Christine Des Rosiers

Montreal Heart Institute, Montréal, Quebec, Canada

Are you Christine Des Rosiers?

Claim your profile

Publications (115)459.38 Total impact

  • Archives of Cardiovascular Diseases Supplements 04/2015; 7(2). DOI:10.1016/S1878-6480(15)30022-7
  • [Show abstract] [Hide abstract]
    ABSTRACT: Extracorporeal membrane oxygenation (ECMO) provides mechanical circulatory support for infants and children with postoperative cardiopulmonary failure. Nutritional support is mandatory during ECMO, although specific actions for substrates on the heart have not been delineated. Prior work shows that enhancing pyruvate oxidation promotes successful weaning from ECMO. Accordingly, we tested the hypothesis that prolonged systemic pyruvate supplementation activates pyruvate oxidation in an immature swine model in vivo. Twelve male mixed breed Yorkshire piglets (age 30-49 days) received systemic infusion of either normal saline (Group C) or pyruvate (Group P) during the final 6 hours of 8 hours of ECMO. Over the final hour piglets received [2-(13)C] Pyruvate, as a reference substrate for oxidation, and [(13)C6]-L-leucine, as an indicator for amino acid oxidation and protein synthesis. A significant increase in lactate and pyruvate concentrations occurred, along with an increase in the absolute concentration of the CAC intermediates. An increase in anaplerotic flux through pyruvate carboxylation in group P occurred compared to no change in pyruvate oxidation. Additionally, pyruvate promoted an increase in the phosphorylation state of several nutrient sensitive enzymes, like AMPK and ACC, suggesting activation for fatty acid oxidation. Pyruvate also promoted O-GlcNAcylation through the hexosamine biosynthetic pathway (HBP). In conclusion, although prolonged pyruvate supplementation did not alter pyruvate oxidation, it did elicit changes in nutrient and energy sensitive pathways. Therefore, the observed results support the further study of pyruvate and its downstream effect on cardiac function. Copyright © 2015, American Journal of Physiology - Heart and Circulatory Physiology.
    AJP Heart and Circulatory Physiology 04/2015; DOI:10.1152/ajpheart.00011.2015 · 4.01 Impact Factor
  • Archives of Cardiovascular Diseases Supplements 04/2015; 7(2):185. DOI:10.1016/S1878-6480(15)30148-8
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background To improve the prevention, treatment and risk prediction of cardiovascular diseases, genetic markers and gene–diet interactions are currently being investigated. The Montreal Heart Institute (MHI) Biobank is suitable for such studies because of its large sample size (currently, n = 17 000), the availability of biospecimens, and the collection of data on dietary intakes of saturated (SFAs) and n-3 and n-6 polyunsaturated (PUFAs) fatty acids estimated from a 14-item food frequency questionnaire (FFQ). We tested the validity of the FFQ by correlating dietary intakes of these fatty acids with their red blood cell (RBC) content in MHI Biobank participants.Methods Seventy-five men and 75 women were selected from the Biobank. We successfully obtained RBC fatty acids for 142 subjects using gas chromatography coupled to mass spectrometry. Spearman correlation coefficients were used to test whether SFA scores and daily intakes (g day−1) of n-3 and n-6 PUFAs correlate with their RBC content.ResultsBased on covariate-adjusted analyses, intakes of n-3 PUFAs from vegetable sources were significantly correlated with RBC α-linolenic acid levels (ρ = 0.23, P = 0.007), whereas n-3 PUFA intakes from marine sources correlated significantly with RBC eicosapentaenoic acid (ρ = 0.29, P = 0.0008) and docosahexaenoic acid (ρ = 0.41, P = 9.2 × 10–7) levels. Intakes of n-6 PUFAs from vegetable sources correlated with RBC linoleic acid (ρ = 0.18, P = 0.04). SFA scores were not correlated with RBC total SFAs.Conclusions The MHI Biobank 14-item FFQ can appropriately estimate daily intakes of n-3 PUFAs from vegetable and marine sources, as well as vegetable n-6 PUFAs, which enables the possibility of using these data in future studies.
