- Email: [email protected]
0307 : Acute activation of the hexosamine biosynthetic pathway promotes electrical instability
210
Archives of Cardiovascular Diseases Supplements (2016) 8, 210-212
Topic 8 – Metabolism: Diabetes, Glucose – A April 07th, Thursday 2016
0132 Oxidative stress and cardio-metabolic alterations induced by postnatal programming can be reversed in adulthood by a short-term moderate caloric restriction Na Li (1), Charles Guenancia (2), Eve Rigal (1), Olivier Hachet (1), Corinne Leloup (3), Luc Rochette (1), Catherine Vergely (1) (1) Université de Bourgogne, Dijon, France – (2) CHU Dijon, Dijon, France – (3) Centre des Sciences du Goût de l'Alimentation, CNRS UMR 6265, INRA UMR 1324, Dijon, France * Corresponding author: [email protected] Postnatal overfeeding (PNOF) in rodents induces early programming of cardio-metabolic risk. Our aim was to determine if a moderate diet restriction could restore cardio-metabolic alterations induced by PNOF. Immediately after birth, litters of C57BL/6 mice were either maintained at 9 (normal litter, NL), or reduced to 3 (small litter, SL) to induce PNOF. At weaning, all mice received a standard diet ad libitum (AL). At 6 month of age, half of the NL and SL mice were assigned to a moderate 20% calorie restriction (CR: NLCR, SLCR) for one month, while the other mice continued to eat AL (AL: NLAL, SLAL). Glucose and insulin tolerance tests, cardiac function (echocardiography), body composition (Echo-MRI), cardiac sensitivity to ischemia-reperfusion injury, mitochondrial function, reactive oxygen species (ROS) generation (EPR spectroscopy) and insulin signaling were assessed before and/or after one month of CR. Adult SL mice presented overweight, fat accumulation, hyperleptinemia, glucose intolerance, insulin resistance and decreased left ventricular ejection fraction (LVEF). After one month of moderate CR, body weight of SLCR was normalized to this of NLAL however their fat mass and leptinemia were not decreased. Glucose metabolism was improved and LVEF was increased In SLCR. After 30 min of global ischemia, hearts isolated from SLCR mice showed better recovery and smaller infarct size than this of others groups. CR increased the cardiac mitochondrial respiratory rate in SLCR mice whereas cardiac ROS production was significantly decreased in SLCR mice. Insulin signaling in heart was affected neither by PNOF nor by CR. Intriguingly, no difference was observed in NLCR mice for most of the parameters investigated. Our results confirmed the programming of early overfeeding on metabolic and cardiac function. A short-term moderate CR in not only normalized body weight in SL mice but also ameliorate the metabolic programming and reverse the cardiac dysfunction induced by PNOF. The author hereby declares no conflict of interest
0080 Involvement of the sympathetic nervous system in the development of carbohydrate metabolism disorders Gaëlle Aubertin-Kirch *, Maud Weiss, Pascal Bousquet, Laurent Monassier, Nathalie Niederhoffer Faculté de Médecine, Strasbourg, France * Corresponding author: [email protected] (Gaëlle Aubertin-Kirch) Introduction The causal role of sympathetic nervous system in the development of metabolic disorders has not been clearly defined. The aim of the study was to determine if a chronic increase of the sympathetic nervous activity can induce and/or accelerate the development of glucose metabolism disorders. For that purpose, we used a transgenic mouse model, in which the gene encoding for the reuptake norepinephrine transporter (NET) has been deleted; these animals display increased urinary catecholamine levels. Methods Carbohydrate homeostasis (intraperitoneal glucose tolerance test, IPGTT, insulin tolerance test, ITT, insulin rates) was studied in heterozygous NET knockout mice (±) or wild-type mice (+/+) at 10, 20 and 25 weeks old.
© Elsevier Masson SAS. All rights reserved.
