Q Timour

University of Lyon, Lyons, Rhône-Alpes, France

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Publications (102)194.18 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The voltage-gated Nav1.5 channel is essential for the propagation of action potentials in the heart. Malfunctions of this channel are known to cause hereditary diseases. It is a prime target for class 1 antiarrhythmic drugs and a number of antidepressants. The purpose of the present study was to investigate the Nav1.5 blocking properties of fluoxetine, a selective serotonin re-uptake inhibitor. Nav1.5 channels were expressed in HEK-293 cells, and Na(+) currents were recorded using the patch-clamp technique. Dose-response curves of racemic fluoxetine (IC50 = 39 μM) and its optical isomers had similar IC50 (40 and 47 μM for the (+) and (-) isomer, respectively). Norfluoxetine, a fluoxetine metabolite, had a higher affinity than fluoxetine, with an IC50 of 29 μM. Fluoxetine inhibited currents in a frequency-dependent manner, shifted steady-state inactivation to more hyperpolarized potentials, and slowed the recovery of Nav1.5 from inactivation. Mutating a phenylalanine (F1760) and a tyrosine (Y1767) in DIVS6, significantly reduced the affinity of fluoxetine and its frequency-dependent inhibition. We used a non-inactivating Nav1.5 mutant to show that fluoxetine displays open-channel block behavior. The molecular model of fluoxetine in Nav1.5 was in agreement with mutational experiments, in which F1760 and Y1767 were found to be the key residues in binding fluoxetine. We concluded that fluoxetine blocks Nav1.5 by binding to the class 1 antiarrhythmic site. The blocking of cardiac Na(+) channels should be taken into consideration when prescribing fluoxetine alone, or in association with other drugs that may be cardiotoxic or for patients with conduction disorders.
    Molecular pharmacology. 07/2014;
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    ABSTRACT: Many elderly patients are routinely exposed to drugs that may prolong the cardiac QT interval and cause Torsades de pointes (TdP). However, predictors of TdP in patients with drug-associated long QT syndrome (LQTS) are not fully understood, especially in the geriatric population. The objective of this study was to identify risk factors of TdP in elderly patients with drug-associated LQTS.
    Drugs & Aging 06/2014; · 2.50 Impact Factor
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    ABSTRACT: The aim of the present study was to determine whether amlodipine and/or perindoprilate injected intravenously (iv) prior to ischemia exerted protective effects on mitochondria structural and functional alterations induced by ischemia and aggravated by reperfusion. Heart rate, the duration of monophasic action potentials (dMAP), peak of the time derivative of left ventricular pressure (LV dP/dt max), mitochondria structural and functional parameters in the left ventricle ischemic area were measured after 45-min ischemia and 1-min reperfusion in domestic pigs either untreated or pretreated with amlodipine, perindoprilate or amlodipine + perindoprilate. Ischemia-reperfusion (I/R) induced tachycardia, reduced dMAP and LV dP/dt max, and causes alterations of mitochondria structural and functional parameters with decreased oxygen consumption, increased reactive oxygen species production and reduced calcium retention capacity (CRC) with opening of mitochondrial permeability transition pores. This opening is mainly due to oxidative stress and calcium overload and seems to be the pivotal event in cell death after I/R. No drug treatment changed hemodynamic and electrophysiological parameters, but amlodipine and perindoprilate, either alone or combined, prevented mitochondrial alterations but only partially. The preservation of mitochondrial structure and functions reported in our study probably plays an important role in preventing calcium overload and mPTP opening during myocardial I/R by a specially increased (CRC) which can explain their cardioprotective effects. This article is protected by copyright. All rights reserved.
