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Title: Metabolic Response to Stress by the Immature Right Ventricle Exposed to Chronic Pressure Overload

Abstract

Background: The right ventricle (RV) 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 (PDH) leads to hypertrophied RV dysfunction when exposed to hemodynamic stress, and PDH 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 right coronary artery on 7-10 days after PAB. RV systolic pressure, RV free wall thickness and individual cardiomyocyte cell size after PAB were significantly elevated compared to Sham. Both fractional glucose and lactate oxidations in PAB group were > 2-fold higher than in Sham. Pigs with overdrive atrial pacing (~80% increase in heart rate) stress after PAB showed only 22% increase in rate-pressure product (RPP) from the baseline before atrial pacing and the limited carbohydrate oxidation rate in RV. Intracoronary infusion of dichloroacetate, a PDH agonist produced higher RPP (59% increase) in response to increased work-load by atrial pacing in associationmore » with a marked increase in lactate oxidation. Conclusions: The immature hypertrophied RV shows limited ability to increase carbohydrate oxidation in response to tachycardic stress leading to energy supply/utilization imbalance and decreased systolic function. Enhanced PDH activation by dichloroacetate increases energy supply and preserves hypertrophied RV contractile function during hemodynamic stress.« less

Authors:
 [1];  [1];  [2];  [3];  [3];  [4]
  1. Seattle Children's Research Institute
  2. BATTELLE (PACIFIC NW LAB)
  3. University of Montreal
  4. Children's Hospital and Regional Medical Center
Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1581782
Report Number(s):
PNNL-SA-143452
DOE Contract Number:  
AC05-76RL01830
Resource Type:
Journal Article
Journal Name:
Journal of the American Heart Association
Additional Journal Information:
Journal Volume: 8; Journal Issue: 17
Country of Publication:
United States
Language:
English
Subject:
myocardial metabolism, congenital heart disease, right ventricle, pressure overload

Citation Formats

Kajimoto, Masaki, Nuri, Muhammad, Isern, Nancy G., Robillard Frayne, Isabelle, Des Rosiers, Christine, and Portman, Michael A. Metabolic Response to Stress by the Immature Right Ventricle Exposed to Chronic Pressure Overload. United States: N. p., 2019. Web. doi:10.1161/JAHA.119.013169.
Kajimoto, Masaki, Nuri, Muhammad, Isern, Nancy G., Robillard Frayne, Isabelle, Des Rosiers, Christine, & Portman, Michael A. Metabolic Response to Stress by the Immature Right Ventricle Exposed to Chronic Pressure Overload. United States. doi:10.1161/JAHA.119.013169.
Kajimoto, Masaki, Nuri, Muhammad, Isern, Nancy G., Robillard Frayne, Isabelle, Des Rosiers, Christine, and Portman, Michael A. Tue . "Metabolic Response to Stress by the Immature Right Ventricle Exposed to Chronic Pressure Overload". United States. doi:10.1161/JAHA.119.013169.
@article{osti_1581782,
title = {Metabolic Response to Stress by the Immature Right Ventricle Exposed to Chronic Pressure Overload},
author = {Kajimoto, Masaki and Nuri, Muhammad and Isern, Nancy G. and Robillard Frayne, Isabelle and Des Rosiers, Christine and Portman, Michael A.},
abstractNote = {Background: The right ventricle (RV) 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 (PDH) leads to hypertrophied RV dysfunction when exposed to hemodynamic stress, and PDH 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 right coronary artery on 7-10 days after PAB. RV systolic pressure, RV free wall thickness and individual cardiomyocyte cell size after PAB were significantly elevated compared to Sham. Both fractional glucose and lactate oxidations in PAB group were > 2-fold higher than in Sham. Pigs with overdrive atrial pacing (~80% increase in heart rate) stress after PAB showed only 22% increase in rate-pressure product (RPP) from the baseline before atrial pacing and the limited carbohydrate oxidation rate in RV. Intracoronary infusion of dichloroacetate, a PDH agonist produced higher RPP (59% increase) in response to increased work-load by atrial pacing in association with a marked increase in lactate oxidation. Conclusions: The immature hypertrophied RV shows limited ability to increase carbohydrate oxidation in response to tachycardic stress leading to energy supply/utilization imbalance and decreased systolic function. Enhanced PDH activation by dichloroacetate increases energy supply and preserves hypertrophied RV contractile function during hemodynamic stress.},
doi = {10.1161/JAHA.119.013169},
journal = {Journal of the American Heart Association},
number = 17,
volume = 8,
place = {United States},
year = {2019},
month = {9}
}

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