Mice were then fed either with normal chow or 30% w/v fructose in drinking water; glucose metabolism was assessed again after 15 weeks of such diet. Results Heterozygous mice displayed glucose intolerance already at 10 weeks old (area under the curve of the IPGTT (AUC; %) = 24859 vs 18016, p=0.004); similar results were obtained at 25 weeks old, i.e, just before starting the fructose diet: AUC = 24524 vs 20573, p=0.005 for ± and +/+ mice respectively. Moreover sensibility to insulin seemed to be diminished in ± mice compared to +/+ mice (insulin rate = 1.12 vs 0.86 μg/L and HOMAIR=11.1 vs 8.4). Heterozygous animals were also much more sensitive to high fructose, since a 20% increase in the AUC of the IPGTT was obtained at the end of the high fructose diet, compared to the 2% increase in +/+ mice. This was associated with a decrease of insulin sensibility (HOMA-IR of ± mice = 11.1 vs 18.1, p=0.01, before and after fructose diet respectively). Conclusion Our data show that constitutive chronic sympathetic hyperactivity can induce the early development of carbohydrate metabolism disorders. Moreover, it seems to represent a major factor of susceptibility to diet-induced metabolic dysfunction. The author hereby declares no conflict of interest
0383 Vascular programming of rats exposed in utero to maternal obesity Cyrielle Payen (1), Maxime Gérard (2), Jennifer Bourreau (1), Géraldine Gascoin (2), Daniel Henrion (1), Celine Fassot * (1) (1) Université d’Angers, UMR CNRS 6214, Biologie Neurovasculaire, Angers, France – (2) CHU Angers, Angers, France * Corresponding author: [email protected] (Celine Fassot) Obesity in women of childbearing age is of particular concern since there is overwhelming evidence that being born to an obese mother increases the risk for the child of developing metabolic (obesity, insulin resistance) and cardiovascular (vascular dysfunction) disorders in later life. These findings suggest that the nutritional stress associated with maternal obesity has an impact on the longterm health of the offspring and could impact directly the fetal vascular function. However, current studies use animals in which vascular dysfunction and metabolic disorders are present simultaneously. Using a model of rats exposed in utero to maternal obesity, we aimed to determine if maternal obesity was able to directly re-program fetal vascular function or if development of such dysfunction was linked to metabolic abnormalities in offspring. Obese female rats (under hight-fat diet) were crossed with non-obese males. The metabolic status of male offspring from obese mothers (OMO) and mothers controls (CMO) was evaluated immediately after weaning (21j) and 2 months later by tolerance tests to insulin (ITT) and glucose (GTT), and plasmatic lipid profile. Vascular reactivity of the aorta was evaluated by myography (vascular reactivity in response to pharmacological agents). At weaning, GTT, ITT, plasmatic lipid profile as well as vascular reactivity of OMO were similar to those of CMO. At 3 months of age, although metabolic and lipid profiles are not modified, endotheliumdependant vasodilation was altered in OMO compared to CMO (acetylcholine dose-response curve EC50: 2,46E-06±5,26E-07 vs 3,60E-07±5,01E-08 for OMO and CMO respectively, p<0,05). In presence of L-NAME, indomethacin (coxinhibitor) improved vasodilation showing that prostaglandins have a more important role in OMO than in CMO. Our results bring out a vascular dysfunction before the development of metabolic disorders and highlight a possible fetal vascular reprogramming in response to maternal obesity. The author hereby declares no conflict of interest
0307 Acute activation of the hexosamine biosynthetic pathway promotes electrical instability Fanny Vaillant *, Emma Abell, Marion Constantin, Philippe Pasdois, Laurent Arsac, Thomas Desplantez, Véronique Deschodt-Arsac, Pierre Dos Santos IHU L'institut de rythmologie et modélisation cardiaque (LIRYC), U1045, Pessac, France * Corresponding author: [email protected] (Fanny Vaillant) Background The hexosamine biosynthetic pathway (HBP) is heightened in cardiomyopathies. We aimed at understanding how over-activation of HBP
211
Archives of Cardiovascular Diseases Supplements (2016) 8, 210-212