    Fundamental and Clinical Pharmacology 03/2014; · 1.99 Impact Factor
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    ABSTRACT: Preventing the consequences of ischemia/reperfusion (I/R)-induced lesions in the clinic requires the administration of pharmacological agents prior to restoring coronary vascularization. The aim of this study was to evaluate the effects of ranolazine and propranolol when administered either alone or combined prior to I/R induction in a pig model. Thirty domestic pigs were randomly assigned to five groups of six animals including (i) sham animals; (ii) untreated animals with 45-min ischemia and 1-min reperfusion; animals administered intravenously with (iii) ranolazine, or (iv) propranolol, or (v) both combined, prior to 45-min ischemia and 1-min reperfusion. The heart rate (HR), duration of monophasic action potentials (dMAP), and peak of the time derivative of left ventricular pressure (LV dP/dt max) were measured during ischemia and after 1 min of reperfusion. Structural and functional parameters of mitochondria were analyzed in tissue samples taken from the left ventricle ischemic area at the end of the experiment. I/R induced expected effects, namely accelerated HR, decreased dMAP and LV dP/dt max, and altered mitochondrial structural and functional parameters including decreased oxygen consumption, increased reactive oxygen species (ROS) production, and reduced calcium retention capacity resulting in the opening of mitochondrial permeability transition pores (mPTP). Ranolazine and propranolol administered either alone or combined prior to I/R significantly decreased all of these deleterious consequences. The protective effects of ranolazine and propranolol are seemingly due to the prevention of calcium overload and resulting lesions in mitochondria.
    Fundamental and Clinical Pharmacology 04/2013; · 1.99 Impact Factor
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    ABSTRACT: Myocardial ischemia affects mitochondrial function leading to ionic imbalance and susceptibility to ventricular fibrillation. Trimetazidine (TMZ), a metabolic agent, is clinically used as an anti-anginal therapy. This study was conducted to compare the effect of TMZ 20 mg immediate release (IR) and TMZ 35 mg modified release (MR), two bioequivalent marketed formulations of TMZ, on cardioprotection during acute ischemia in pigs. A 4-day oral treatment with TMZ 20 mg IR (800 mg, tid) or TMZ 35 mg MR (1,400 mg, bid) had no effect on ventricular fibrillation threshold (VFT) prior to ischemia but significantly prevented the decrease in VFT observed in placebo-treated groups after a 1-min left anterior descending coronary artery occlusion. This effect occurred without modifying cardiac hemodynamic and conduction parameters. In both TMZ-treated groups, a significant reduction of the ischemic area as well as a protection of cardiomyocytes were observed. Cardiac enzymatic activity (phosphorylase, succinate dehydrogenase, ATPase) was increased in TMZ-treated groups. Both formulations preserved mitochondrial structure and improved mitochondrial function as demonstrated by a twofold increase of oxidative phosphorylation, by a reduction of reactive oxygen species (ROS) production (>30 %) and by a trend to increase the mitochondrial calcium retention capacity. In this model of ischemia, both TMZ formulations, leading to equivalent TMZ plasma exposures, demonstrated similar cardioprotective effects. This protection could be attributed to a preservation of mitochondrial structure and function, which plays a central role in ATP and ROS production and consequently could be considered as a target of cardioprotection.
    Archiv für Experimentelle Pathologie und Pharmakologie 12/2012; · 2.15 Impact Factor
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    ABSTRACT: OBJECTIVE: Heart rate reduction (HRR) has shown a beneficial impact on the prevention of ventricular fibrillation, which could be explained by increased myocardial blood flow and preservation of mitochondrial structure. Here, we assessed the HRR impact on time to onset of ventricular fibrillation (TOVF) and myocardial metabolic energy status. METHODS AND RESULTS: An acute myocardial ischaemia was induced in pigs until ventricular fibrillation onset and TOVF was then measured. High-energy phosphates were measured in ventricular samples from the ischaemic region by nuclear magnetic resonance. Saline, ivabradine (IVA, a selective heart rate-lowering agent) and propranolol (PROPRA, a β-blocker) were administered intravenously, 30 and 60min respectively prior to ischaemia to ensure stable HRR. To study specifically the HRR impact, another set of animals received IVA and was submitted to rapid atrial pacing (200bpm) to abolish HRR. IVA and PROPRA induced a similar HRR (IVA: 22-26%, PRORA: 20-21%, p<0.01 vs. control), which was associated with a significant increase in TOVF with IVA (2325s) compared to PROPRA (682s) and saline (401s). This effect was abolished by atrial pacing performed during ischaemia and throughout the entire experimental session. Only IVA partially prevented the decrease in phosphocreatine-to-ATP ratio (CrP/ATP) ratio and the ADP accumulation at the onset of ventricular fibrillation. Finally, CrP/ATP ratio levels were correlated with TOVF (r=0.74, p<0.001). CONCLUSION: Unlike PROPRA, IVA delayed the time to onset of ischaemia-induced ventricular fibrillation by preserving myocardial energy status, supporting the pertinence of IVA in the management of patients with coronary artery disease.
