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LAN Carole

T AP

carole.lan@univ-amu.fr
tel : +33 4 91 32 48 08
Key Words
- Heart
- endothelial dysfunction, ischaemia-reperfusion injury
- nitric oxide, long-term heart preservation
- cardioplegia, type 2 diabetic heart

Current Research Interest and projects

Research in the field of Magnetic Resonance Spectroscopy (MRS) applications to biological systems: heart disease in diabetes mellitus, heart failure and myocardial protection during long term preservation based on hemodynamic, metabolic (using P-31 MRS) and biochemical evaluation (HPLC, Western blot…).

Relevant scientific techniques and skills acquired

I have some experience in the preparation of the isolated and perfused rat heart (Langendorff method, isovolumic mode). I used 31-P magnetic resonance spectroscopy (Bruker-Nicolet WP-200 spectrometer) and High Performance Liquid Chromatography. I also know various biochemical (UV spectrophotometry) enzymatic (CK, LDH) and immunological assays (Western blot).

Publications

2017

Journal Article

  • DESROIS M., LAN C., MOVASSAT J., BERNARD M. “Reduced up-regulation of the nitric oxide pathway and impaired endothelial and smooth muscle functions in the female type 2 diabetic goto-kakizaki rat heart.”. Nutrition & Metabolism [En ligne]. 2017. Vol. 14, p. 6. Disponible sur : < http://dx.doi.org/10.1186/s12986-016-0157-z > (consulté le no date)
    Résumé : BACKGROUND: Type 2 diabetes is associated with greater relative risk of cardiovascular diseases in women than in men, which is not well understood. Consequently, we have investigated if male and female displayed differences in cardiac function, energy metabolism, and endothelial function which could contribute to increased cardiovascular complications in type 2 diabetic female. METHODS: Male and female Control and type 2 diabetic Goto-Kakizaki (GK) isolated rat hearts were perfused during 28 min with a physiological buffer before freeze-clamping for biochemical assays. High energy phosphate compounds and intracellular pH were followed using (31)P magnetic resonance spectroscopy with simultaneous measurement of contractile function. Nitric oxide (NO) pathway and endothelium-dependent and independent vasodilatations were measured as indexes of endothelial function. Results were analyzed via two-way ANOVA, p < 0.05 was considered as statistically significant. RESULTS: Myocardial function was impaired in male and female diabetic versus Control groups (p < 0.05) without modification of energy metabolism. Coronary flow was decreased in both diabetic versus Control groups but to a higher extent in female GK versus male GK rat hearts (p < 0.05). NO production was up-regulated in diabetic groups but to a less extent in female GK rat hearts (p < 0.05). Endothelium-dependent and independent vasodilatations were impaired in female GK rat compared with male GK (p < 0.05) and female Control (p < 0.05) rat hearts. CONCLUSIONS: We reported here an endothelial damage characterized by a reduced up-regulation of the NO pathway and impaired endothelial and smooth muscle functions, and coronary flow rates in the female GK rat hearts while energy metabolism was normal. Whether these results are related to the higher risk of cardiovascular complications among type 2 diabetic female needs to be further elicited in the future.
    Mots-clés : Cardiac function, crmbm, Endothelial function, Energy Metabolism, Gender differences, Type 2 diabetic heart.

2016

Journal Article

  • BERNARD M., MAIXENT J. - M., GERBI A., LAN C., COZZONE P. J., PIERONI G., ARMAND M., COSTE T. C. “Dietary docosahexaenoic acid-enriched glycerophospholipids exert cardioprotective effects in ouabain-treated rats via physiological and metabolic changes.”. Food & Function [En ligne]. 2016. Vol. 7, n°2, p. 798-804. Disponible sur : < http://dx.doi.org/10.1039/c5fo01300c > (consulté le no date)
    Résumé : Docosahexaenoic acid (DHA) might prevent heart failure or optimise drug treatments by improving cardiac contraction. We investigated whether DHA-enriched avian glycerophospholipids (GPL-DHA) exert cardioprotection in ouabain-treated rats after 4 weeks of dietary supplementation with 10, 35 or 60 mg DHA per kg body weight versus none (DHA10, DHA35, DHA60 and control groups, respectively). The contractile responsiveness to different doses of ouabain (10(-7) to 10(-4) M), ouabain intoxication (at 3 × 10(-4) M), and relative variations in cardiac energy metabolism were determined using (31)P NMR in isolated perfused rat hearts. The fatty acid composition of cardiac membranes was analysed by gas chromatography. DHA accretion in the heart was dose-dependent (+8%, +30% and +45% for DHA10, DHA35 and DHA60, respectively). The cardiac phosphocreatine content significantly increased at the baseline in DHA35 (+45%) and DHA60 groups (+85%), and at the different doses of ouabain in the DHA60 group (+73% to 98%). The maximum positive inotropy achieved at 10(-4) M ouabain was significantly increased in all DHA groups versus control (+150%, +122.5% and +135% for DHA10, DHA35 and DHA60, respectively), and ouabain intoxication was delayed. The increase in myocardial phosphocreatine content and the improved efficacy of ouabain on myocardial contraction without toxicity suggest the potential of GPL-DHA as a dietary supplement or ingredient for functional food, and possibly as a co-treatment with digitalis drugs in humans.
    Mots-clés : crmbm.

