Affiliation:
1. Center for Integrative Brain Research Seattle Children's Research Institute Seattle WA
2. Division of Pediatric Cardiac Surgery Seattle Children's Hospital Seattle WA
3. Environmental Molecular Sciences Laboratory Pacific Northwest National Laboratories Richland WA
4. Department of Nutrition Université de Montréal and Montreal Heart Institute Montréal Quebec Canada
5. Division of Cardiology Department of Pediatrics University of Washington Seattle WA
Abstract
Background
The right ventricle exposed to chronic pressure overload exhibits hypertrophy and decompensates when exposed to stress. We hypothesize that impaired ability to increase myocardial oxidative flux through pyruvate dehydrogenase leads to hypertrophied right ventricular (
RV
) dysfunction when exposed to hemodynamic stress, and pyruvate dehydrogenase stimulation can improve
RV
function.
Methods and Results
Infant male Yorkshire piglets (13.5±0.6 kg weight, n=19) were used to assess substrate fractional contribution to the citric acid cycle after sustained pulmonary artery banding (
PAB
). Carbon 13–labeled glucose, lactate, and leucine, oxidative substrate tracers for the citric acid cycle, were infused into the right coronary artery on 7 to 10 days after
PAB
.
RV
systolic pressure,
RV
free wall thickness, and individual cardiomyocyte cell size after
PAB
were significantly elevated compared with the sham group. Both fractional glucose and lactate oxidations in the
PAB
group were >2‐fold higher than in the sham group. Pigs with overdrive atrial pacing (≈80% increase in heart rate) stress after
PAB
showed only a 22% increase in rate‐pressure product from baseline before atrial pacing and limited carbohydrate oxidation rate in the right ventricle. Intracoronary infusion of dichloroacetate, a pyruvate dehydrogenase agonist, produced higher rate‐pressure product (59% increase) in response to increased workload by atrial pacing in association with a marked increase in lactate oxidation.
Conclusions
The immature hypertrophied right ventricle shows limited ability to increase carbohydrate oxidation in response to tachycardia stress leading to energy supply/utilization imbalance and decreased systolic function. Enhanced pyruvate dehydrogenase activation by dichloroacetate increases energy supply and preserves hypertrophied
RV
contractile function during hemodynamic stress.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine
Cited by
5 articles.
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