    Resuscitation 08/2012; · 4.10 Impact Factor
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    ABSTRACT: The involvement of psychotropic drugs in sudden deaths has been highlighted. The objective of this work was to establish a link between selenium levels in heart tissue, psychotropic treatment and sudden death. Selenium levels were measured by electrothermal atomic absorption spectroscopy post-mortem in heart, brain and liver. Histological examination evidenced dilated cardiomyopathy in 45% of cases, left ventricular hypertrophy in 36%, and ischemic coronaropathy in 18%. A significant reduction of myocardial selenium levels compared to controls was seen in patients treated with neuroleptic drugs or meprobamate. No changes in brain or liver selenium levels were seen. These results suggest that selenium deficiency can facilitate sudden death in patients on psychotropic drugs. The reduced activity of glutathione peroxidase due to selenium deficiency can result in augmented oxidative stress in myocardial cells and myocardiopathy leading to sudden death.
    Journal of Trace Elements in Medicine and Biology 06/2012; 26(2-3):170-3. · 1.96 Impact Factor
  • Timour Q, Morel E, Bui-Xuan B
    Journal of Cardiovascular Pharmacology 06/2012; J Cardiovasc Pharmacol. 2012 Jun;59(6):523-8. doi: 10.1097/FJC.0b013e31824d89fe. Chronic oral amiodarone but not dronedarone therapy increases ventricular defibrillation threshold during acute myocardial ischemia in a closed-chest animal model. Chevalier P, T. · 2.38 Impact Factor
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    ABSTRACT: Dronedarone, a recently approved antiarrhythmic drug, has been shown to have fewer side effects than amiodarone, particularly with regard to thyroid and neurologic events. Since the effects of either drug on ventricular defibrillation threshold during ischemia are unknown, the aim of this study was to compare the effects of dronedarone and amiodarone on defibrillation efficacy during ischemia in a closed-chest animal model. Dronedarone (30 mg·kg·d) and amiodarone (20 mg·kg·d) were administered orally for 3 weeks to 19 and 21 pigs, respectively. A control group (no treatment) comprised 19 pigs. A 2-lead endovascular defibrillation system was used. Each biphasic shock was delivered after 8 seconds of ventricular fibrillation. A step-up/step-down protocol was used to calculate mean defibrillation threshold before and 10 minutes after coronary artery occlusion using an angioplasty balloon in the left descending artery. At basal state, defibrillation threshold did not differ between the control (20.8 ± 4.8 J), amiodarone (21.2 ± 2 J), and dronedarone (19.5 ± 3 J) groups. After ischemia, the amiodarone group had a significantly higher defibrillation threshold than the control group (29.6 ± 3 J vs. 21.8 ± 5 J, respectively; P = 0.015), but the dronedarone (22.8 ± 4 J) and control groups had similar defibrillation threshold values. These data indicate that oral dronedarone treatment, unlike oral amiodarone, does not affect defibrillation threshold during ischemia in pigs.
    Journal of cardiovascular pharmacology 02/2012; 59(6):523-8. · 2.83 Impact Factor
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    ABSTRACT: The human cardiac sodium channel Na(v)1.5 encoded by the SCN5A gene plays a critical role in cardiac excitability and the propagation of action potentials. Na(v)1.5 dysfunctions due to mutations cause cardiac diseases such as the LQT3 form of long QT syndrome, conduction disorders, and Brugada syndrome (BrS). They have also recently been associated with dilated cardiomyopathy. BrS is characterized by coved ST-segment elevation on surface ECGs and lethal ventricular arrhythmias in an apparently structurally normal heart. Na(v)1.5 mutations that cause BrS result in a loss of channel function. Our aim was to functionally characterize two novel Na(v)1.5 mutations (A124D and V1378M) in BrS patients. Wild-type (WT) and mutant Na(v)1.5 channels were expressed in tsA201 cells in the presence of the β(1)-auxiliary subunit. The patch-clamp technique and immunocytochemistry approaches were used to study the mutant channels and their cellular localization. The two mutant channels displayed a dramatic reduction in current density but had normal gating properties. The reduction in current density was caused by the retention of channel proteins in the endoplasmic reticulum (ER). Mutant channel retention could be partially reversed by incubating transfected cells at 25°C and by treating them with mexiletine (for V1378M but not A124D), or with curcumin or thapsigargin, two drugs that target ER resident proteins. It is likely that the clinical phenotypes observed in these two BrS patients were related to a surface expression defect caused by ER retention.