impacts on cardiac electrophysiology, and acts as a trigger or a substrate of cardiac arrhythmias. Methods Overactivation of the HBP by injection of glucosamine (GlcN 270mg/kg) was assessed under basal conditions and during beta-adrenergic stress on the myocardial energetic status (phosphocreatine to ATP ratio) of rats by 31P nuclear magnetic resonance spectroscopy. Rat hearts were perfused ex vivo to evaluate the effects of the HBP activation (physiologically: glutamine 0.5mM – gln; overactivated: GlcN 1mM) on: cardiac function, MVO2, and arrhythmia score (AS) under basal (spontaneous arrhythmias: sAS) and pacing (pAS) conditions. At the cellular level (HL1 cells), HBP overactivation (GlcN) was assessed on conduction velocity characterized by micro-electrode arrays recordings, and properties of voltage gated ionic channels involved in cellular excitability and conduction by patch clamp experiments. Results In vivo GlcN did not modify PCr/ATP of the left ventricle under basal conditions. This ratio was significantly decreased during beta-adrenergic stress, while a similar increased heart rate was reported. When hearts were isolated and perfused ex vivo, GlcN induced a decrease of the heart rate and MVO2 temporarily, and an increase of the sAS and pAS. Physiological activation of HBP with gln did not impact the ex vivo cardiac function and the sAS, but further increased the probability of atrial arrhythmias during pacing. In HL1 cells, GlcN reduced the rate of spontaneous depolarization, modified the direction and the velocity of the impulse propagation, and altered activation and inactivation properties of the sodium channel. Conclusion Acute HBP activation is associated with an increased vulnerability for arrhythmias and alteration of impulse conduction, suggesting its potential role in the atrial and ventricular arrhythmias. The author hereby declares no conflict of interest *
Corresponding author: [email protected]
0379 Inhibition of glucose transport in cardiac myocytes exposed to free fatty acids: role of FAK, PKCs and PKD in the restoration of glucose transport by chronic phorbol ester treatment Christelle Viglino, Bahareh Khoramdin, Guillaume Praplan, Christophe Montessuit * Université de Genève, Genève, Suisse * Corresponding author: [email protected] (Christophe Montessuit) Background Stimulation of glucose transport is an important determinant of myocardial susceptibility to ischemia and reperfusion. Stimulation of glucose transport of markedly impaired in cardiomyocytes exposed to free fatty acids (FFA), in part due to inhibition of Focal Adhesion Kinase (FAK). Aim To determine whether reactivation of FAK by chronic phenylephrine (PE) or phorbol ester (tetradecanoyl phorbol acetate; TPA) treatment improves glucose transport in cardiomyocytes exposed to FFA. Methods Isolated cultured cardiomyocytes were chronically exposed to FFA±PE or TPA. Glucose transport was measured during acute stimulation either by insulin or by metabolic inhibition with oligomycin resulting in AMPK activation. Results Chronic treatment with PE or TPA improved basal and stimulated glucose transport in FFA-exposed, but not in control cardiomyocytes. These effects were associated with increased FAK activity. However, the effect of TPA was much more pronounced than that of PE, despite similar FAK reactivation, suggesting additional effects of TPA. Chronic FFA exposure induced the activation of PKCδ and PKCε. TPA markedly downregulated the expression of PKCα, PKCδ and PKCε, suggesting that PKCδ or PKCε activation could contribute to inhibition of glucose transport by FFA. Rottlerin, a specific PKCδ inhibitor, improved glucose transport in FFA-exposed cardiomyocytes; and PKCδ was reduced in the particulate fraction of FFA + TPAexposed cardiomyocytes. TPA also activated Protein Kinase D 1(PKD1) in FFA-exposed cardiomyocytes, as assessed by autophosphorylation of PKD1 on Y916. Pharmaceutical inhibition of PKD1 only partially prevented the improvement of glucose transport by TPA. Conclusions basal and stimulated glucose transport in cardiomyocytes is reduced by chronic FFA exposure, but restored by concomitant treatment with
a phorbol ester. The mechanism of action of phorbol esters may involve FAK activation, downregulation of PKCδ and activation of PKD1. The author hereby declares no conflict of interest
0349 Chronic heart failure and diabetes: two frequent companions in clinical practice Ichraq Nassiri *, Fatima Aghlad, Hayat Najih, Adolf Kasongo, Malika Nourddine, Rachida Habbal CHU Ibn Rochd Casablanca, Maroc * Corresponding author: [email protected] (Ichraq Nassiri) Objective The objectives of our study are to show prevalence of diabetics in heart failure population and to compare epidemiological profiles of diabetics and non diabetics. Material and methods we included 1613 patients, diabetics and non diabetics, admitted in united of heart failure in our center of Cardiology 2006 to 2015. All patients were evaluated clinically with monitoring of blood pressure (BP), 6 min walk test and electrocardiogram. Two-dimensional echocardiography and laboratory tests were performed in all patients. Coronarography was realised at 298 patients. The data are presented as