    Journal of Human Nutrition and Dietetics 09/2014; DOI:10.1111/jhn.12272 · 2.07 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background-Angiopoietin-like-2 (angptl2) is produced by several cell types including endothelial cells, adipocytes and macrophages, and contributes to the inflammatory process in cardiovascular diseases. We hypothesized that angptl2 impairs endothelial function, and that lowering angptl2 levels protects the endothelium against high-fat diet (HFD)-induced fat accumulation and hypercholesterolemia. Methods and Results-Acute recombinant angptl2 reduced (P<0.05) acetylcholine-mediated vasodilation of isolated wild-type (WT) mouse femoral artery, an effect reversed (P<0.05) by the antioxidant N-acetylcysteine. Accordingly, in angptl2 knockdown (KD) mice, ACh-mediated endothelium-dependent vasodilation was greater (P<0.05) than in WT mice. In arteries from KD mice, prostacyclin contributed to the overall dilation unlike in WT mice. After a 3-month HFD, overall vasodilation was not altered, but dissecting out the endothelial intrinsic pathways revealed that NO production was reduced in arteries isolated from HFD-fed WT mice (P<0.05), while NO release was maintained in KD mice. Similarly, endothelium-derived hyperpolarizing factor (EDHF) was preserved in mesenteric arteries from HFD-fed KD mice but not in those from WT mice. Finally, the HFD increased (P<0.05) total cholesterol-to-high-density lipoprotein ratios, low-density lipoprotein-to-high-density lipoprotein ratios, and leptin levels in WT mice only, while glycemia remained similar in the 2 strains. KD mice displayed less triglyceride accumulation in the liver (P<0.05 versus WT), and adipocyte diameters in mesenteric and epididymal white adipose tissues were smaller (P<0.05) in KD than in WT fed an HFD, while inflammatory gene expression increased (P<0.05) in the fat of WT mice only. Conclusions-Lack of angptl2 expression limits the metabolic stress induced by an HFD and maintains endothelial function in mice.
    Journal of the American Heart Association 06/2014; 3(4):e001024-e001024. DOI:10.1161/JAHA.114.001024 · 2.88 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background It was demonstrated that branched-chain amino acids like leucine induce insulin resistance in muscle and adipose tissues. The mechanism proposed to explain leucine action involves mTOR/p70S6K signaling. This pathway can be activated by leucine and is implicated in the stimulation of an insulin negative feedback loop. Knowing that insulin-resistance participates in diabetic cardiomyopathy, we were interested in studying leucine effect in cardiomyocytes. Methods Primary cultured adult rat cardiomyocytes were pretreated with different concentrations of leucine (from 1 to 10 mM) during different periods of time (up to 20h) before being exposed to insulin (3x10−9 M, 30 min). Results In absence of leucine, insulin induced a 6-fold increase in glucose uptake (0.31+/−0.04 vs. 0.05+/−0.01 μmoles/mg.h). This correlated with the increase in phosphorylation state of PKB and AS160, both known to regulate glucose transport downstream of insulin. Pre-incubation with leucine for 1 h stimulated mTOR/p70S6K pathway resulting in the inhibiting phosphorylation of IRS-1 located in the proximal insulin signaling pathway. This is accompanied by a significant decrease in PKB and AS160 phosphorylation but, surprisingly, insulin-stimulated glucose uptake was preserved (0.31+/–0.05 μmoles/mg.h). On the other hand, a longer incubation (14h) with leucine induced a drastic decrease in glucose transport (0.056+/–0.01 μmoles/mg.h). The mTOR/p70S6K inhibitor rapamycin did not prevent this inhibition. Moreover, the non-metabolized leucine analog BCH was able to stimulate mTOR/p70S6K pathway but had no effect on the insulin-mediated stimulation of glucose uptake. By contrast, intermediates of leucine catabolism, alpha-ketoisocaproate, acetoacetate and betahydroxybutyrate, inhibited glucose uptake similarly to leucine. Conclusion Leucine catabolism reduces insulin-dependent glucose transport independently of insulin signaling.
