (TOF) (no increased PBF), and 10 controls.
Plasma levels of carnitine metabolites, lactate-to-pyruvate ratio (mitochondrial function indicator), superoxide, hydrogen peroxide, and NOx were measured and compared.

Main Results:

Patients with VSD exhibited significantly higher baseline acylcarnitine levels and acylcarnitine-to-free carnitine ratios compared to TOF patients.
The lactate-to-pyruvate ratio was significantly elevated in VSD patients compared to TOF patients, indicating impaired mitochondrial function.
Superoxide and H2O2 levels were higher, while NOx levels were lower in VSD patients compared to controls and TOF patients.

Conclusions:

Increased PBF in VSD is associated with disrupted carnitine and mitochondrial homeostasis, reduced NO signaling, and elevated ROS production.
These findings in pediatric patients align with previous animal model data, suggesting a causal link between carnitine metabolism disruption and endothelial dysfunction.
Carnitine supplementation may represent a potential therapeutic strategy to mitigate endothelial dysfunction in patients with increased PBF, warranting further investigation.

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Abstract

Objectives:

Congenital heart disease with increased pulmonary blood flow results in progressive pulmonary vascular endothelial dysfunction and associated increased perioperative morbidity. Using our ovine model of congenital heart disease with increased pulmonary blood flow, we have previously demonstrated progressive endothelial dysfunction associated with disruption in carnitine homeostasis, mitochondrial dysfunction, decreased nitric oxide signaling, and enhanced reactive oxygen species generation. However, potential alterations in these parameters in patients with congenital heart disease have not been investigated. The objective of this study was to test the hypothesis that children with increased pulmonary blood flow will have evidence of altered carnitine homeostasis, mitochondrial dysfunction, decreased nitric oxide levels, and increased reactive oxygen species generation.

Design:

A prospective single-center cohort study.

Setting:

A tertiary care cardiac ICU/PICU.

Patients:

Arterial blood samples from 18 patients with congenital heart disease associated with increased pulmonary blood flow (ventricular septal defect), 20 with congenital heart disease without increased pulmonary blood flow (tetralogy of Fallot), and 10 without heart disease (controls) were obtained.

Interventions:

Plasma levels of total carnitine, free carnitine, acylcarnitine, and lactate-to-pyruvate ratios, an indicator of mitochondrial function, were determined and compared. In addition, levels of superoxide and hydrogen peroxide were determined and compared in patients with ventricular septal defect and controls. Statistical analysis was performed using an unpaired t test and analysis of variance.

Measurements And Main Results:

Baseline acylcarnitine levels (25.7 ± 13 vs 12.7 ± 8.3; p < 0.05), the acylcarnitine-to-free carnitine ratio (0.8 ± 0.1 vs 0.3 ± 0.05; p < 0.05), and the lactate-to-pyruvate ratio were higher in ventricular septal defect (27.5 ± 3.8 vs 11.1 ± 4.1, p < 0.05) than tetralogy of Fallot; there were no differences between tetralogy of Fallot and control. Superoxide and H2O2 levels were also higher in ventricular septal defect compared with controls, and NOx levels were lower in ventricular septal defect patients compared with tetralogy of Fallot and controls (p < 0.05).

Conclusions:

These data suggest that increased pulmonary blood flow from ventricular septal defect results in altered carnitine and mitochondrial homeostasis, decreased nitric oxide signaling, and increased reactive oxygen species production. These data are consistent with our animal data demonstrating that altered carnitine homeostasis results in mitochondrial dysfunction, increased reactive oxygen species production, and decreased bioavailable nitric oxide. Since disruption of carnitine metabolism may contribute to endothelial dysfunction, carnitine supplementation may attenuate endothelial dysfunction associated with increased pulmonary blood flow and warrants further investigation.

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