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Repetitive transcranial magnetic stimulation (rTMS), based on the principle of electromagnetic induction, consists of applying series of magnetic impulses to the cerebral cortex so as to modulate neurone activity in a target zone. This technique, still experimental, could prove promising in the field of psychiatry, in particular for the treatment of major depressive disorder. It is important for the clinician to be able to assess the response potential of a given patient to rTMS, and this among other things requires relevant predictive factors to be available. This review of the literature aims to determine and analyse reported predictive factors for therapeutic response to rTMS treatment in major depressive disorder. Different parameters are studied, in particular age, the severity of the depressive episode, psychological dimensions, genetic factors, cerebral blood flows via cerebral imagery, and neuronavigation. The factors found to be associated with better therapeutic response were young age, low level of severity of the depressive episode, motor threshold intensity over 100%, more than 1000 stimulations per session, more than 10 days treatment, L/L genotype on the 5-HTTLPR transporter gene, C/C homozygosity on the promotor regions of the 5-HT1A receptor gene, Val/Val homozygosity on the BDNF gene, cordance analyses by EEG, and finally the accurate localisation provided by neuronavigation. The authors conclude that investigations in larger patient samples are required in the future, and that the work already achieved should provide lines of approach for the coming experimental studies., (Copyright © 2016 L'Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.)

Accidental intravascular or high-dose injection of local anesthetics (LA) can result in serious, potentially life-threatening complications. Indeed, adequate supportive measures and the administration of lipid emulsions are required in such complications. The study's objectives were threefold: (i) evaluate the myocardial toxicity of levobupivacaine when administered intravenously; (ii) investigate levobupivacaine toxicity on cardiomyocytes mitochondrial functions and cellular structure; (iii) assess the protective effects of a lipid emulsion in the presence or absence of myocardial ischemia. Domestic pigs randomized into two groups of 24 animals each, with either preserved coronary circulation or experimental myocardial ischemia. Six animals from each group received either: (i) single IV injection of saline, (ii) lipid emulsion (Intralipid(®) ), (iii) levobupivacaine, (iv) combination levobupivacaine-Intralipid(®) . Serially measured endpoints included: heart rate, duration of the monophasic action potentials (dMAP), mean arterial pressure, and peak of the time derivative of left ventricular pressure (LV dP/dtmax ). In addition, the following cardiomyocytes mitochondrial functions were measured: reactive oxygen species (ROS) production, oxidative phosphorylation, and calcium retention capacity (CRC) as well as the consequences of ROS production on lipids, proteins, and DNA. IV injection of levobupivacaine induced sinus bradycardia and reduced dMAP and LV dP/dtmax . At the mitochondrial level, oxygen consumption and CRC were decreased. In contrast, ROS production was increased leading to enhanced lipid peroxidation and structural alterations of proteins and DNA. Myocardial ischemia was associated with global worsening of all changes. Intralipid(®) quickly improved haemodynamics. However, beneficial effects of Intralipid(®) were less clear after myocardial ischemia., (© 2015 Société Française de Pharmacologie et de Thérapeutique.)

The aim of this 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 haemodynamic 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., (© 2014 Société Française de Pharmacologie et de Thérapeutique.)

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. Our study investigated the Nav1.5 blocking properties of fluoxetine, a selective serotonin reuptake 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 a similar IC50 [40 and 47 μM for the (+) and (-) isomers, 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 the S6 segment of domain (D) IV (DIVS6) significantly reduced the affinity of fluoxetine and its frequency-dependent inhibition. We used a noninactivating 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., (Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.)