    Frontiers in Pharmacology 01/2012; 3:62.
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    ABSTRACT: Mortality rate is high in psychiatric patients versus general population. An important cause of this increased mortality is sudden cardiac death (SCD) as a major side-effect of psychotropic drugs. These SCDs generally result from arrhythmias occurring when the posology is high and may attain a toxic threshold but also at dosages within therapeutic range, in the presence of risk factors. There are three kinds of risk factors: physiological (e.g., low cardiac rate of sportsmen), physiopathological (e.g., hepatic insufficiency, hypothyroidism) and "therapeutic" (due to interactions between psychotropic drugs and other medicines). Association of pharmacological agents may increase the likelihood of SCDs either by (i) a pharmacokinetic mechanism (e.g., increased torsadogenic potential of a psychotropic drug when its destruction and/or elimination are compromised) or (ii) a pharmacodynamical mechanism (e.g., mutual potentiation of proarrhythmic properties of two drugs). In addition, some psychotropic drugs may induce sudden death in cases of pre-existing congenital cardiopathies such as (i) congenital long QT syndrome, predisposing to torsade de pointes that eventually cause syncope and sudden death. (ii) A Brugada syndrome, that may directly cause ventricular fibrillation due to reduced sodium current through Nav1.5 channels. Moreover, psychotropic drugs may be a direct cause of cardiac lesions also leading to SCD. This is the case, for example, of phenothiazines responsible for ischemic coronaropathies and of clozapine that is involved in the occurrence of myocarditis. The aims of this work are to delineate: (i) the risk of SCD related to the use of psychotropic drugs; (ii) mechanisms involved in the occurrence of such SCD; (iii) preventive actions of psychotropic drugs side effects, on the basis of the knowledge of patient-specific risk factors, documented from clinical history, ionic balance, and ECG investigation by the psychiatrist.
    Frontiers in Pharmacology 01/2012; 3:76.
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    ABSTRACT: Myocardial ischaemia affects mitochondrial function leading to ionic imbalance and susceptibility to ventricular fibrillation. Trimetazidine (TMZ), a metabolic agent, is clinically used as an anti-anginal therapy. This study was conducted to compare the effect of Vastarel 20 mg IR (immediate release) and Vastarel 35 mg MR (modified release), two bioequivalent marketed formulations of TMZ, on cardioprotection during acute ischaemia in pigs. A 4-day oral treatment with Vastarel 20 mg IR (800 mg three time a day) or Vastarel 35 mg MR (1400 mg twice daily) had no effect on ventricular fibrillation threshold (VFT) prior to ischaemia, but significantly prevented the decrease in VFT observed in placebo-treated groups after a 1-min left anterior descending coronary artery occlusion. This effect occurred without modifying cardiac haemodynamic and conduction parameters. In both Vastarel-treated groups, a significant reduction of the ischaemic area as well as a protection of cardiomyocytes were observed. Cardiac enzymatic activity (phosphorylase, succino dehydrogenase, ATPase) was increased in Vastarel-treated groups. Both formulations preserved mitochondrial structure and improved mitochondrial function as demonstrated by a twofold increase of oxidative phosphorylation, by a reduction of ROS production (>30%) and by a trend to increase the mitochondrial calcium retention capacity. In this model of ischaemia, both Vastarel formulations, leading to equivalent TMZ plasma exposures, demonstrated similar cardioprotective effects. This protection could be attributed to a preservation of mitochondrial structure and function, which plays a central role in ATP and ROS production and consequently could be considered as a target of cardioprotection.