numbers, percentages, and medians with interquartile range. The distribution of variables was compared between diabetics and non diabetics by chi2 test with confidence intervals. Results 1613 patients were studied, the median age was 65 years (42-94 years) and 63% were men. 519 (32%) had diabetes. Diabetic patients were younger than non diabetics (56 years and 66 years). Stroke (23% and 18%) and myocardial infarction (37% and 27%) were more frequent and renal function was more affected in diabetics group. Atrial fibrillation was lower in diabetics group (7% and 17%). Ejection fraction of left ventricle was higher (48,5% and 35%) in diabetics group, but 51% of them had diastolic dysfunction with higher filling pressures. There weren't differences in coronarography. Concerning treatment, 34% of diabetics arrive at maximal beta-blockers treatment (more than non diabetics 16%). Frequence of decompensation was more important in diabetics group. Conclusions So, frequence of diabetes in Moroccan heart failure population is higher. Significant differences exist in comorbidities, ventricular function, maximal beta-blockers treatment and frequence of decompessation between diabetics and non diabetics with chronic heart failure. These findings emphasize the importance of individualised management and need for more comprehensive recruitment of diabetics in clinical trials. The author hereby declares no conflict of interest
0318 Left ventricular diastolic dysfunction in asymptomatic type 1 diabetic children: two-dimensional echocardiography study Rim Ben Said *, Ihsen Zairi, Khadija Mzoughi, Fathia Ben Moussa, Sana Fennira, Sondos Kraiem Hôpital Militaire, Exploration Cardiologique, Tunis, Tunisie * Corresponding author: [email protected] (Rim Ben Said) Introduction Diabetic cardiomyopathie (DCM) is a distinct new entity. Pathophysiological mechanisms are not well known. It’s defined as the presence of abnormal myocardial performance or abnormal structure in the absence of epicardial coronary artery disease, hypertension and significant valvular disease. The relationship between type 1 diabetes (T1D) and cardiac function in children is not well established. Demonstration of an early diastolic and systolic dysfunction help us to diagnose children’s DCM, and is important for the timely interventions. The objective of this study was to characterize diastolic function abnormalities using two-dimensional echocardiography in T1D children. Methods Twenty four T1D children were compared to 20 healthy control matched for age, gender and body mass index and having normal echocardiography. A standard 12-lead electrocardiogram was recorded followed by measurement of blood pressure. Laboratory investigations included mean hemoglobin (HbA1c). Echocardiography with simultaneous ECG (standard
© Elsevier Masson SAS. All rights reserved.
Archives of Cardiovascular Diseases Supplements (2016) 8, 210-212
Topic 8 – Metabolism: Diabetes, Glucose – A April 07th, Thursday 2016
0132 Oxidative stress and cardio-metabolic alterations induced by postnatal programming can be reversed in adulthood by a short-term moderate caloric restriction Na Li (1), Charles Guenancia (2), Eve Rigal (1), Olivier Hachet (1), Corinne Leloup (3), Luc Rochette (1), Catherine Vergely (1) (1) Université de Bourgogne, Dijon, France – (2) CHU Dijon, Dijon, France – (3) Centre des Sciences du Goût de l'Alimentation, CNRS UMR 6265, INRA UMR 1324, Dijon, France * Corresponding author: [email protected] Postnatal overfeeding (PNOF) in rodents induces early programming of cardio-metabolic risk. Our aim was to determine if a moderate diet restriction could restore cardio-metabolic alterations induced by PNOF. Immediately after birth, litters of C57BL/6 mice were either maintained at 9 (normal litter, NL), or reduced to 3 (small litter, SL) to induce PNOF. At weaning, all mice received a standard diet ad libitum (AL). At 6 month of age, half of the NL and SL mice were assigned to a moderate 20% calorie restriction (CR: NLCR, SLCR) for one month, while the other mice continued to eat AL (AL: NLAL, SLAL). Glucose and insulin tolerance tests, cardiac function (echocardiography), body composition (Echo-MRI), cardiac sensitivity to ischemia-reperfusion injury, mitochondrial function, reactive oxygen species (ROS) generation (EPR spectroscopy) and insulin signaling were assessed before and/or after one month of CR. Adult SL mice presented overweight, fat accumulation, hyperleptinemia, glucose intolerance, insulin resistance and decreased left ventricular ejection fraction (LVEF). After one month of moderate CR, body weight of SLCR was normalized to this of NLAL however their fat mass and leptinemia were not decreased. Glucose metabolism was