Objective: 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., Methods: In this retrospective, case-control study, documented reports of drug-associated LQTS plus TdP (n = 125) and LQTS without TdP (n = 81) in patients ≥65 years of age were retrieved from the French Pharmacovigilance Database over a 10-year period. Available clinical, biological, and drug therapy data were compared in the two groups and logistic regression was performed to identify significant predictors of TdP., Results: The uncorrected QT interval was significantly longer in patients with TdP than in patients without TdP (577 ± 79 vs. 519 ± 68 ms; p = 0.0001). The number of drugs with a known risk of TdP administered to each patient was not a predictor of arrhythmia, nor was female gender. Logistic regression analysis identified the uncorrected QT interval as the only significant predictor of TdP. The receiver operating characteristic curve analysis was characterized by an area under the curve of 0.77 (95 % confidence interval 0.64-0.88) and a QT cutoff of 550 ms., Conclusion: The uncorrected QT interval was significantly associated with the probability of TdP in elderly patients with acquired, drug-associated LQTS.

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., (© 2013 The Authors Fundamental and Clinical Pharmacology © 2013 Société Française de Pharmacologie et de Thérapeutique.)

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 60 min 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 (200 bpm) 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., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

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.

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.

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., (Copyright © 2012 Elsevier GmbH. All rights reserved.)

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.

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.

Aims: 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., Methods and Results: 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., Conclusion: 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., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

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.

Purpose: To evaluate the in vivo toxicity and efficacy of previously developed poly-(lactide-co-glycolide)-vancomycin-based microparticles (V-MPLs) for eventual use for endophthalmitis prophylaxis during cataract surgery., Methods: The intraocular vancomycin concentration profile was evaluated after V-MPL injection into the anterior chamber of rabbit eyes. The toxicology of V-MPLs versus MPLs alone was tested by corneal cellular counting and retinal histology. The prophylactic efficacy of the V-MPLs was evaluated by bacterial counts after introducing contaminated intraocular lenses (IOLs) together with the V-MPLs into one anterior chamber of phakic rabbit eyes or without V-MPLs in control rabbit eyes., Results: Intraocular V-MPLs produced effective vancomycin concentrations over at least 6 hours. Corneal counts revealed no significant increase in dead cells. Retinal toxicity manifested as inflammation 3 hours after injection, reaching its maximum between 12 hours and 24 hours, decreasing by 48 hours, and completely disappearing at 72 hours. Inflammation was similar between V-MPLs and MPLs. Untreated eyes implanted with highly infected IOLs showed severe, reproducible endophthalmitis. No sign of infection was observed with infected IOLs and concomitant V-MPL treatment, supported by bacterial counts showing a significant decrease in colony-forming Staphylococcus epidermidis units in the anterior chamber and on the implant surfaces within 6 hours., Conclusions: The present study demonstrated the release and toxicologic properties of the authors' newly developed V-MPLs in vivo. In addition, the rabbit model shows that V-MPLs are effective in reducing the risk of experimental endophthalmitis.

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.

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.

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.

Background: Tachycardia often facilitates ischemic ventricular fibrillation (VF)., Objective: 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., Methods: 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., Results: 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)., Conclusion: HR reduction and the decrease in myocardial damage induced by IVA protected against primary ischemic VF without altering myocardial contractility.

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.

Purpose: Ventricular fibrillation (VF) is a possible consequence of brief myocardial ischemia. Such a short ischemia does not provoke cell damage, but induces changes in intracellular cardiac metabolism due to diminished oxygen supply to the heart. Trimetazidine (TMZ) is a drug able to restore the metabolic balance between fatty acid and glucose oxidation in ischemic myocardial cells. The aim of this double-blind study was to investigate TMZ effect on VF in pigs during short-term ischemia., Methods: Ischemia was induced after thoracotomy by complete, but brief (1 min) occlusion of the left anterior descending coronary artery under electrical stimulation. The ventricular fibrillation threshold (VFT), heart rate (HR), various hemodynamic parameters and malondialdehyde (MDA) blood levels were measured before and during ischemia in two groups of eight anesthetized pigs. The mass of ischemic myocardial tissue was also evaluated., Results: No effects on either the HR or the hemodynamic parameters were observed during myocardial ischemia, whereas TMZ increased the VFT and decreased both MDA blood levels (an index of lipid peroxidation) and the ischemic area., Conclusions: TMZ limited ischemia-induced electrical dysfunction leading to cardiac susceptibility to VF by decreasing lipid peroxidation and maintaining ionic homeostasis. TMZ could therefore provide protection against ischemia-induced VF.