2015

Journal Article

  • MACIA M., PECCHI E., VILMEN C., DESROIS M., LAN C., PORTHA B., BERNARD M., BENDAHAN D., GIANNESINI B. “Insulin Resistance Is Not Associated with an Impaired Mitochondrial Function in Contracting Gastrocnemius Muscle of Goto-Kakizaki Diabetic Rats In Vivo.”. PloS One [En ligne]. 2015. Vol. 10, n°6, p. e0129579. Disponible sur : < http://dx.doi.org/10.1371/journal.pone.0129579 > (consulté le no date)
    Résumé : Insulin resistance, altered lipid metabolism and mitochondrial dysfunction in skeletal muscle would play a major role in type 2 diabetes mellitus (T2DM) development, but the causal relationships between these events remain conflicting. To clarify this issue, gastrocnemius muscle function and energetics were investigated throughout a multidisciplinary approach combining in vivo and in vitro measurements in Goto-Kakizaki (GK) rats, a non-obese T2DM model developing peripheral insulin resistant without abnormal level of plasma non-esterified fatty acids (NEFA). Wistar rats were used as controls. Mechanical performance and energy metabolism were assessed strictly non-invasively using magnetic resonance (MR) imaging and 31-phosphorus MR spectroscopy (31P-MRS). Compared with control group, plasma insulin and glucose were respectively lower and higher in GK rats, but plasma NEFA level was normal. In resting GK muscle, phosphocreatine content was reduced whereas glucose content and intracellular pH were both higher. However, there were not differences between both groups for basal oxidative ATP synthesis rate, citrate synthase activity, and intramyocellular contents for lipids, glycogen, ATP and ADP (an important in vivo mitochondrial regulator). During a standardized fatiguing protocol (6 min of maximal repeated isometric contractions electrically induced at a frequency of 1.7 Hz), mechanical performance and glycolytic ATP production rate were reduced in diabetic animals whereas oxidative ATP production rate, maximal mitochondrial capacity and ATP cost of contraction were not changed. These findings provide in vivo evidence that insulin resistance is not caused by an impairment of mitochondrial function in this diabetic model.
    Mots-clés : crmbm.

2014

Journal Article

  • DESROIS M., PICCARDO A., ZOGHEIB E., DALMASSO C., LAN C., FOURRÉ D., COZZONE P. J., CAUS T., BERNARD M. “Heart donation after cardiac death: preliminary study on an isolated, perfused Swine heart after 20 minutes of normothermic ischemia.”. Transplantation Proceedings [En ligne]. 2014. Vol. 46, n°10, p. 3314-3318. Disponible sur : < http://dx.doi.org/10.1016/j.transproceed.2014.04.021 > (consulté le no date)
    Résumé : BACKGROUND: We measured the functional and metabolic status of hearts submitted to normothermic ischemia before preservation through the use of an ex vivo pig heart model to assess the feasibility of donation after cardiac death (DCD) in heart transplantation. METHODS: Ten pigs were separated into 2 groups: control (n = 6, brain-dead group) and DCD (n = 4, heart donation after cardiac death). In the control group, hearts were excised 20 minutes after the brachiocephalic trunk cross-clamping and were immediately reperfused. In DCD, hearts were excised 20 minutes after exsanguination and asphyxia, stored in the Centre de Résonance Magnétique Biologique et Médicale (CRMBM) solution for 2 hours, and then were reperfused. Cardioplegic arrest was induced with the use of 1 L of CRMBM solution (4°C) and the heart was reperfused for 60 minutes through the use of an ex vivo perfusion system in Langendorff mode with normothermic autologous blood. During reperfusion, functional parameters were analyzed. Biochemical assays were performed in myocardial effluents and freeze-clamped hearts. RESULTS: No electromechanical activity was found in DCD compared with control. Creatine kinase (CK) was higher at 2 minutes of reperfusion in DCD versus control (P = .005). Adenosine triphosphate was lower in DCD versus control (P = .0019). Malondialdehyde, an oxidative stress index, was present only in DCD. The nitric oxide (NO) pathway was impaired in DCD versus control, with lower eNOS expression (P < .0001) and total nitrate concentration content (P = .04). CONCLUSIONS: We reported no cardiac functional and metabolic recovery in the DCD group after normothermic ischemia and reperfusion, which indicates that a single immersion of the cardiac graft during storage does not provide an optimal protection. New strategies in heart preservation are necessary for recruiting heart donation after cardiac death.
    Mots-clés : crmbm.