    Heart (British Cardiac Society) 12/2011; 97(24):e8. · 5.01 Impact Factor
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    ABSTRACT: We showed previously that ivabradine (IVA), a selective inhibitor of the cardiac pacemaker I(f) current, achieved protection against ischaemia-induced ventricular fibrillation (VF) in pigs by increasing the VF threshold (VFT). This was correlated to the heart rate reduction (HRR), the limitation of monophasic action potential shortening and the reduction of the hypoxic area. This study investigated myocyte ultrastructure and regional myocardial blood flow (RMBF), potentially involved in these cardioprotective effects of IVA. Myocardial ischaemia was induced in pigs by total 1-min occlusion of the left anterior descending coronary artery following i.v. administration of saline (n=6) or IVA (0.25 mg/kg, n=6). Electrophysiological and haemodynamic parameters, the hypoxic area and the presence of myocyte ultrastructural lesions were evaluated. The RMBF was assessed using positron emission tomography following ischaemia/reperfusion in IVA (0.25 mg/kg, i.v., n=6) or vagal stimulation (n=4) groups. Compared with saline, IVA induced a 32% HRR (p<0.01), a 2.9-fold increase in the VFT (p<0.001) and a reduction of the hypoxic area without any change in left ventricular dP/dt(max). IVA preserved cardiomyocyte morphology, particularly mitochondrial ultrastructure. Compared with baseline, RMBF during reperfusion was increased in the hypoxic area following IVA administration (+218% vs. +97%, p<0.05) or vagal stimulation (+195% vs. +127%, p<0.05). This increase was sharply reduced by atrial pacing in IVA-group. IVA exerts a cardioprotection from ischaemia-induced VF by increasing RMBF and preserving cardiomyocyte and mitochondrial ultrastructure, which opens new perspectives regarding potential targets that would be involved in the anti-ischaemic effects of IVA.
    Resuscitation 04/2011; 82(8):1092-9. · 4.10 Impact Factor
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    ABSTRACT: Tako-Tsubo cardiomyopathy (also known as apical ballooning syndrome) is a relatively new clinical entity characterized by reversible left ventricular dysfunction. Its clinical presentation and electrocardiographic findings are similar to acute myocardial infarction but without significant coronary artery disease. Cardiotoxicity is a major complication of various anticancer drugs; however, only a few cases of Tako-Tsubo cardiomyopathy associated with anticancer drugs, including 5-fluorouracil, have been reported. We describe a 48-year-old man who developed acute coronary syndrome, thought to be similar to Tako-Tsubo syndrome, after receiving a chemotherapy regimen consisting of 5-fluorouracil, oxaliplatin, and calcium folinate (FOLFOX protocol) for colic adenocarcinoma. Approximately 24 hours after receiving his first cycle of chemotherapy, the patient, who did not have a history of cardiovascular disease, developed chest pain, with abnormal electrocardiographic results and a mildly increased troponin T level. Coronary angiography did not show any significant coronary lesions. Echocardiography revealed marked left ventricular dysfunction (left ventricular ejection fraction [LVEF] 15%) with severe hypokinesia in all apical and median segments. The patient was stabilized with the introduction of an intraaortic balloon pump and pressor therapy. One month later, myocardial magnetic resonance imaging confirmed total recovery of left ventricular systolic function. Thus, the second chemotherapy cycle was administered at half the dose-intensity, along with ramipril and diltiazem. The chemotherapy regimen was well tolerated. Two weeks later, at the end of the third chemotherapy cycle, administered using the full-dose regimen, the patient experienced cardiac arrest, necessitating cardiopulmonary resuscitation. After transfer to the cardiology intensive care unit, acute heart failure recurred (LVEF 35%). Normal recovery of left ventricular function occurred a few days later. Chemotherapy was discontinued, and treatment with bisoprolol was started. Four months later, the patient remained completely asymptomatic of any cardiac manifestations. Use of the Naranjo adverse drug reaction probability scale indicated a probable relationship (score of 8) between the patient's development of acute coronary Tako-Tsubo-like syndrome and 5-fluorouracil. Clinicians should be aware of this potential adverse effect when monitoring patients receiving chemotherapy with 5-fluorouracil.
    Pharmacotherapy 02/2011; 31(2):226. · 2.31 Impact Factor
  • Archives of Cardiovascular Diseases Supplements 01/2011; 3(1):83-83.