The effects of chronic oral azimilide therapy on the ventricular defibrillation threshold (DFT) during ischemia are unknown. The effects of azimilide on defibrillation efficacy under ischemic condition were investigated in a closed-chest animal model. Azimilide (20 mg/kg/d) was administered orally for 7 days to 10 pigs (20 to 25 kg). The control group (no treatment) comprised 15 pigs. A 2-lead defibrillation system was used. Each shock was delivered after 8 seconds of ventricular fibrillation. A step-up and step-down protocol was used to calculate mean DFT before and 10 minutes after coronary artery occlusion using an angioplasty balloon in the left descending artery. The basal DFT of the azimilide group did not differ from controls (20.8 +/- 4.8 versus 18.8 +/- 2.8; P = 0.33). After ischemia, the mean DFT of the azimilide-treated animals was similar to controls (21.8 +/- 5.2 versus 23.2 +/- 3.8 J; P = 0.54), despite significant lengthening of ventricular repolarisation (428.2 +/- 51.8 versus 494.1 +/- 46.6 msec; P = 0.005) and significant prolongation of the ventricular fibrillation cycle length (85.1 +/- 13 versus 104.7 +/- 24 msec; P < 0.04). Chronic oral azimilide treatment does not affect the DFT at baseline or during acute myocardial ischemia.

Glycol ethers (GE) belong to two main series: series E, which include ethylene glycol ethers (EGE) and series P which include propylene glycol ethers (PGE). GE are widely used as solvents in a large number of industrial, household and cosmetic applications. EGE can be found in water paints, varnishes, inks, household products. Severe adverse effects have been noted with pharmaceutical formulations containing diethylene glycol monoethyl-ethers and this led to withdrawal from the French market. The toxicity of GE depends on the molecular weight and the metabolites generated. It can manifest following acute or chronic exposure by disorders of the nervous system, bone marrow, immune system, kidneys as well as fertility, reproduction and embryofetal development. Several EGE are mutagenic. The carcinogenic risk is not known. The most toxic derivatives EGME, EGMEA, EGEE and EGEEA alter male and female fertility, and induce malformations. Taking these toxic effects into consideration, what is the place of GE as absorption promoting agents? An example is DEGEE, which facilitates estradiol penetration when used as a gel in the treatment of estrogen deficiency. This review is intended to address this issue.

Cardiotoxicity is a rare, but well-recognized complication of treatments with the anti-cancer drug 5-fluorouracil (5FU). The underlying mechanism, however, is not fully elucidated. A spasm of the coronary arteries is often considered to be the leading cause of myocardial ischemia and decreased contractility associated with 5FU. As spasm cannot account for all reported adverse cardiac effects, the present study was undertaken to search for alternative mechanisms. Groups of six rabbits were given either a single intravenous dose of 50 mg/kg 5FU or four intravenous doses of 15 mg/kg 5FU at 7-day intervals. A third group served as control. The heart was removed shortly after death or scheduled sacrifice of the animals, to perform macroscopic and microscopic examinations of the heart and to evidence apoptosis by the TUNEL method. Following a single dose of 50 mg/kg 5FU, all animals rapidly developed a massive hemorrhagic myocardial infarct with spasms of the proximal coronary arteries. Repeated infusions of 15 mg/kg 5FU induced left ventricular hypertrophy, foci of myocardial necrosis, thickening of intra-myocardial arterioles, and disseminated apoptosis in myocardial cells of the epicardium, as well as endothelial cells of the distal coronary arteries. These results indicate that a spasm of the coronary arteries is not the only mechanism of 5FU cardiotoxicity, and that apoptosis of myocardial and endothelial cells can result in inflammatory lesions mimicking toxic myocarditis.