  • DESROIS M., KOBER F., LAN C., DALMASSO C., COLE M., CLARKE K., COZZONE P. J., BERNARD M. “Effect of isoproterenol on myocardial perfusion, function, energy metabolism and nitric oxide pathway in the rat heart – a longitudinal MR study.”. NMR in Biomedicine [En ligne]. 2014. Vol. 27, n°5, p. 529-538. Disponible sur : < http://dx.doi.org/10.1002/nbm.3088 >
    Résumé : The chronic administration of the β-adrenoreceptor agonist isoproterenol (IsoP) is used in animals to study the mechanisms of cardiac hypertrophy and failure associated with a sustained increase in circulating catecholamines. Time-dependent changes in myocardial blood flow (MBF), morphological and functional parameters were assessed in rats in vivo using multimodal cardiac MRI. Energy metabolism, oxidative stress and the nitric oxide (NO) pathway were evaluated in isolated perfused rat hearts following 7 days of treatment. Male Wistar rats were infused for 7 days with IsoP or vehicle using osmotic pumps. Cine-MRI and arterial spin labeling were used to determine left ventricular morphology, function and MBF at days 1, 2 and 7 after pump implantation. Isolated hearts were then perfused, and high-energy phosphate compounds and intracellular pH were followed using 31P MRS with simultaneous measurement of contractile function. Total creatine and malondialdehyde (MDA) contents were measured by high-performance liquid chromatography. The NO pathway was evaluated by NO synthase isoform expression and total nitrate concentration (NOx). In IsoP-treated rats, left ventricular mass was increased at day 1 and maintained. Wall thickness was increased with a peak at day 2 and a tendency to return to baseline values at day 7. MBF was markedly increased at day 1 and returned to normal values between days 1 and 2. The rate–pressure product and phosphocreatine/adenosine triphosphate ratio in perfused hearts were reduced. MDA, endothelial NO synthase expression and NOx were increased. Sustained high cardiac function and normal MBF after 24 h of IsoP infusion indicate imbalance between functional demand and blood flow, leading to morphological changes. After 1 week, cardiac hypertrophy and decreased function were associated with impaired phosphocreatine, increased oxidative stress and up-regulation of the NO pathway. These results provide supplemental information on the evolution of the different contributing factors leading to morphological and functional changes in this model of cardiac hypertrophy and failure. Copyright © 2014 John Wiley & Sons, Ltd.
    Mots-clés : cine-MRI, crmbm, Function, Heart, isoproterenol, Metabolism, nitric oxide pathway, perfusion, rat.

2010

Journal Article


  • DESROIS M., CLARKE K., LAN C., DALMASSO C., COLE M., PORTHA B., COZZONE P. J., BERNARD M. “Upregulation of eNOS and unchanged energy metabolism in increased susceptibility of the aging type 2 diabetic GK rat heart to ischemic injury.”. American Journal of Physiology - Heart and Circulatory Physiology [En ligne]. 2010. Vol. 299, n°5, p. H1679-H1686. Disponible sur : < http://dx.doi.org/10.1152/ajpheart.00998.2009 >
    Résumé : We investigated the tolerance of the insulin-resistant diabetic heart to ischemic injury in the male Goto-Kakizaki (GK) rat, a model of type 2 diabetes. Changes in energy metabolism, nitric oxide (NO) pathway, and cardiac function were assessed in the presence of physiological substrates. Age-matched control Wistar (n = 19) and GK (n = 18) isolated rat hearts were perfused with 0.4 mM palmitate, 3% albumin, 11 mM glucose, 3 U/l insulin, 0.2 mM pyruvate, and 0.8 mM lactate for 24 min before switching to 1.2 mM palmitate (11 rats/group) during 32 min low-flow (0.5 ml·min−1·g wet wt−1) ischemia. Next, flow was restored with 0.4 mM palmitate buffer for 32 min. A subset of hearts from each group (n = 8 for control and n = 7 for GK groups) were freeze-clamped for determining baseline values after the initial perfusion of 24 min. ATP, phosphocreatine (PCr), and intracellular pH (pHi) were followed using 31P magnetic resonance spectroscopy with simultaneous measurement of contractile function. The NO pathway was determined by nitric oxide synthase (NOS) isoform expression and total nitrate concentration (NOx) in hearts. We found that coronary flow was 26% lower (P < 0.05) during baseline conditions and 61% lower (P < 0.05) during reperfusion in GK vs. control rat hearts. Rate pressure product was lower during reperfusion in GK vs. control rat hearts (P < 0.05). ATP, PCr, and pHi during ischemia-reperfusion were similar in both groups. Endothelial NOS expression was increased in GK rat hearts during baseline conditions (P < 0.05). NOx was increased during baseline conditions (P < 0.05) and after reperfusion (P < 0.05) in GK rat hearts. We report increased susceptibility of type 2 diabetic GK rat heart to ischemic injury that is not associated with impaired energy metabolism. Reduced coronary flow, upregulation of eNOS expression, and increased total NOx levels confirm NO pathway modifications in this model, presumably related to increased oxidative stress. Modifications in the NO pathway may play a major role in ischemia-reperfusion injury of the type 2 diabetic GK rat heart.
    Mots-clés : Aging, Animals, Coronary Vessels, crmbm, Diabetes Mellitus, Type 2, Disease Models, Animal, Energy Metabolism, Heart, Male, Myocardial Reperfusion Injury, Nitric Oxide, Nitric Oxide Synthase Type III, Rats, Rats, Mutant Strains, Rats, Wistar, Regional Blood Flow, Up-Regulation.