improved and LVEF was increased In SLCR. After 30 min of global ischemia, hearts isolated from SLCR mice showed better recovery and smaller infarct size than this of others groups. CR increased the cardiac mitochondrial respiratory rate in SLCR mice whereas cardiac ROS production was significantly decreased in SLCR mice. Insulin signaling in heart was affected neither by PNOF nor by CR. Intriguingly, no difference was observed in NLCR mice for most of the parameters investigated. Our results confirmed the programming of early overfeeding on metabolic and cardiac function. A short-term moderate CR in not only normalized body weight in SL mice but also ameliorate the metabolic programming and reverse the cardiac dysfunction induced by PNOF. The author hereby declares no conflict of interest
0080 Involvement of the sympathetic nervous system in the development of carbohydrate metabolism disorders Gaëlle Aubertin-Kirch *, Maud Weiss, Pascal Bousquet, Laurent Monassier, Nathalie Niederhoffer Faculté de Médecine, Strasbourg, France * Corresponding author: [email protected] (Gaëlle Aubertin-Kirch) Introduction The causal role of sympathetic nervous system in the development of metabolic disorders has not been clearly defined. The aim of the study was to determine if a chronic increase of the sympathetic nervous activity can induce and/or accelerate the development of glucose metabolism disorders. For that purpose, we used a transgenic mouse model, in which the gene encoding for the reuptake norepinephrine transporter (NET) has been deleted; these animals display increased urinary catecholamine levels. Methods Carbohydrate homeostasis (intraperitoneal glucose tolerance test, IPGTT, insulin tolerance test, ITT, insulin rates) was studied in heterozygous NET knockout mice (±) or wild-type mice (+/+) at 10, 20 and 25 weeks old.
© Elsevier Masson SAS. All rights reserved.
Mice were then fed either with normal chow or 30% w/v fructose in drinking water; glucose metabolism was assessed again after 15 weeks of such diet. Results Heterozygous mice displayed glucose intolerance already at 10 weeks old (area under the curve of the IPGTT (AUC; %) = 24859 vs 18016, p=0.004); similar results were obtained at 25 weeks old, i.e, just before starting the fructose diet: AUC = 24524 vs 20573, p=0.005 for ± and +/+ mice respectively. Moreover sensibility to insulin seemed to be diminished in ± mice compared to +/+ mice (insulin rate = 1.12 vs 0.86 μg/L and HOMAIR=11.1 vs 8.4). Heterozygous animals were also much more sensitive to high fructose, since a 20% increase in the AUC of the IPGTT was obtained at the end of the high fructose diet, compared to the 2% increase in +/+ mice. This was associated with a decrease of insulin sensibility (HOMA-IR of ± mice = 11.1 vs 18.1, p=0.01, before and after fructose diet respectively). Conclusion Our data show that constitutive chronic sympathetic hyperactivity can induce the early development of carbohydrate metabolism disorders. Moreover, it seems to represent a major factor of susceptibility to diet-induced metabolic dysfunction. The author hereby declares no conflict of interest
0383 Vascular programming of rats exposed in utero to maternal obesity Cyrielle Payen (1), Maxime Gérard (2), Jennifer Bourreau (1), Géraldine Gascoin (2), Daniel Henrion (1), Celine Fassot * (1) (1) Université d’Angers, UMR CNRS 6214, Biologie Neurovasculaire, Angers, France – (2) CHU Angers, Angers, France * Corresponding author: [email protected] (Celine Fassot) Obesity in women of childbearing age is of particular concern since there is overwhelming evidence that being born to an obese mother increases the risk for the child of developing metabolic (obesity, insulin resistance) and cardiovascular (vascular dysfunction) disorders in later life. These findings suggest that the nutritional stress associated with maternal obesity has an impact on the longterm health of the offspring and could impact directly the fetal vascular function. However, current studies use animals in which vascular dysfunction and metabolic disorders are present simultaneously. Using a model of rats exposed in utero to maternal obesity, we aimed to determine if maternal obesity was able to directly re-program fetal vascular function or if development of such dysfunction was linked to metabolic abnormalities in offspring. Obese female rats (under hight-fat diet) were crossed with non-obese males. The metabolic status of male offspring from obese mothers (OMO) and mothers controls (CMO) was evaluated immediately after weaning (21j) and 2 months later by tolerance tests to insulin (ITT) and glucose (GTT), and plasmatic lipid profile. Vascular reactivity of the aorta was evaluated by myography (vascular