To show the nature and magnitude of EKG anomalies subsequent to 5-fluorouracil (5FU) administration and determine whether the onset is dependent on a pre-existing cardiovascular pathological condition. 1,350 patients were treated by 5FU between 1995 and 2000. EKG were recorded in all patients before each administration of 5FU. All cases of 5FU related cardiotoxicity were analyzed and recorded by the Lyon Pharmacovigilance Center. Clinical symptoms included chest pain in 10 patients with an infarct-like pattern in 2 (including one death), and heart failure in one. Three patients suffered from anginal pain without EKG changes and two had electrocardiographic changes without clinical symptoms. Coronary disorders resolved completely on cessation of 5FU therapy, except in one patient who died two months later of heart infarct. The patient with heart failure required specific treatment. Based on both the clinical and electrocardiographic changes, the causative role of 5FU is highly likely. The incidence of cardiotoxicity was 1.2% among these patients, which is close to previous data from the literature. These 16 case reports confirm the cardiotoxic potential of 5FU and argue for the need of a careful cardiac monitoring of 5FU treated cancer patients. The mechanism of 5FU cardiotoxicity is not elucidated. Coronary spasm is the most commonly suspected hypothesis, but further studies are warranted to seek for toxic inflammatory lesions of the myocardium (apoptosis, necrosis, fibrosis).

Sudden death seems to be more frequent following treatment with neuroleptic drugs in patients with pre-existing cardiac lesions, especially dilated and hypertrophic myocardiopathy. The present study was undertaken to confirm the hypothesis that myocardial lesions can be induced by neuroleptic drugs. Eight groups of 6 New-Zealand White rabbits were treated for 3 months: group I: controls (saline); group II: 15 mg/kg/day amisulpride; group III: 0.20 mg/kg/day haloperidol; group IV: 3 mg/kg/day levomepromazine; group V: 0.30 mg/kg/day olanzapine; group VI: 1.0 mg/kg risperidone, every 15 days; group VII: levomepromazine+haloperidol, same dose levels as single treatments; group VIII: levomepromazine+risperidone, same dose levels as single treatments. The hearts were immediately weighted and fixed, and paraffin sections were prepared and examined. Ventricular hypertrophy was observed following treatment with olanzapine and was still more marked with the combinations levomepromazine+haloperidol and levomepromazine+risperidone. Amisulpride and haloperidol induced necrotic lesions and levomepromazine, endocardial fibrosis. There was a lack of severe cardiac lesions following treatment with risperidone. The observed cardiac lesions can be compared to those seen in toxic myocarditis. These findings confirm the hypothesis that some neuroleptic drugs induce myocardial lesions. Further studies are warranted to demonstrate the effects of treatments of longer duration and the influence of pre-existing cardiac lesions.

A major risk associated with bupivacaine during myocardial ischemia is ventricular fibrillation. We investigated the influence of ropivacaine on cardiac contractility and the propensity to ventricular fibrillation before and after myocardial ischemia in a placebo-controlled pig study. Anesthetized domestic pigs were administered 1 mg.kg(-1) of ropivacaine intravenously over 1 min and then 0.03 mg.kg(-1).min(-1) as a 30-min infusion, or saline. The following endpoints were measured before and after ropivacaine administration: (1) the ventricular fibrillation threshold (VFT) before and during myocardial ischemia induced by total transient ligation of the anterior interventricular artery and (2) electrophysiological (sinus heart rate, duration of QRS and QT intervals) and hemodynamic (blood pressure, the time derivative of left ventricular pressure [peak LV dP/dt]) parameters. Ropivacaine induced no changes in sinus heart rate, QRS, and or QT before or during ischemia. In contrast, there was a mild increase in the VFT before ischemia, which was drastically and significantly reduced during ischemia. The reduction of peak LV dP/dt during ischemia was further increased by ropivacaine. We also found that the effect of ropivacaine on the VFT was coronary blood flow-dependent, with a markedly decreased threshold in the presence of ischemia. Similar effects have been observed in humans with several other local anesthetics, as well as with class I antiarrhythmic drugs. The results of this study should be taken into account by anesthesiologists when administering ropivacaine to coronary patients.