2009

Journal Article
  • DESROIS M., CAUS T., DALMASSO C., LAN C., COZZONE P. J., BERNARD M. “Expression of the three nitric oxide synthase isoforms and nitric oxide level in the rat heart during cold storage and blood reperfusion.”. Cellular and molecular biology (Noisy-le-Grand, France). 2009. Vol. 55 Suppl, p. OL1208-1214.
    Résumé : Maintenance of nitric oxide (NO) homeostasis is an important concept for myocardial protection. Here, we have investigated the NO pathway by analysing total nitrate concentration (NOx) and NO synthase (NOS) isoforms expression as well as the myocardial integrity by lactate dehydrogenase and creatine kinase contents in the rat heart graft arrested by CRMBM solution, submitted to 3 hr cold ischemia in the same solution and 24 hr blood reperfusion following heterotopic abdominal heart transplantation. NOx level was similar to baseline value after ischemia and significantly increased after 24 hr reperfusion. NOS isoforms expression was highly modulated after cold ischemia followed by blood reperfusion. Endothelial NOS expression was decreased after ischemia but restored after 24 hr reperfusion. Neuronal NOS expression was drastically decreased after ischemia and 24 hr reperfusion. Inducible NOS protein was present only after 24 hr reperfusion. Cold ischemia induced a severe loss of creatine kinase without any modification after blood reperfusion. In conclusion, we show here that CRMBM solution did not increase NO production during ischemia but induced an enhanced synthesis of NO during reperfusion which may be related to restoration of endothelial NOS expression and/or induction of inducible NOS expression.
    Mots-clés : Cold Temperature, Gene Expression Regulation, Enzymologic, Heart, Heart Transplantation, Isoenzymes, Myocardial Ischemia, Myocardial Reperfusion, Nitric Oxide, Nitric Oxide Synthase Type I, Nitric Oxide Synthase Type II, Nitric Oxide Synthase Type III, Rats, Rats, Inbred Lew, Tissue and Organ Harvesting.

2008

Journal Article

  • DESROIS M., CAUS T., BELLES P. M., DALMASSO C., LAN C., COZZONE P. J., BERNARD M. “Limitation of myocardial and endothelial injury of the rat heart graft after preservation with Centre de Résonance Magnétique Biologique et Médicale (CRMB) solution.”. Transplant international: official journal of the European Society for Organ Transplantation [En ligne]. 2008. Vol. 21, n°3, p. 276-283. Disponible sur : < http://dx.doi.org/10.1111/j.1432-2277.2007.00602.x > (consulté le no date)
    Résumé : Myocardial injury caused by prolonged storage compromises post-transplantation contractile performance and induces endothelial injury. The aim of this study was to compare a solution developed in our laboratory [Centre de Résonance Magnétique Biologique et Médicale (CRMBM) solution] with a widely used solution (Celsior, Genzyme, Saint Germain en Laye, France). Metabolic and contractile parameters as well as indexes of endothelial injury were measured in a heterotopic rat heart transplantation model with a 3-h ischaemia and a 1-h reperfusion. The two solutions were randomly used for cardioplegia and graft preservation in six experiments each. During reperfusion, developed pressure and rate pressure product were higher with CRMBM compared with Celsior (P = 0.0002 and P = 0.0135, respectively). Phosphocreatine and adenosine triphosphate (ATP) concentrations after reperfusion were significantly higher with CRMBM (P = 0.0069 and P = 0.0053, respectively). Endothelial nitric oxide synthase (eNOS) and neuronal nitric oxide synthase (nNOS) protein expression were decreased to the same extent after reperfusion compared with baseline with CRMBM (P = 0.0001 and P < 0.0001, respectively) and Celsior (P = 0.0007 and P < 0.0001, respectively). Total nitrate concentration (NOx) was significantly increased after reperfusion with CRMBM (P < 0.0001 versus baseline and P < 0.0001 versus Celsior). Na,K-ATPase activity was decreased in both groups versus baseline after reperfusion (P < 0.0001 for CRMBM and P < 0.0001 for Celsior). We showed limitation of both myocardial and endothelial damage with CRMBM compared with Celsior during heterotopic rat heart transplantation in vivo.
    Mots-clés : Adenosine Triphosphate, Animals, crmbm, Disaccharides, Electrolytes, Endothelium, Vascular, Glutamates, Glutathione, Heart Transplantation, Histidine, Mannitol, Nitric Oxide, Organ Preservation, Organ Preservation Solutions, Phosphocreatine, Rats, Rats, Inbred Lew, Reperfusion, Transplantation, Isogeneic.