    Archives of Cardiovascular Diseases Supplements 04/2014; 6:13. DOI:10.1016/S1878-6480(14)71296-0
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Extracorporeal membrane oxygenation (ECMO) provides a bridge to recovery after myocardial injury in infants and children, yet morbidity and mortality remain high. Weaning from the circuit requires adequate cardiac contractile function, which can be impaired by metabolic disturbances induced either by ischemia-reperfusion and/or by ECMO. We tested the hypothesis that although ECMO partially ameliorates metabolic abnormalities induced by ischemia-reperfusion, these abnormalities persist or recur with weaning. We also determined if thyroid hormone supplementation (triiodothyronine) during ECMO improves oxidative metabolism and cardiac function. Neonatal piglets underwent transient coronary ischemia to induce cardiac injury then were separated into 4 groups based on loading status. Piglets without coronary ischemia served as controls. We infused into the left coronary artery [2-(13)C]pyruvate and [(13)C6, (15)N]l-leucine to evaluate oxidative metabolism by gas chromatography-mass spectroscopy and nuclear magnetic resonance methods. ECMO improved survival, increased oxidative substrate contribution through pyruvate dehydrogenase, reduced succinate and fumarate accumulation, and ameliorated ATP depletion induced by ischemia. The functional and metabolic benefit of ECMO was lost with weaning, yet triiodothyronine supplementation during ECMO restored function, increased relative pyruvate dehydrogenase flux, reduced succinate and fumarate, and preserved ATP stores. Although ECMO provides metabolic rest by decreasing energy demand, metabolic impairments persist, and are exacerbated with weaning. Treating ECMO-induced thyroid depression with triiodothyronine improves substrate flux, myocardial oxidative capacity and cardiac contractile function. This translational model suggests that metabolic targeting can improve weaning.
    Journal of the American Heart Association 03/2014; 3(2):e000680. DOI:10.1161/JAHA.113.000680 · 2.88 Impact Factor
  • Diabetes & Metabolism 03/2014; 40:A65. DOI:10.1016/S1262-3636(14)72444-9 · 2.85 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Anesthetics used in infants and children are implicated in the development of neurocognitive disorders. Although propofol induces neuroapoptosis in developing brain, the underlying mechanisms require elucidation and may have an energetic basis. We studied substrate utilization in immature swine anesthetized with either propofol or isoflurane for 4 hours. Piglets were infused with 13-Carbon-labeled glucose and leucine in the common carotid artery to assess citric acid cycle (CAC) metabolism in the parietal cortex. The anesthetics produced similar systemic hemodynamics and cerebral oxygen saturation by near-infrared spectroscopy. Compared with isoflurane, propofol depleted ATP and glycogen stores. Propofol decreased pools of the CAC intermediates, citrate, and α-ketoglutarate, while markedly increasing succinate along with decreasing mitochondrial complex II activity. Propofol also inhibited acetyl-CoA entry into the CAC through pyruvate dehydrogenase, while promoting glycolytic flux with marked lactate accumulation. Although oxygen supply appeared similar between the anesthetic groups, propofol yielded a metabolic phenotype that resembled a hypoxic state. Propofol impairs substrate flux through the CAC in the immature cerebral cortex. These impairments occurred without systemic metabolic perturbations that typically accompany propofol infusion syndrome. These metabolic abnormalities may have a role in the neurotoxity observed with propofol in the vulnerable immature brain.Journal of Cerebral Blood Flow & Metabolism advance online publication, 8 January 2014; doi:10.1038/jcbfm.2013.229.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 01/2014; DOI:10.1038/jcbfm.2013.229 · 5.34 Impact Factor
  • AJP Heart and Circulatory Physiology 12/2013; 306(2). DOI:10.1152/ajpheart.00938.2013 · 4.01 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aim: In mice, genetic background is known to influence various parameters, including cardiac function. Its impact on cardiac energy substrate metabolism - a factor known to be closely related to function and contributes to disease development - is, however, unclear. This was examined in this study. Methods & Results: In commonly-used control mouse substrains SJL/JCrNTac, 129S6/SvEvTac, C57Bl/6J and C57Bl/6NCrl, we assessed the functional and metabolic phenotypes of 3 month old working mouse hearts perfused ex vivo with physiological concentrations of 13C labeled carbohydrates (CHO) and a fatty acid (FA). Marked variations in various functional and metabolic flux parameters were observed among all mouse substrains, although the pattern observed differed for these parameters. For example, among all strains, C57Bl/6NCrl hearts had a greater cardiac output (+1.7 fold vs SJL/JCrNTac and C57Bl/6J; P<0.05), while at the metabolic level, 129S6/SvEvTac hearts stood out by displaying (vs. all 3 strains) a striking shift from exogenous FA (~ -3.5-fold) to CHO oxidation as well as increased glycolysis (+1.7-fold) and FA incorporation into triglycerides (+2-fold). Correlation analyses revealed, however, specific linkages between glycolysis, FA oxidation and pyruvate metabolism and cardiac work, oxygen consumption with heart rate, respectively. This implies that any genetically-determined factors affecting a given metabolic flux parameter may impact on the associated functional parameters. Conclusion: Our results emphasize the importance of selecting the appropriate control strain for cardiac metabolic studies using transgenic mice, a factor that has often been neglected. Understanding the molecular mechanisms underlying the diversity of strain-specific cardiac metabolic and functional profiles, particularly the 129S6/SvEvTac, may ultimately disclose new specific metabolic targets for interventions in heart disease.