Objective: To confirm the hypothesis that psychotropic drugs, especially neuroleptics, lithium, and antidepressants, are implicated as a cause of unexpected sudden death in psychiatric patients because of their cardiotoxicity, especially when hidden cardiac lesions are present., Method: We performed a full pathological examination of 14 psychiatric patients who unexpectedly and suddenly died between 1980 and 1999., Results: Neuroleptics were involved in 13 instances, antidepressants in 9, and anxiolytics in 5. Psychotropic drugs were combined in all but a single patient. In all 14 patients, toxicological analyses discarded drug overdose as cause of death. At postmortem examination, the brain and abdominal organs were normal. In 13 patients, the following lesions were found in the heart and lungs: dilated cardiomyopathy (6 patients), left ventricular hypertrophy (2 patients, 1 of which was associated with mitral prolapse and anomalies of His bundle), arrhythmogenic cardiopathy of the right ventricle (1 patient), pericarditis (1 patient), mitral prolapse (1 patient), muscular bridge on the anterior interventricular artery (1 patient), and Mendelsons syndrome (1 patient). In 1 case, no changes were seen. Most of the drugs that were taken immediately prior to death can induce arrhythmias either by prolonging the QT interval, potentially resulting in torsades de pointes, or by widening QRS complexes, possibly leading to reentry and ventricular fibrillation., Conclusion: Our findings suggest that the arrhythmogenic effects of psychotropic drugs can be exacer bated when preexisting hidden cardiac lesions are present and can result in sudden death. Patients should be systematically evaluated for cardiac lesions prior to starting any treatment with psychotropic drugs; the minimal effective dosage should be used.

Purpose: The present study was undertaken following the observation of a marked decrease in myocardial contractility after ropivacaine in a patient on amiodarone, in order to investigate the cardiovascular effects of combining ropivacaine with anti-arrhythmic drugs (AARD)., Methods: Anesthetized domestic pigs were treated with disopyramide, flecainide, atenolol, amiodarone, diltiazem or nicardipine at a dose leading to blood levels obtained in treated patients, then received 1 mg*kg(-1) ropivacaine. Blood pressure (BP), left venticular (LV) dP/dt max, sinus heart rate, and intraventricular conduction time were measured before and following the administration of AARD, and following ropivacaine at different time points., Results: All tested AARD induced the expected hemodynamic and electrophysiologic effects. Following ropivacaine, a 20 to 35% decrease in LV dP/dt max of prolonged duration was observed with amiodarone only. A brief 10 to 20% decrease in mean BP was observed in all animals, except those treated with nicardipine who sustained an important and prolonged decrease in BP. All other variables were not significantly affected., Discussion: The combination of ropivacaine with AARD was always associated with a slight drop in LV dP/dt max. The effect on mean BP was slight, except with nicardipine. Clinicians should be aware of the interactions of ropivacaine with AARD, especially amiodarone and nicardipine.

5-fluorouracil (5-FU), a fluoropyrimidine antimetabolite, is widely used in the treatment of cancers of the digestive tract and breast. The clinical cardiotoxicity of 5-FU was first reported in 1975. Adverse cardiac effects include coronary disorders, heart failure and sudden death of suspected cardiac origin. Six new cases are reported, including 5 cases of angina and one of heart failure. The patients, 4 males and 2 females, were 26 to 71 years of age (mean: 56.2). They had no medical history of heart failure, myocardial ischemia or electrocardiographic anomalies prior to 5-FU treatment. Three patients had hypertension of whom one had had type-II diabetes mellitus for the past 20 years. Clinical symptoms included chest pain in 4 patients and heart failure in one, whereas the last patient had ECG changes with no associated clinical symptoms. Clinical symptoms of angina totally disappeared after the cessation of 5-FU administration, but heart failure was alleviated only after the introduction of digitalis, a converting-enzyme inhibitor and a diuretic. It has been estimated that 1.6% of patients treated with 5-FU develop adverse cardiac effects. Patients at greater risk are those with a history of ischemic cardiac disease, thoracic radiotherapy or high-dose 5-FU therapy. The mechanism involved is not clearly elucidated. Spasms of the coronary arteries or toxic inflammation of the myocardium have been suspected. These 6 new cases confirm the potential for cardiotoxicity of 5-FU and the need for careful cardiac monitoring of treated patients.