2005

Journal Article

  • DESROIS M., CAUS T., BELLES P. M., DALMASSO C., LAN C., COZZONE P. J., BERNARD M. “Nitric oxide pathway after long-term cold storage and reperfusion in a heterotopic rat heart transplantation model.”. Transplantation proceedings [En ligne]. 2005. Vol. 37, n°10, p. 4553-4555. Disponible sur : < http://dx.doi.org/10.1016/j.transproceed.2005.10.105 > (consulté le no date)
    Résumé : Recent studies have suggested the involvement of the nitric oxide (NO) pathway in ischemia-reperfusion injury related to cardiac transplantation. Herein, we assessed the NO pathway by quantifying endothelial (e) and inducible (i) nitric oxide synthase (NOS) expression and total NOS activity in a rat heart transplant model during cold ischemia with Celsior cardioplegia and reperfusion. Experiments were performed using a modified Lewis-Lewis heterotopic abdominal heart transplantation with 3 or 6 hours of ischemia with or without 1 hour of blood reperfusion. NOS expression and activity were determined using Western blotting and colorimetric assays, respectively, on freeze-clamped hearts after ischemia without (n = 10) or with reflow (n = 12) compared with basal values. Hearts submitted to 3 hours of ischemia and 1 hour of reperfusion showed a postischemic rate pressure product of 5190 +/- 3047 mm Hg/min (reversible ischemia), but no contractility was observed after 6 hours of ischemia. eNOS protein levels were lower after 3 hours of ischemia compared with the basal value (P = .0005) and were further decreased after 6 hours of ischemia (P < .0001 versus basal value and P = .0018 versus 3 hours of ischemia). Reperfusion did not further decrease eNOS protein levels. iNOS protein was not detected in any condition. NOS activity was increased after 3 hours of ischemia versus basal value (P = .0065) but not after 6 hours of ischemia without any effect of reperfusion. We concluded that eNOS expression was altered during ischemia and the amplitude of the alteration depended on the duration of ischemia. Reversible ischemia was associated with increased NOS activity at the end of ischemia with no variation at reperfusion.
    Mots-clés : Blood Pressure, crmbm, Heart Transplantation, Models, Animal, Myocardial Contraction, Myocardial Ischemia, Nitric Oxide, Nitric Oxide Synthase, Nitric Oxide Synthase Type III, Rats, Rats, Inbred Lew, Reperfusion Injury, Transplantation, Isogeneic.

  • ILTIS I., KOBER F., DALMASSO C., LAN C., COZZONE P. J., BERNARD M. “In vivo assessment of myocardial blood flow in rat heart using magnetic resonance imaging: effect of anesthesia.”. Journal of magnetic resonance imaging: JMRI [En ligne]. 2005. Vol. 22, n°2, p. 242-247. Disponible sur : < http://dx.doi.org/10.1002/jmri.20352 > (consulté le no date)
    Résumé : PURPOSE: To assess the influence of isoflurane and pentobarbital anesthesia and the carrier gases on myocardial blood flow (MBF) in the rat heart in vivo. MATERIALS AND METHODS: MBF was quantified in vivo using arterial spin-labeling (ASL) magnetic resonance imaging (MRI). Left ventricular (LV) function was estimated during the same experiment using cine-MRI. Thirty-four male Wistar-Kyoto rats were divided in four groups, one anesthetized with isoflurane in oxygen:nitrous oxide mix (ISO), the three others with intraperitoneal pentobarbital, and breathing either room air (PB), oxygen:nitrous oxide (PB + N(2)O), or oxygen:nitrogen (PB + N(2)). RESULTS: MBF was significantly higher in the ISO and PB + N(2)O groups vs. PB and in ISO vs. PB + N(2), with the following respective MBF values: ISO, 5.9 +/- 1.1; PB, 4.0 +/- 0.8; PB + N(2)O, 5.1 +/- 1.4; and PB + N(2), 4.6 +/- 0.8 mL/g/minute, mean +/- SD. Ejection fractions were reduced by 10% in PB and PB + N(2)O rats vs. ISO rats. Cardiac output (CO) and index (CI) were 25 to 30% lower in all rats anesthetized with pentobarbital than with isoflurane. CONCLUSION: Isoflurane and nitrous oxide induce a higher MBF than pentobarbital. Isoflurane also induces a higher ejection fraction in healthy rats.
    Mots-clés : Anesthesia, Inhalation, Anesthetics, Inhalation, Animals, Coronary Circulation, crmbm, Disease Models, Animal, Female, Hemodynamics, Isoflurane, Magnetic Resonance Angiography, Magnetic Resonance Imaging, Cine, Male, Myocardium, Nitrous Oxide, Pentobarbital, Rats, Rats, Wistar, Sensitivity and Specificity, Stroke Volume.
  • ILTIS I., KOBER F., DESROIS M., DALMASSO C., LAN C., PORTHA B., COZZONE P. J., BERNARD M. “Defective myocardial blood flow and altered function of the left ventricle in type 2 diabetic rats: a noninvasive in vivo study using perfusion and cine magnetic resonance imaging.”. Investigative Radiology. 2005. Vol. 40, n°1, p. 19-26.
    Résumé : OBJECTIVE: In type 2 diabetes mellitus, cardiovascular complications are related to microvascular abnormalities. In this work, we aimed at characterizing in vivo myocardial blood flow and left ventricular function of the Goto-Kakizaki (GK) rat as a nonobese model of type 2 diabetes. MATERIALS AND METHODS: We performed arterial spin labeling magnetic resonance imaging (MRI) for myocardial blood flow quantification and cine MRI for functional evaluation in free-breathing isoflurane-anesthetized animals. RESULTS: Myocardial blood flow was altered in adult female GK rats compared with age-matched female Wistar rats (4.7 +/- 1.6 vs. 7.1 +/- 1.2 mL/g/min respectively, P = 0.0022). Ejection fraction was decreased in GK compared with Wistar rats (64 +/- 7 vs. 78 +/- 8% respectively, P <0.005), mainly as a result of a loss in left ventricular longitudinal contraction. CONCLUSIONS: Adult female GK rats have defective myocardial blood flow associated with altered left ventricular function. This multiparametric MRI approach in the GK rat is of particular interest for the study of type 2 diabetic cardiomyopathy.
    Mots-clés : Animals, Coronary Circulation, crmbm, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 2, Female, Magnetic Resonance Imaging, Cine, Rats, Rats, Wistar, Ventricular Dysfunction, Left.