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    ABSTRACT: Neuroleptics are a suspected cause of sudden death in psychiatric patients, especially in those with pre-existing cardiac lesions. As these lesions were previously shown to be associated with selenium (Se) deficiency, the aim of the present study was to evidence the possible protective effect of Se supplementation against cardiac lesions induced by the combination of the neuroleptic drugs levomepromazine and risperidone in the rabbit. Two groups of 6 rabbits were treated with 3 mg/kg of levomepromazine daily intramuscularly combined with 1 mg/kg of risperidone intramuscularly every other week for 3 consecutive months, and one group additionally received a solution of sodium selenite (2 microg/kg/day) intramuscularly during the whole treatment period. Furthermore, one group of six untreated animals was given the Se supplementation and another group of six control animals received saline daily. Blood samples were drawn before and at the end of the treatment period for the measurement of serum Se levels. At the end of the study, all animals were sacrificed and their hearts were removed for the measurement of tissue Se concentrations. In addition, the hearts were prepared for histopathological examination. A variety of cardiac lesions was found in the neuroleptics-treated animals without supplementation and to a lesser extent in the control and Se-supplemented untreated animals. Importantly, only rare cardiac lesions were observed in neuroleptics-Se-treated animals. The most striking differences in Se concentrations were noted in the myocardium: as compared to controls, there was a 43% reduction in neuroleptics-treated, but non-Se-supplemented animals (p < .01), at the end of the treatment period, whereas only a 14% reduction (p < .05) was noted in the neuroleptics-Se-treated animals. These results confirm that neuroleptics induce cardiac lesions associated with Se deficiency. Selenium supplementation markedly decreased the incidence and severity of neuroleptics-induced cardiac lesions and these findings may serve as a basis for further evaluation of the protective role of Se supplementation in neuroleptics-treated patients. However, Se supplementation in normal animals without Se deficiency was also shown to be cardiotoxic.
    Human & Experimental Toxicology 09/2009; 28(8):461-7. · 1.31 Impact Factor
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    ABSTRACT: Further to our previous observation of post-mortem cardiac lesions after sudden death in several athletes with a history of anabolic steroid abuse, this study was intended to reproduce these lesions in rabbits administered testosterone oenanthate, a prototypic anabolic steroid abused by athletes, and to provide evidence for the protective effects of trimetazidine and dexrazoxane that are used as antianginal and cardioprotective drugs, respectively. Groups of six rabbits each were administered saline, testosterone, or a combination of testosterone and either trimetazidine or dexrazoxane for 3 months. Histologic cardiac lesions including necrosis, misshapen cell nuclei, interstitial and endocardial fibrosis, lymphocytic infiltrates, and vascular dystrophies were observed in testosterone-treated rabbits. In contrast, no significant lesions were observed in the animals treated with testosterone combined with either trimetazidine or dexrazoxane. This is the first study providing evidence for testosterone cardiotoxicity following sub-chronic exposure in laboratory animals. In addition, these results suggest the protective role of trimetazidine and dexrazoxane.
    Cardiovascular toxicology 07/2009; 9(2):64-9. · 2.56 Impact Factor
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    ABSTRACT: Among 15,000 forensic post-mortem examinations performed on the coroner's order over a 24-year period (January 1981-December 2004) in the area of Lyon, France (population: 2,000,000), 2250 cases of unexpected cardiac sudden death were identified retrospectively according to WHO criteria. Of these, 108 occurred during recreational sport and 12 occurred in athletes. In the latter category, a history of anabolic steroid abuse was found in 6 cases, whereas pre-existing ordinary cardiac lesions were observed in the 6 remaining cases. To shed light on the possible role of anabolic steroids in the induction of cardiac lesions, an experimental study was conducted in rabbits that were treated orally with norethandrolone 8mg/kg/day for 60 days, and sacrificed at day 90. The histopathological examination of the heart from treated animals showed coronary thrombosis associated with left ventricle hypertrophy in 3 cases, and lesions analogous to toxic or adrenergic myocarditis in all other treated animals. These findings were very similar to those observed after cardiac sudden death in the 6 athletes with a history of anabolic steroid abuse. In addition, elevated caspase-3 activity in the heart of treated rabbits as compared to controls suggests that apoptosis is involved in the induction of norethandrolone-induced cardiac lesions. These results confirm the cardiotoxic potential of anabolic steroid abuse.