We carried out a retrospective analysis of 1500 forensic autopsies following sudden unexpected cardiac death. This analysis showed a group of 43 cases that could have been related to surgery and/or anaesthesia. Pathological examination revealed the existence of cardiac lesions in 40 cases: arrhythmogenic right ventricular cardiomyopathy (14 cases), coronary artery disease (9 cases), cardiomyopathy (8 cases), structural abnormalities of the His bundle (7 cases), mitral valve prolapse (1 case) and acute myocarditis (1 case). These disorders are compatible with a paroxysmal (rhythmic) phenomenon at the origin of the cardiac arrest. Identification of the cause of death in a patient who was presumed to be at low risk may provide major relief to the patient's family and the medical staff.

It is now accepted that serotonin can either initiate or aggravate myocardial ischaemia through a vasoconstrictor action and platelet activation. It is therefore possible that substances likely to neutralize the effects of serotonin could be used, without any danger, in humans with ischaemic heart disease. This type of action may therefore be exerted by 5-HT2 antagonists, such as naftidrofuryl. A recent double-blind clinical study has in fact shown that administration of naftidrofuryl versus placebo leads to better exercise tolerance, with an increase in the maximum level and delay in ST segment shift (increase in the threshold of onset of ischaemia). The purpose of this study was therefore to evaluate, in an animal model (pig) of acute myocardial ischaemia (occlusion of the proximal section of the left anterior descending coronary artery), the action of serotonin, naftidrofuryl and a combination of both substances on the following parameters: 1) electrophysiological (sinus heart rate, ST segment shift, T-wave amplitude, duration of monophasic action potentials, intraventricular conduction time); 2) haemodynamic (systolic, diastolic and mean blood pressure, first derivative of rate of increase of left ventricular pressure with time: LV dP/dt max); and 3) biochemical (malonedialdehyde concentration as an index, cell peroxidation index, creatine phosphate and adenosine triphosphate). It was found that co-infusion of serotonin aggravated the myocardial ischemia and that naftidrofuryl exerted beneficial effects on the serotonin-mediated aggravation of myocardial ischaemia.

The retrospective analysis of 1700 forensic autopsies over 17 years (1981-97) following unexpected sudden cardiac death revealed a group of 50 cases that could have been related to surgery and/or anaesthesia. Patients were young with no history of cardiac disease. Surgery was performed for uncomplicated disorders, all classified as ASA 1. Cardiac arrest took place at induction of anaesthesia in 16% of cases, during surgery in 64% and at the end of surgery in 20%. Investigation and expertise reports ordered by the public prosecutor revealed none of the typical causes of death usually associated with surgery or anaesthesia. Pathological examination showed cardiac lesions in 47 cases: arrhythmogenic right ventricular cardiomyopathy in 18 cases, coronary artery disease in 10 cases, cardiomyopathy in eight cases, structural abnormalities of the His bundle in nine cases, mitral valve prolapse in one case, and acute myocarditis in one case. Identification of the cause of death of patients at low risk may provide major relief to the family of the patient and the medical staff.