2004

Journal Article
  • GERBI A., BERNARD M., GLEIZE B., COSTE T. C., MAIXENT J. M., LAN C., PAGANELLI F., PIERONI G. “Dose dependent accretion of docosahexaenoic acid (DHA) in cardiac membranes of rats fed egg yolk powder enriched in DHA.”. Cellular and molecular biology (Noisy-le-Grand, France). 2004. Vol. 50, n°7, p. 855-860.
    Résumé : We tested the hypothesis that enrichment of the diet with docosahexaenoic acid (DHA) enriched egg yolk powder could modify specifically the (n-3) fatty acids content of rat plasma, red blood cells and heart membranes. Dose-dependent effect of DHA was studied in rats supplemented during 4 weeks. Three groups of adult male rats, DHA10, DHA35 and DHA60 (n = 5 each), had their diet supplemented with 10 mg, 35 mg or 60 mg DHA/kg body weight/day, respectively. Fatty acid composition of membranes and plasma lipids were determined. A significant dose-dependent increase in DHA was observed in all three types of samples. Arachidonic acid (AA) levels did not change in heart and red blood cell membranes whereas it increased significantly in plasma with the DHA35 diet. These results contrast with that previously reported for fish oil supplementation where a decrease in AA levels was reported. Hence, DHA enriched egg yolk supplementation leads to a specific accretion of DHA without competition on AA status.
    Mots-clés : Arachidonic Acid, Cell Membrane, Dietary Supplements, Docosahexaenoic Acids, Egg Yolk, Erythrocyte Membrane, Erythrocytes, Fatty Acids, Omega-3, Heart Ventricles, Microsomes, Myocytes, Cardiac, Powders, Rats, Rats, Sprague-Dawley.

2003

Journal Article
  • CAUS T., DESROIS M., IZQUIERDO M., LAN C., LEFUR Y., CONFORT-GOUNY S., MéTRAS D., CLARKE K., COZZONE P. J., BERNARD M. “NOS substrate during cardioplegic arrest and cold storage decreases stunning after heart transplantation in a rat model.”. The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation. 2003. Vol. 22, n°2, p. 184-191.
    Résumé : BACKGROUND: In this study, we evaluated how adding L-arginine to Centre de Résonance Magnétique Biologique et Médicale (CRMBM) solution affected myocardial performance during post-ischemic in vivo reperfusion. METHODS: Experiments were conducted using a modified Lewis-Lewis heterotopic heart transplantation model, with a total ischemic time of 3 hours followed by 1 or 24 hours of blood reperfusion. Heart grafts were arrested using intra-aortic injection of CRMBM solution, either supplemented or not supplemented with 2 mmol/liter L-arginine (n = 12 in each group). We measured systolic indexes and simultaneously performed phosphorus magnetic resonance spectroscopy ((31)P MRS). We quantified total endothelial nitric oxide synthase (eNOS) protein using the Western blot test of freeze-clamped hearts. RESULTS: Contractility during early reperfusion was significantly better in grafts arrested with CRMBM solution enriched with L-arginine: mean rate pressure product, 11249 +/- 1548 vs 5637 +/- 1118 mm Hg/min (p = 0.05), and maximal first derivative of the pressure signal (dP/dt(max)), 1721 +/- 177 vs 1214 +/- 321 mm Hg/sec (p = 0.013). Conversely, during late reperfusion, contractility did not relate to the nature of the preservation solution. The presence of L-arginine in the CRMBM solution did not alter time-related variations of high-energy phosphate ratios measured using in vivo (31)P MRS. The eNOS protein level decreased significantly during early compared with late reperfusion, with no effect caused by L-arginine. CONCLUSIONS: During early reperfusion, the limited myocardial stunning observed with CRMBM solution containing L-arginine does not relate to energy metabolism but to better preservation of the NO pathway.
    Mots-clés : Allopurinol, Animals, Arginine, Blotting, Western, Cardioplegic Solutions, Cold Temperature, Glutathione, Heart Arrest, Induced, Heart Transplantation, Myocardial Reperfusion, Myocardial Stunning, Nitric Oxide Synthase, Nitric Oxide Synthase Type III, Organ Preservation, Raffinose, Rats, Rats, Inbred Lew.

  • DESROIS M., SCIAKY M., LAN C., COZZONE P. J., BERNARD M. “Preservation of amino acids during long term ischemia and subsequent reflow with supplementation of L-arginine, the nitric oxide precursor, in the rat heart.”. Amino acids [En ligne]. 2003. Vol. 24, n°1-2, p. 141–148. Disponible sur : < http://link.springer.com/article/10.1007/s00726-002-0321-9 >
    Mots-clés : Amino Acids, Arginine, Chromatography, High Pressure Liquid, Chromatography, Ion Exchange, Creatine Kinase, L-Lactate Dehydrogenase, Myocardial Ischemia, Myocardial Reperfusion, Myocardium, Nitric Oxide, Rats, Rats, Sprague-Dawley.