reactivity in response to pharmacological agents). At weaning, GTT, ITT, plasmatic lipid profile as well as vascular reactivity of OMO were similar to those of CMO. At 3 months of age, although metabolic and lipid profiles are not modified, endotheliumdependant vasodilation was altered in OMO compared to CMO (acetylcholine dose-response curve EC50: 2,46E-06±5,26E-07 vs 3,60E-07±5,01E-08 for OMO and CMO respectively, p<0,05). In presence of L-NAME, indomethacin (coxinhibitor) improved vasodilation showing that prostaglandins have a more important role in OMO than in CMO. Our results bring out a vascular dysfunction before the development of metabolic disorders and highlight a possible fetal vascular reprogramming in response to maternal obesity. The author hereby declares no conflict of interest
0307 Acute activation of the hexosamine biosynthetic pathway promotes electrical instability Fanny Vaillant *, Emma Abell, Marion Constantin, Philippe Pasdois, Laurent Arsac, Thomas Desplantez, Véronique Deschodt-Arsac, Pierre Dos Santos IHU L'institut de rythmologie et modélisation cardiaque (LIRYC), U1045, Pessac, France * Corresponding author: [email protected] (Fanny Vaillant) Background The hexosamine biosynthetic pathway (HBP) is heightened in cardiomyopathies. We aimed at understanding how over-activation of HBP
211
Archives of Cardiovascular Diseases Supplements (2016) 8, 210-212
impacts on cardiac electrophysiology, and acts as a trigger or a substrate of cardiac arrhythmias. Methods Overactivation of the HBP by injection of glucosamine (GlcN 270mg/kg) was assessed under basal conditions and during beta-adrenergic stress on the myocardial energetic status (phosphocreatine to ATP ratio) of rats by 31P nuclear magnetic resonance spectroscopy. Rat hearts were perfused ex vivo to evaluate the effects of the HBP activation (physiologically: glutamine 0.5mM – gln; overactivated: GlcN 1mM) on: cardiac function, MVO2, and arrhythmia score (AS) under basal (spontaneous arrhythmias: sAS) and pacing (pAS) conditions. At the cellular level (HL1 cells), HBP overactivation (GlcN) was assessed on conduction velocity characterized by micro-electrode arrays recordings, and properties of voltage gated ionic channels involved in cellular excitability and conduction by patch clamp experiments. Results In vivo GlcN did not modify PCr/ATP of the left ventricle under basal conditions. This ratio was significantly decreased during beta-adrenergic stress, while a similar increased heart rate was reported. When hearts were isolated and perfused ex vivo, GlcN induced a decrease of the heart rate and MVO2 temporarily, and an increase of the sAS and pAS. Physiological activation of HBP with gln did not impact the ex vivo cardiac function and the sAS, but further increased the probability of atrial arrhythmias during pacing. In HL1 cells, GlcN reduced the rate of spontaneous depolarization, modified the direction and the velocity of the impulse propagation, and altered activation and inactivation properties of the sodium channel. Conclusion Acute HBP activation is associated with an increased vulnerability for arrhythmias and alteration of impulse conduction, suggesting its potential role in the atrial and ventricular arrhythmias. The author hereby declares no conflict of interest *
Corresponding author: [email protected]
0379 Inhibition of glucose transport in cardiac myocytes exposed to free fatty acids: role of FAK, PKCs and PKD in the restoration of glucose transport by chronic phorbol ester treatment Christelle Viglino, Bahareh Khoramdin, Guillaume Praplan, Christophe Montessuit * Université de Genève, Genève, Suisse * Corresponding author: [email protected] (Christophe Montessuit) Background Stimulation of glucose transport is an important determinant of myocardial susceptibility to ischemia and reperfusion. Stimulation of glucose transport of markedly impaired in cardiomyocytes exposed to free fatty acids (FFA), in part due to inhibition of Focal Adhesion Kinase (FAK). Aim To determine whether reactivation of FAK by chronic phenylephrine (PE) or phorbol ester (tetradecanoyl phorbol acetate; TPA) treatment improves glucose transport in cardiomyocytes exposed to FFA. Methods Isolated cultured cardiomyocytes were chronically exposed to FFA±PE or TPA. Glucose transport was measured during acute stimulation either by insulin or by metabolic inhibition with oligomycin resulting in AMPK activation. Results Chronic treatment with PE or TPA improved basal and stimulated glucose transport in FFA-exposed, but not in control cardiomyocytes. These effects were associated with increased FAK activity. However, the effect of TPA was much more pronounced than that of PE, despite similar FAK