    AJP Heart and Circulatory Physiology 11/2013; 306(1). DOI:10.1152/ajpheart.00465.2013 · 4.01 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose Extracorporeal membrane oxygenation (ECMO) is increasingly used as a rescue technique for cardiopulmonary support in infants and children for a wide range of clinical scenarios. However, morbidity and mortality remains high and is directly proportional to duration of use. Prior work has shown that ECMO causes hormone and metabolic disturbances which may be counterproductive to recovery after critical illness. Therefore, we developed a model of cardiac injury rescued by ECMO. We hypothesized that supplementing triiodothyronine (T3) would facilitate weaning from ECMO by improving substrate utilization and citric acid cycle (CAC) flux. Methods Twenty-two neonatal piglets underwent transient coronary ischemia to induce cardiac injury. They were then separated into 4 groups based on loading status: normal circulation (LOAD), 8 hours of ECMO (UNLOAD), post-wean from ECMO (RELOAD), and post-wean from ECMO with T3 supplementation (RELOAD + T3). We infused [2-13C]-pyruvate as an oxidative substrate into the coronary circulation. Gas chromatography / mass spectroscopy (GCMS) and nuclear magnetic resonance (NMR) traced substrates through oxidative metabolism. Results ECMO depressed circulating T3 levels to 35% of baseline at 8 hours. LOAD decreased systolic function which did not recover after ECMO support (RELOAD). T3 supplementation restored systolic function to above baseline values without increasing myocardial oxygen consumption reflecting increased cardiac efficiency. Both LOAD and RELOAD increased accumulation of pyruvate, lactate and CAC intermediates indicative of metabolic block. However, ECMO +T3 decreased pyruvate (p=0.02) and lactate (p=0.02) accumulation and increased the oxidative flux through pyruvate dehydrogenase (p=0.04). NMR confirmed increased pyruvate entry into the CAC with T3 supplementation (p=0.05). Conclusion T3 supplementation promotes cardiac oxidative metabolism during weaning from ECMO by removing a metabolic block at the level of pyruvate dehydrogenase and increasing CAC flux. This translates to improved cardiac efficiency during critical illness. These findings indicate that T3 depression during ECMO support is maladaptive and that supplementation may serve as therapeutic agent for children with refractory heart failure. Future work will investigate the acute mechanisms of T3 on neonatal myocardial metabolism.
    2013 American Academy of Pediatrics National Conference and Exhibition; 10/2013
  • [Show abstract] [Hide abstract]
    ABSTRACT: Marine n-3 polyunsaturated fatty acids alter cardiac phospholipids and prevent cardiac pathology in rodents subjected to pressure overload. This approach has not been evaluated in humans or large animals with hypertension-induced pathological hypertrophy. We evaluated docosahexaenoic acid (DHA) in old female dogs with hypertension caused by 16 weeks of aldosterone infusion. Aldosterone-induced hypertension resulted in concentric left ventricular (LV) hypertrophy and impaired diastolic function in placebo-treated dogs. DHA supplementation increased DHA and depleted arachidonic acid in cardiac phospholipids, but did not improve LV parameters compared to placebo. Surprisingly, DHA significantly increased serum aldosterone concentration and blood pressure compared to placebo. Cardiac mitochondrial yield was decreased in placebo-treated hypertensive dogs compared to normal animals, which was prevented by DHA. Extensive analysis of mitochondrial function found no differences between DHA and placebo groups. In conclusion, DHA did not favorably impact mitochondrial or LV function in aldosterone hypertensive dogs.