2002

Journal Article
  • DESROIS M., CAUS T., LAN C., SCIAKY M., COZZONE P. J., BERNARD M. “Comparative effects of Celsior and a new cardioplegic solution on function, energy metabolism, and intracellular pH during long-term heart preservation.”. Transplantation proceedings. 2002. Vol. 34, n°4, p. 1259-1261.
    Mots-clés : Allopurinol, Cardioplegic Solutions, Coronary Circulation, Disaccharides, Electrolytes, Glutamates, Glutathione, Heart, Histidine, Mannitol, Myocardial Ischemia, Myocardial Reperfusion, Myocardium, Organ Preservation, Raffinose, Rats.

2001

Journal Article
  • CAUS T., IZQUIERDO M., LAN C., LE FUR Y., CONFORT-GOUNY S., COZZONE P. J., BERNARD M. “Simultaneous study of metabolism and function following cardioplegic arrest: a novel method of evaluation of the transplanted heart in the rat.”. The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation. 2001. Vol. 20, n°5, p. 575-582.
    Résumé : BACKGROUND: Limitations of the isolated perfused rat heart model for heart preservation studies include short study time due to the lack of stability of the preparation. We aimed to develop a new experimental model based on heterotopic heart transplantation in the rat to achieve simultaneous (31)P magnetic resonance spectroscopy (MRS) and functional study of the transplanted heart during early and late blood reperfusion. METHODS: Twenty-five Lewis rats underwent heterotopic abdominal isograft heart transplantation and were randomized in two groups. Hearts were harvested after cardioplegic arrest induced with Centre de Résonance Magnétique Biologique et Médicale (CRMBM) solution and then stored at 4 degrees C for a total ischemic time of 3 hours. Graft contractility measurement and simultaneous (31)P MRS were performed after 1 hour and 24 hours of blood reperfusion, respectively, in groups I (n = 12) and II (n =13). RESULTS: Contractility improved during reperfusion. The mean rate pressure product plus or minus standard error of mean increased from 11,373 +/- 1,377 mm Hg/min in group I to 24,363 +/- 3,860 mm Hg/min in group II (P = 0.003), while mean dP/dtmax increased from 1,642 +/- 173 mm Hg/sec to 2,571 +/- 333 mm Hg/sec, respectively (p = 0.03). Simultaneously, both the phosphocreatine/adenosine triphosphate (ATP) and inorganic phosphate/ATP ratios decreased from group I to group II (p = 0.025 and p = 0.015, respectively), suggesting regeneration of the intracellular pool of ATP in group II. CONCLUSIONS: Simultaneous functional and metabolic studies of the transplanted heart are feasible in rats. Improvement in contractility during late reperfusion is contemporary with significant changes in energetic metabolism. Our model should be useful for the further improvement of heart preservation, which may result in significant clinical progress.
    Mots-clés : Adenosine Triphosphate, Animals, Heart, Heart Arrest, Induced, Heart Rate, Heart Transplantation, Magnetic Resonance Spectroscopy, Male, Models, Animal, Myocardial Contraction, Myocardium, Phosphocreatine, Phosphorus, Rats, Rats, Inbred Lew, Reperfusion, Time Factors, Ventricular Pressure.

2000

Journal Article
  • BERNARD M., CABANES E., BAETZ D., EL BANANI H., LAN C., IZQUIERDO M., COZZONE P., FEUVRAY D. “Intracellular sodium in the ischemic and reperfused heart and its role in injury.”. Magma (New York, N.Y.). 2000. Vol. 11, n°1-2, p. 5-6.
    Mots-clés : Carnitine O-Palmitoyltransferase, Enzyme Inhibitors, Epoxy Compounds, Fatty Acids, Intracellular Fluid, Myocardial Ischemia, Myocardial Reperfusion Injury, Myocardium, perfusion, Rats, Sodium.
  • CAUS T., IZQUIERDO M., LAN C., LE FUR Y., CONFORT-GOUNY S., COZZONE P. J., BERNARD M. “In vivo functional and MRS metabolic evaluation of the heart graft; application to improvements of cardiac preservation.”. Magma (New York, N.Y.). 2000. Vol. 11, n°1-2, p. 20-22.
    Mots-clés : Animals, Heart, Heart Transplantation, Magnetic Resonance Spectroscopy, Male, Myocardium, Organ Preservation, Rats, Rats, Inbred Lew.


