Pulmonary vascular disease is perhaps the most important complication for children with common congenital heart defects (CHD) that result in increased pulmonary blood flow (PBF) and pressure, such as large ventricular septal defects (VSD) and atrioventricular septal defects (AVSD). Beginning immediately after birth, the pulmonary vasculature in these patients is subjected to pathologic mechanical forces, such as increased shear stress, resulting in early functional abnormalities of the vascular endothelium, including decreased bioavailable nitric oxide (NO). Repairing these defects in infancy or early childhood mostly prevents the development of irreversible pulmonary vascular disease, however perioperative pulmonary vascular dysfunction, particularly following cardiopulmonary bypass (CPB), continues to contribute to the morbidity and mortality of these patients. Utilizing our clinically relevant lamb model of CHD, we have generated compelling data demonstrating that increased PBF impairs carnitine homeostasis, in association with mitochondrial dysfunction, decreased HSP90/eNOS interactions, increased reactive oxygen species (ROS) production, and decreased bioavailable NO, and that eNOS mitochondrial translocation and the loss of CrAT activity is pivotal to this pathobiology. In addition, our preliminary data indicate that treatment with exogenous L-carnitine can attenuate these effects. Importantly, we also have novel preliminary data demonstrating altered carnitine homeostasis, mitochondrial dysfunction, and ROS production in infants with VSDs. Thus, we hypothesize that: (1) increased PBF associated with CHD induces early aberrations in carnitine homeostasis that ultimately result in decreased bioavailable NO and altered pulmonary vascular function;and (2) L-carnitine treatment can attenuate this pathobiology and improve clinical outcomes. In order to test these hypotheses, we propose a translational project that integrates cell culture, animal and human based studies to accomplish the following aims: (1) To determine the effect of L-carnitine treatment on carnitine homeostasis, mitochondrial function, ROS production, bioavailable NO, and vascular reactivity in a lamb model of CHD;(2) To determine the effect of acute IV L-carnitine treatment on pulmonary vascular resistance, vascular reactivity, and myocardial performance following CPB in a lamb model of CHD;(3A) To determine perioperative alterations in carnitine homeostasis, mitochondrial function, ROS production, and NO bioavailability in infants with VSD and AVSD;and (3B) To pilot a trial assessing the safety and pharmacokinetics of perioperative IV L-carnitine administration in these patients, and begin to assess its effect on post-operative clinical outcomes. Importantly, L-carnitine has been administered to children for decades, with an excellent safety profile, and can be delivered orally as well as IV. Taken together, our pre-clinical and preliminary human data and the feasibility of L-carnitine therapy represent an important opportunity to translate basic mechanisms into a novel targeted therapeutic strategy for pulmonary vascular disease in a high-risk patient population.

Public Health Relevance

Pulmonary vascular disease is perhaps the most important complication for children with common congenital heart defects (CHD) that result in increased pulmonary blood flow (PBF) and pressure, such as large ventricular septal defects (VSD) and atrioventricular septal defects (AVSD). In this proposal we will comprehensively elucidate the role of altered carnitine homeostasis in this pathobiology, and the potential therapeutic benefit o L-carnitine administration. The data from these cell culture, animal and human studies may easily translate into a novel therapeutic target for infants with CHD and increased PBF.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL061284-14A1
Application #
8532692
Study Section
Special Emphasis Panel (ZRG1-CVRS-G (02))
Program Officer
Lin, Sara
Project Start
1999-07-01
Project End
2017-03-31
Budget Start
2013-04-15
Budget End
2014-03-31
Support Year
14
Fiscal Year
2013
Total Cost
$665,026
Indirect Cost
$170,148
Name
University of California San Francisco
Department
Pediatrics
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Radman, Monique; Mack, Ricardo; Barnoya, Joaquin et al. (2014) The effect of preoperative nutritional status on postoperative outcomes in children undergoing surgery for congenital heart defects in San Francisco (UCSF) and Guatemala City (UNICAR). J Thorac Cardiovasc Surg 147:442-50
Bertero, Thomas; Lu, Yu; Annis, Sofia et al. (2014) Systems-level regulation of microRNA networks by miR-130/301 promotes pulmonary hypertension. J Clin Invest 124:3514-28
Sun, Xutong; Sharma, Shruti; Fratz, Sohrab et al. (2013) Disruption of endothelial cell mitochondrial bioenergetics in lambs with increased pulmonary blood flow. Antioxid Redox Signal 18:1739-52

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