    Journal of Cardiovascular Translational Research 09/2013; 6(6). DOI:10.1007/s12265-013-9511-y · 2.69 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Supplementation with the n3 polyunsaturated fatty acid docosahexaenoic acid (DHA) is beneficial in heart failure patients, however the mechanisms are unclear. DHA is incorporated into membrane phospholipids, which may prevent mitochondrial dysfunction. Thus we assessed the effects of DHA supplementation on cardiac mitochondria and the development of heart failure caused by aortic pressure overload. Pathological cardiac hypertrophy was generated in rats by thoracic aortic constriction. Animals were fed either a standard diet or were supplemented with DHA (2.3 % of energy intake). After 14 weeks, heart failure was evident by left ventricular hypertrophy and chamber enlargement compared to shams. Left ventricle fractional shortening was unaffected by DHA treatment in sham animals (44.1 ± 1.6 % vs. 43.5 ± 2.2 % for standard diet and DHA, respectively), and decreased with heart failure in both treatment groups, but to a lesser extent in DHA treated animals (34.9 ± 1.7 %) than with the standard diet (29.7 ± 1.5 %, P < 0.03). DHA supplementation increased DHA content in mitochondrial phospholipids and decreased membrane viscosity. Myocardial mitochondrial oxidative capacity was decreased by heart failure and unaffected by DHA. DHA treatment enhanced Ca(2+) uptake by subsarcolemmal mitochondria in both sham and heart failure groups. Further, DHA lessened Ca(2+)-induced mitochondria swelling, an index of permeability transition, in heart failure animals. Heart failure increased hydrogen peroxide-induced mitochondrial permeability transition compared to sham, which was partially attenuated in interfibrillar mitochondria by treatment with DHA. DHA decreased mitochondrial membrane viscosity and accelerated Ca(2+) uptake, and attenuated susceptibility to mitochondrial permeability transition and development of left ventricular dysfunction.
    Cardiovascular Drugs and Therapy 09/2013; DOI:10.1007/s10557-013-6487-4 · 2.95 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Extracorporeal membrane oxygenation (ECMO) unloads the heart, providing a bridge to recovery in children after myocardial stunning. ECMO also induces stress which can adversely affect the ability to reload or wean the heart from the circuit. Metabolic impairments induced by altered loading and/or stress conditions may impact weaning. However, cardiac substrate and amino acid requirements upon weaning are unknown. We assessed the hypothesis that ventricular reloading with ECMO modulates both substrate entry into the citric acid cycle (CAC) and myocardial protein synthesis. Sixteen immature piglets (7.8 to 15.6 kg) were separated into 2 groups based on ventricular loading status: 8-hour ECMO (UNLOAD) and postwean from ECMO (RELOAD). We infused into the coronary artery [2-(13)C]-pyruvate as an oxidative substrate and [(13)C6]-L-leucine as an indicator for amino acid oxidation and protein synthesis. Upon RELOAD, each functional parameter, which were decreased substantially by ECMO, recovered to near-baseline level with the exclusion of minimum dP/dt. Accordingly, myocardial oxygen consumption was also increased, indicating that overall mitochondrial metabolism was reestablished. At the metabolic level, when compared to UNLOAD, RELOAD altered the contribution of various substrates/pathways to tissue pyruvate formation, favoring exogenous pyruvate versus glycolysis, and acetyl-CoA formation, shifting away from pyruvate decarboxylation to endogenous substrate, presumably fatty acids. Furthermore, there was also a significant increase of tissue concentrations for all CAC intermediates (≈80%), suggesting enhanced anaplerosis, and of fractional protein synthesis rates (>70%). RELOAD alters both cytosolic and mitochondrial energy substrate metabolism, while favoring leucine incorporation into protein synthesis rather than oxidation in the CAC. Improved understanding of factors governing these metabolic perturbations may serve as a basis for interventions and thereby improve success rate from weaning from ECMO.