  • DESROIS M., SCIAKY M., LAN C., COZZONE P. J., BERNARD M. “L-arginine during long-term ischemia: effects on cardiac function, energetic metabolism and endothelial damage.”. The Journal of Heart and Lung Transplantation [En ligne]. 2000. Vol. 19, n°4, p. 367-376. Disponible sur : < http://dx.doi.org/10.1016/S1053-2498(00)00063-2 >
    Résumé : Background: We have evaluated the addition of L-arginine, a precursor of nitric oxide, to a cardioplegic solution (named CRMBM) designed for long-term heart preservation. Methods Isolated isovolumic-perfused rat hearts (n = 22) were arrested with the CRMBM solution either with (Arg) or without L-arginine (2 mmol/L) (Arg group, n = 12, vs control group n = 10), submitted to 8 hours of cold storage (4° C) in the solution, and then reperfused for 60 minutes at 37° C. In 11 hearts, we evaluated the quality of cardiac preservation with P-31 magnetic resonance spectroscopy and the measure of function and cellular integrity. Endothelium-dependent and independent vasodilatations were measured in 11 other hearts, using 5-hydroxytryptamine and papaverine to assess endothelial and smooth muscle function. Results Adding L-arginine to the cardioplegic solution improved functional recovery during reflow, as shown by the rate pressure product (31% ± 3% for control vs 47% ± 3% for Arg, p = 0.003) together with higher coronary flow and diminished contracture. Purine release in coronary effluents during reperfusion was lower in the Arg group. During ischemia and reflow kinetics of intracellular pH and high-energy phosphates were similar in both groups. Coronary endothelium-dependent vasodilatation was similarly impaired in both groups, but smooth muscle was less altered with L-arginine. Conclusion As an additive to the CRMBM cardioplegic solution, L-arginine provides a protective effect for long-term heart preservation. Our data do not show coronary endothelial protection as the prominent mechanism.
    Mots-clés : Arginine, Cardioplegic Solutions, Coronary Circulation, Endothelium, Vascular, Hemodynamics, Myocardial Ischemia, Organ Preservation, Rats, Rats, Sprague-Dawley.

1999

Journal Article
  • BERNARD M., CAUS T., SCIAKY M., LAN C., COZZONE P. J. “Optimized cardiac graft preservation: a comparative experimental study using P-31 magnetic resonance spectroscopy and biochemical analyses.”. The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation. 1999. Vol. 18, n°6, p. 572-581.
    Résumé : BACKGROUND: The University of Wisconsin (UW), St. Thomas (ST) and Broussais (B) solutions were compared to the CRMBM solution, that we developed for long term heart preservation. METHODS: Isolated isovolumic rat hearts were arrested with each cardioplegic solution (n = 5) to 8 hearts in each group), submitted to 12 hours of cold storage (4 degrees C) in the same solution and then reperfused for 60 minutes at 37 degrees C. Function was measured during control and reflow. High energy phosphates and intracellular pH were monitored by P-31 magnetic resonance spectroscopy. Analyses were performed by biochemical assays and HPLC in coronary effluents (CK, Pi, lactate, purines) and in freeze-clamped hearts (amino acids, nucleotides, CK, LDH) at the end of reperfusion. RESULTS: Functional recovery was significantly improved with the new cardioplegic solution (50+/-12% recovery for the rate pressure product at the end of reflow vs 8+/-3% with UW, 0% with B and with ST). This result was correlated with the best metabolic and cellular protection as assessed in particular by higher PCr levels during reflow (30+/-3% vs 10+/-3% with UW, 8+/-4% with B, and 7+/-1% with ST) as well as reduced creatine kinase leakage during reflow (110+/-15 IU/60 minute vs 270 +/- 57 IU/60 minute with UW, 323+/-36 IU/60 minute with Broussais solution and 237+/-18 IU/60 minute with ST). CONCLUSION: This new solution is more effective in prolonged myocardial protection than the three most widely used solutions.
    Mots-clés : Acid-Base Equilibrium, Adenosine, Adenosine Triphosphate, Allopurinol, Amino Acids, Bicarbonates, Calcium Chloride, Cardioplegic Solutions, Coronary Circulation, Glutathione, Heart Transplantation, Hydrogen-Ion Concentration, Insulin, Magnesium, Myocardial Reperfusion Injury, Organ Preservation, Organ Preservation Solutions, Phosphates, Potassium Chloride, Raffinose, Rats, Rats, Sprague-Dawley, Sodium Chloride.

  • DESROIS M., SCIAKY M., LAN C., COZZONE P. J., BERNARD M. “Metabolic and functional effects of low-potassium cardioplegic solutions for long-term heart preservation.”. Magnetic Resonance Materials in Physics, Biology and Medicine [En ligne]. 1999. Vol. 8, n°2, p. 77–82. Disponible sur : < http://link.springer.com/article/10.1007/BF02590522 >
    Mots-clés : Blood Pressure, Cardioplegic Solutions, Creatine Kinase, Heart Arrest, Induced, Heart Rate, L-Lactate Dehydrogenase, Lactic Acid, Myocardial Ischemia, Organ Preservation, Potassium, Purines, Rats, Rats, Sprague-Dawley, Reperfusion.

  • MAIXENT J. - M., GERBI A., BARBEY O., LAN C., JAMME I., BURNET H., NOUVELOT A., LÉVY S., COZZONE P. J., BERNARD M. “Dietary fish oil promotes positive inotropy of ouabain in the rat heart.”. American Journal of Physiology-Heart and Circulatory Physiology [En ligne]. 1999. Vol. 277, n°6, p. H2290–H2297. Disponible sur : < http://ajpheart.physiology.org/content/277/6/H2290.short >
    Mots-clés : Cell Membrane, Dietary Fats, Unsaturated, Dietary Supplements, Fish Oils, Myocardial Contraction, Myocardium, Ouabain, Rats, Rats, Wistar, Sodium-Potassium-Exchanging ATPase.
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