reactivation, suggesting additional effects of TPA. Chronic FFA exposure induced the activation of PKCδ and PKCε. TPA markedly downregulated the expression of PKCα, PKCδ and PKCε, suggesting that PKCδ or PKCε activation could contribute to inhibition of glucose transport by FFA. Rottlerin, a specific PKCδ inhibitor, improved glucose transport in FFA-exposed cardiomyocytes; and PKCδ was reduced in the particulate fraction of FFA + TPAexposed cardiomyocytes. TPA also activated Protein Kinase D 1(PKD1) in FFA-exposed cardiomyocytes, as assessed by autophosphorylation of PKD1 on Y916. Pharmaceutical inhibition of PKD1 only partially prevented the improvement of glucose transport by TPA. Conclusions basal and stimulated glucose transport in cardiomyocytes is reduced by chronic FFA exposure, but restored by concomitant treatment with
a phorbol ester. The mechanism of action of phorbol esters may involve FAK activation, downregulation of PKCδ and activation of PKD1. The author hereby declares no conflict of interest
0349 Chronic heart failure and diabetes: two frequent companions in clinical practice Ichraq Nassiri *, Fatima Aghlad, Hayat Najih, Adolf Kasongo, Malika Nourddine, Rachida Habbal CHU Ibn Rochd Casablanca, Maroc * Corresponding author: [email protected] (Ichraq Nassiri) Objective The objectives of our study are to show prevalence of diabetics in heart failure population and to compare epidemiological profiles of diabetics and non diabetics. Material and methods we included 1613 patients, diabetics and non diabetics, admitted in united of heart failure in our center of Cardiology 2006 to 2015. All patients were evaluated clinically with monitoring of blood pressure (BP), 6 min walk test and electrocardiogram. Two-dimensional echocardiography and laboratory tests were performed in all patients. Coronarography was realised at 298 patients. The data are presented as numbers, percentages, and medians with interquartile range. The distribution of variables was compared between diabetics and non diabetics by chi2 test with confidence intervals. Results 1613 patients were studied, the median age was 65 years (42-94 years) and 63% were men. 519 (32%) had diabetes. Diabetic patients were younger than non diabetics (56 years and 66 years). Stroke (23% and 18%) and myocardial infarction (37% and 27%) were more frequent and renal function was more affected in diabetics group. Atrial fibrillation was lower in diabetics group (7% and 17%). Ejection fraction of left ventricle was higher (48,5% and 35%) in diabetics group, but 51% of them had diastolic dysfunction with higher filling pressures. There weren't differences in coronarography. Concerning treatment, 34% of diabetics arrive at maximal beta-blockers treatment (more than non diabetics 16%). Frequence of decompensation was more important in diabetics group. Conclusions So, frequence of diabetes in Moroccan heart failure population is higher. Significant differences exist in comorbidities, ventricular function, maximal beta-blockers treatment and frequence of decompessation between diabetics and non diabetics with chronic heart failure. These findings emphasize the importance of individualised management and need for more comprehensive recruitment of diabetics in clinical trials. The author hereby declares no conflict of interest
0318 Left ventricular diastolic dysfunction in asymptomatic type 1 diabetic children: two-dimensional echocardiography study Rim Ben Said *, Ihsen Zairi, Khadija Mzoughi, Fathia Ben Moussa, Sana Fennira, Sondos Kraiem Hôpital Militaire, Exploration Cardiologique, Tunis, Tunisie * Corresponding author: [email protected] (Rim Ben Said) Introduction Diabetic cardiomyopathie (DCM) is a distinct new entity. Pathophysiological mechanisms are not well known. It’s defined as the presence of abnormal myocardial performance or abnormal structure in the absence of epicardial coronary artery disease, hypertension and significant valvular disease. The relationship between type 1 diabetes (T1D) and cardiac function in children is not well established. Demonstration of an early diastolic and systolic dysfunction help us to diagnose children’s DCM, and is important for the timely interventions. The objective of this study was to characterize diastolic function abnormalities using two-dimensional echocardiography in T1D children. Methods Twenty four T1D children were compared to 20 healthy control matched for age, gender and body mass index and having normal echocardiography. A standard 12-lead electrocardiogram was recorded followed by measurement of blood pressure. Laboratory investigations included mean hemoglobin (HbA1c). Echocardiography with simultaneous ECG (standard
© Elsevier Masson SAS. All rights reserved.