    Journal of the American Heart Association 07/2013; 2(4):e000106. DOI:10.1161/JAHA.113.000106 · 2.88 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective Measurements of oxidative stress biomarkers in patients with heart failure (HF) have yielded controversial results. This study aimed at testing the hypothesis that circulating levels of the lipid peroxidation product 4-hydroxynonenal bound to thiol proteins (4HNE-P) are strongly associated with those of its potential precursors, namely n-6 polyunsaturated fatty acids (PUFA).Methods & ResultsCirculating levels of 4HNE-P were evaluated by gas chromatography-mass spectrometry in 71 control subjects and 61 ambulatory symptomatic HF patients along with various other clinically- and biochemically-relevant parameters, including other oxidative stress markers, and total levels of fatty acids from all classes, which reflect both free and bound to cholesterol, phospholipids and triglycerides. All HF patients had severe systolic functional impairment despite receiving optimal evidence-based therapies. Compared to controls, HF patients displayed markedly lower circulating levels of HDL- and LDL-cholesterol, which are major PUFA carriers, as well as of PUFA of the n-6 series, specifically linoleic acid (LA; P=0.001). Circulating 4HNE-P in HF patients was similar to controls, albeit multiple regression analysis revealed that LA was the only factor that was significantly associated with circulating 4HNE-P in the entire population (R2=0.086; P=0.02). In HF patients only, 4HNE-P was even more strongly associated with LA (P=0.003) and HDL-cholesterol (p<0.0002). Our results demonstrate that 4HNE-P levels, expressed relative to HDL-cholesterol, increase as HDL-cholesterol plasma levels decrease in the HF group only.Conclusion Results from this study emphasize the importance of considering changes in lipids and lipoproteins in the interpretation of measurements of lipid peroxidation products. Further studies appear warranted to explore the possibility that HDL-cholesterol particles may be a carrier of 4HNE adducts.
    01/2013; 2. DOI:10.1016/j.redox.2013.12.009
  • [Show abstract] [Hide abstract]
    ABSTRACT: Endothelial dysfunction is a turning point in the initiation and development of atherosclerosis and its complications and is predictive of future cardiovascular events. Ingestion of high-carbohydrate or high-fat meals often results in postprandial hyperglycaemia and/or hypertriacylglycerolaemia that may lead to a transient impairment in endothelial function. The present review will discuss human studies evaluating the impact of high-carbohydrate and high-fat challenges on postprandial endothelial function as well as the potential role of oxidative stress in such postprandial metabolic alterations. Moreover, the present review will differentiate the postprandial endothelial and oxidative impact of meals rich in varying fatty acid types.
    Nutrition Research Reviews 12/2012; 25(2):288-301. DOI:10.1017/S0954422412000182 · 3.86 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Extracorporeal membrane oxygenation (ECMO) provides mechanical circulatory support essential for survival in infants and children with acute cardiac decompensation. However, ECMO also causes metabolic disturbances, which contribute to total body wasting and protein loss. Cardiac stunning can also occur which prevents ECMO weaning, and contributes to high mortality. The heart may specifically undergo metabolic impairments, which influence functional recovery. We tested the hypothesis that ECMO alters oxidative . Wefocused on the amino acid leucine, and integration with myocardial protein synthesis. We used a translational immature swine model in which we assessed in heart (i) the fractional contribution of leucine (FcLeucine) and pyruvate (FCpyruvate) to mitochondrial acetyl-CoA formation by nuclear magnetic resonance and (ii) global protein fractional synthesis (FSR) by gas chromatography-mass spectrometry. Immature mixed breed Yorkshire male piglets (n = 22) were divided into four groups based on loading status (8 hours of normal circulation or ECMO) and intracoronary infusion [(13)C(6),(15)N]-L-leucine (3.7 mM) alone or with [2-(13)C]-pyruvate (7.4 mM). ECMO decreased pulse pressure and correspondingly lowered myocardial oxygen consumption (~ 40%, n = 5), indicating decreased overall mitochondrial oxidative metabolism. However, FcLeucine was maintained and myocardial protein FSR was marginally increased. Pyruvate addition decreased tissue leucine enrichment, FcLeucine, and Fc for endogenous substrates as well as protein FSR. Conclusion: The heart under ECMO shows reduced oxidative metabolism of substrates, including amino acids, while maintaining (i) metabolic flexibility indicated by ability to respond to pyruvate, and (ii) a normal or increased capacity for global protein synthesis.