It is known that class I antiarrhythmic drugs lose their antifibrillatory activity with severe ischaemia, whereas class IV antiarrhythmic drugs acquire such activity. Tachycardia, which is also a depolarizing factor, has recently been shown to give rise to an alteration of ion transmembrane exchanges which is particularly marked in the case of calcium. This leads one to wonder if the change in antifibrillatory activity of antiarrhythmic drugs caused by ischaemia depends on the same process. The change in antifibrillatory activity was studied in normal conditions ranging to those of severe ischaemia with a class I antiarrhythmic drug, flecainide (1.00 mg x kg(-1) plus 0.04 mg x kg(-1)x min(-1), a sodium channel blocker, and a class IV antiarrhythmic drug, verapamil (50 microg x kg(-1) plus 2 microg x kg(-1) x min(-1)), a calcium channel blocker. The experiments were performed in anaesthetized, open-chest pigs. The resulting blockade of each of these channels was assessed at the end of ischaemic periods of increasing duration (30, 60, 120, 180, 300, and 420 s) by determining the ventricular fibrillation threshold (VFT). VFT was determined by means of trains of diastolic stimuli of 100 ms duration delivered by a subepicardial electrode introduced into the myocardium (heart rate 180 beats per min). Ischaemia was induced by completely occluding the left anterior descending coronary artery. The monophasic action potential was recorded concurrently for the measurement of ventricular conduction time (VCT). The monophasic action potential duration (MAPD) varied with membrane polarization of the fibres. The blockade of sodium channels by flecainide, which normally raises VFT (7.0 +/- 0.4 to 13.8 +/- 0.8 mA, p < 0.001) and lengthens VCT (28 +/- 3 to 44 +/- 5 ms, p < 0.001), lost its effects in the course of ischaemia. This resulted in decreased counteraction of the ischaemia-induced fall of VFT and decreased aggravation of the ischaemia-induced lengthening of VCT. The blockade of calcium channels, which normally does not alter VFT (between 7.2 +/- 0.6 and 8.4 +/- 0.7 mA, n.s.) or VCT (between 30 +/- 2 and 34 +/- 3 ms, n.s.), slowed the ischaemia-induced fall of VFT. VFT required more time to reach 0 mA, thus delaying the onset of fibrillation. Membrane depolarization itself was opposed as the shortening of MAPD and the lengthening of VCT were also delayed. Consequently there is a progressive decrease in the role played by sodium channels during ischaemia in the rhythmic systolic depolarization of the ventricular fibres. This reduces or suppresses the ability of sodium channel blockers to act on excitability or conduction, and increases the role of calcium channel blockers in attenuating ischaemia-induced disorders.

Epicardial radiofrequency catheter ablation of the atria in the open-chest dog has been shown to reduce inducibility of atrial fibrillation. Video-assisted endoscopic techniques decrease the operative trauma in adult thoracic surgery. We report our results of video-assisted thoracoscopic radiofrequency catheter ablation of the atria for the prevention of atrial fibrillation induction in canines. In 12 consecutive anesthetized dogs, induction of sustained atrial fibrillation was reproducibly obtained by burst pacing and cervical vagal stimulation. In six dogs, biatrial ablation was performed through right and left minithoracotomies and guided by video-assisted endoscopic techniques. The remaining six dogs underwent a video-guided left atrial procedure. Long continuous and transmural lesions were produced using epicardial temperature controlled radiofrequency energy delivery according to a simplified maze approach. Transmural lesions were demonstrated at the end of the study by examination of the heart. Sustained atrial fibrillation was still inducible after the right atrial ablation but sustained atrial fibrillation could not be induced following left atrial ablation. In acute canine studies: (1) epicardial radiofrequency catheter ablation of the atria is feasible using video-assisted endoscopic techniques; (2) ablation extended or confined to the left atrium appears to be effective in preventing the inducibility of sustained vagal atrial fibrillation; and (3) ablation of the right atrium alone had no antiarrhythmic effect.