    Experimental and toxicologic pathology: official journal of the Gesellschaft fur Toxikologische Pathologie 12/2008; 61(4):317-23. · 1.43 Impact Factor
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    ABSTRACT: Tachycardia often facilitates ischemic ventricular fibrillation (VF). This study assessed the impact of ivabradine (IVA), a selective inhibitor of the cardiac pacemaker If current, on ventricular fibrillation threshold (VFT) during acute myocardial ischemia. The experiments were conducted on a total of 54 domestic pigs. Myocardial ischemia was induced in anesthetized pigs by total 1-minute coronary occlusion at baseline and then on 2 occasions after intravenous administration of saline or 0.5 mg/kg of IVA. VF was triggered by electrical stimuli of increasing intensity at a fixed rate. Heart rate (HR), VFT, monophasic action potential duration, and peak of the time derivative of left ventricular pressure (LV dP/dt max) were monitored on each occasion. The activity of mitochondrial succinodehydrogenase was measured on heart sections. Compared with controls, IVA induced a 31% reduction in HR, a 2.9-fold increase in VFT, and prevented ischemia-induced monophasic action potential duration shortening (+1 +/- 12 vs. -14 +/- 11 milliseconds) without affecting peak LV dP/dt. This beneficial effect on VFT was mainly due to HR reduction and was accompanied by a significant reduction in the hypoxic area (26% +/- 1% vs. 38% +/- 1%, P < 0.0001). HR reduction and the decrease in myocardial damage induced by IVA protected against primary ischemic VF without altering myocardial contractility.
    Journal of cardiovascular pharmacology 12/2008; 52(6):548-54. · 2.83 Impact Factor
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    ABSTRACT: Organic and/or functional heart lesions sometimes resulting in sudden death have been described in psychiatric patients treated with neuroleptics. As selenium has been suggested previously to play a role in the development of such lesions, the present study was undertaken to determine whether a correlation could be found between heart lesions induced by neuroleptics and changes in blood selenium as well as myocardial tissue concentrations in the rabbit. Twelve NZW adult rabbits were treated intramuscularly with both levomepromazine (3 mg kg(-1) day(-1)) and risperidone (1 mg kg(-1) once every other week) for 3 months, and compared with 12 saline-treated controls. Blood samples were drawn before and at the end of the study. Tissue samples from the heart, liver and kidneys were obtained at the end of treatment, and the hearts were examined histologically. Heart lesions including disorganization of cardiac fibers, myolysis, interstitial and endocardial fibrosis, and necrosis were noted in treated animals, but not in controls. There was a 20% decrease in selenium blood levels and a 50% decrease in selenium myocardial tissue levels in treated animals compared with controls (P < 0.001). In contrast, no differences in selenium levels in liver and kidneys were found across the experimental groups. These results suggest a possible correlation between selenium depletion and neuroleptics-induced heart lesions.
    Journal of Applied Toxicology 04/2008; 28(2):212-6. · 2.60 Impact Factor

Publication Stats

459 Citations
194.18 Total Impact Points

Institutions

  • 2014
    • University of Lyon
      Lyons, Rhône-Alpes, France
  • 1987–2014
    • Claude Bernard University Lyon 1
      • Institut de médecine légale
      Villeurbanne, Rhône-Alpes, France
  • 2012
    • L'Institut universitaire en santé mentale de Québec
      • Centre de Recherche
      Québec, Quebec, Canada
  • 2011
    • Hospices Civils de Lyon
      Lyons, Rhône-Alpes, France
  • 2007
    • Centre Hospitalier Lyon Sud
      Lyons, Rhône-Alpes, France
    • Hôpital Louis Pradel
      Lyons, Rhône-Alpes, France
  • 2004
    • Centre Hospitalier Le Vinatier
      Rhône-Alpes, France
  • 2002
    • CHU de Lyon - Hôpital Gériatrique des Charpennes
      Lyons, Rhône-Alpes, France
  • 1994–2000
    • Centre Hospitalier Saint Joseph Saint Luc
      Lyons, Rhône-Alpes, France
  • 1988–1996
    • Centre Hospitalier Universitaire de Dijon
      Dijon, Bourgogne, France
  • 1993–1995
    • Hôpital Saint Joseph
      Marsiglia, Provence-Alpes-Côte d'Azur, France