    AJP Heart and Circulatory Physiology 11/2012; 304(3). DOI:10.1152/ajpheart.00672.2012 · 4.01 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: RATIONALE AND GOAL: Glutamine, the most abundant amino acid in plasma, has attracted considerable interest for its cardioprotective properties. The primary effect of glutamine in the heart is commonly believed to be mediated via its anaplerotic metabolism to citric acid cycle (CAC) intermediates; however, there is little direct evidence to support this concept. Another potential candidate is the hexosamine biosynthetic pathway (HBP), which has recently been shown to modulate cardiomyocyte function and metabolism. Therefore, the goal of this study was to evaluate the contribution of anaplerosis and the HBP to the acute metabolic effects of glutamine in the heart. METHODS: Normoxic ex vivo working rat hearts were perfused with (13)C-labeled substrates to assess relevant metabolic fluxes perfused with a physiological mixture of carbohydrates and a fatty acid (control) or under conditions of restricted pyruvate anaplerosis RESULTS: Addition of a physiological concentration of glutamine (0.5 mM) had no effect on contractile function of hearts perfused under the control condition, but improved that of hearts perfused under restricted pyruvate anaplerosis. Changes in CAC intermediate concentrations as well as (13)C-enrichment from [U-(13)C]glutamine did not support a major role of glutamine anaplerosis under any conditions. Under the control condition, however, glutamine significantly increased the contribution of exogenous oleate to β-oxidation, 1.6-fold, and triglyceride formation, 2.8-fold. Glutamine had no effect on malonyl-CoA or AMPK kinase activity levels; however, it resulted in a higher plasma membrane level of the fatty acid transporter CD36. These metabolic effects of glutamine were reversed by azaserine, which inhibits glucose entry into the HPB CONCLUSION: Our results reveal a metabolic role of physiological concentration of glutamine in the healthy working heart beyond anaplerosis. This role appears to involve the HBP and regulation of fatty acid entry and metabolism via CD36.
    Journal of Molecular and Cellular Cardiology 11/2012; 55. DOI:10.1016/j.yjmcc.2012.11.008 · 5.22 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Mitochondrial dysfunction in heart failure includes greater susceptibility to mitochondrial permeability transition, which may worsen cardiac function and decrease survival. Treatment with a mixture of the n3 polyunsaturated fatty acids (n3 PUFA) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) is beneficial in heart failure patients, and increases resistance to mitochondrial permeability transition in animal models. We assessed if DHA and EPA have similar effects when given individually, and if they prolong survival in heart failure. Male δ-sarcoglycan null cardiomyopathic hamsters were untreated or given either DHA, EPA or a 1:1 mixture of DHA+EPA at 2.1% of energy intake. Treatment did not prolong survival: mean survival was 298±15 days in untreated hamsters, and was 335±17, 328±14 and 311±15 days with DHA, EPA and DHA+EPA, respectively (n=27-32/group). A subgroup of cardiomyopathic hamsters treated for 26 weeks had impaired LV function and increased cardiomyocyte apoptosis compared to normal hamsters, which was unaffected by n3 PUFA treatment. Evaluation of oxidative phosphorylation in isolated subsarcolemmal (SSM) and interfibrillar (IFM) mitochondria with substrates for complex I or II showed no effect of n3 PUFA treatment. On the other hand, IFM from cardiomyopathic hamsters were significantly more sensitive to Ca(2+)-induced mitochondrial permeability transition, which was completely normalized by treatment with DHA, and partial corrected by EPA. In conclusion, treatment with DHA or EPA normalizes Ca(2+)-induced MPT in cardiomyopathic hamsters, but does not prolong survival or improve cardiac function.
    AJP Heart and Circulatory Physiology 10/2012; 304(1). DOI:10.1152/ajpheart.00657.2012 · 4.01 Impact Factor

Publication Stats

2k Citations
459.38 Total Impact Points


  • 2007–2015
    • Montreal Heart Institute
      Montréal, Quebec, Canada
    • University of Alberta
      Edmonton, Alberta, Canada
  • 1990–2015
    • Université de Montréal
      • Department of Nutrition
      Montréal, Quebec, Canada
  • 2013
    • Seattle Children’s Research Institute
      Seattle, Washington, United States
  • 1989–2005
    • Case Western Reserve University
      • • Department of Nutrition
      • • Department of Physiology and Biophysics
      • • Department of Biomedical Engineering
      Cleveland, Ohio, United States
  • 1988–2004
    • McGill University
      • Division of Experimental Medicine
      Montréal, Quebec, Canada
  • 2001–2002
    • George Washington University
      Washington, Washington, D.C., United States
  • 1987
    • Massachusetts Institute of Technology
      Cambridge, Massachusetts, United States