Objectives: To investigate the prevention of ventricular fibrillation with a beta-adrenergic receptor (beta-AR) antagonist in anaesthetized, open-chest pigs in a model of ischaemia, intended to reproduce what happens either in anginal attack or in the first hour of infarction., Methods: Ventricular fibrillation threshold (VFT) was determined with trains of diastolic stimuli of 100 ms duration delivered by a subepicardial electrode inserted in the area subjected to ischaemia. Ischaemia was obtained by the complete occlusion of the left anterior descending coronary artery, either near its origin during brief but increasing periods (30, 60, 90, 120, 150, 180, 240, 300 s), or half-way from its origin for a much longer time (more than 60 min)., Results: During transient proximal occlusion and isoprenaline infusion (0.25 microgram/kg/min), propranolol (50 micrograms/kg plus 2 micrograms/kg/min) attenuated both tachycardia and the fall in VFT to 0 mA. The shortening of MAP duration accompanying depolarization of the fibres was concurrently slowed down, and time to fibrillation prolonged (122 +/- 15 to 262 +/- 14 s, p < 0.001). In the absence of isoprenaline infusion, propranolol exerted similar effects, but to a lesser degree, in proportion to heart rate dependent on sympathetic activity. In contrast, it became unable to raise VFT before and during ischaemia, when heart rate was kept constant by pacing. After persistent midportion occlusion, significant differences in VFT were found only at the 5th min, depending on whether heart rate was accelerated by isoprenaline (0.8 +/- 0.2 mA), left normal (1.8 +/- 0.3 mA) or slowed down by propranolol (1.6 +/- 0.3 mA). Later on, especially after 15 and 25 min of ischaemia, VFT, which was below 1.0 mA, did not appear to be influenced by the activation or blockade of beta-ARs: spontaneous fibrillations were observed in the same number in this period with or without the administration of propranolol. Beyond 30 min after occlusion, the rise in VFT, subsequent to the first irreversible cell damage, also occurred in the same way., Conclusions: The prevention of ischaemic ventricular fibrillation by a beta-AR antagonist, judged from VFT, is easily checked experimentally when ischaemia is only transitory, especially if sympathetic activity is high. The maintenance of VFT at a relatively high level is essentially related to the depressant effect on the sinus rate. The same animal model does not give support to an effective protection in the first hour of infarction. However, the control of heart rate may also be beneficial in these circumstances by attenuating systemic haemodynamic disorders.

Cardiac disorders are observed when excessive plasma concentrations of local anaesthetics are reached, following for instance intravascular accidental injection for epidural anaesthesia or brachial plexus block. Bupivacaine particularly, which is one of the most used local anaesthetics, adversely affects intraventricular conduction and cardiac contractile strength from the 3.0-4.0 micrograms/ml blood levels. Depression of conduction is especially to be feared, for it can result in reentrant arrhythmias likely to degenerate into often fatal ventricular fibrillation. Such accidents may sometimes occur at far lower concentrations, subsequent to diffusion into systemic circulation from the injection site (0.4-1.2 micrograms/ml). These accidents were probably due to various factors which concomitantly intervene during the anaesthesia. We could identify a number of these factors by associating them to an intravenous infusion of bupivacaine (0.04 mg/kg/min after a loading dose of 1.00 mg/kg) in animals (dogs and pigs) under electrocardiographic monitoring, in which conduction time, monophasic action potential duration, effective refractory period and electrical fibrillation threshold were determined in the ventricular fibres. The electrophysiological changes due to bupivacaine may be enhanced by 1) dilution hyponatremia (115-110 mmol/l) induced by a short (5 min) intravenous 10 ml/kg/min infusion of hypotonic solution and/or hyperkalemia (7-8 mmol/l) induced by 0.05 mmol/kg/min infusion of potassium chloride; 2) the acceleration of cardiac contractions (180-210 beats/min) induced by ventricular pacing; 3) mild hypothermia (35-34 degrees C) induced by blood cooling in an extracorporeal circuit; 4) myocardial ischaemia induced by complete temporary occlusion of the left anterior descending coronary artery near its origin. The risk of cardiac accidents, possibly severe, is therefore enhanced by each of these factors capable of lowering the concentration required for their triggering and, of course, the combination of two or several of them. On the contrary, the knowledge of these factors should allow to prevent most of cardiac accidents of locoregional anaesthesia.

Class I antiarrhythmic drugs do not decrease, but increase, the risk of ventricular fibrillation in the ischemic myocardium. On the contrary, vulnerability to fibrillation related to ischemia appears to be substantially reduced by calcium antagonists. We assessed whether the calcium antagonist diltiazem (0.50 mg/kg bolus plus 0.02 mg/kg/min infusion) could prevent the profibrillatory effect or even partially restore the antifibrillatory effect of a class I antiarrhythmic drug, flecainide (1 mg/kg bolus plus 0.04 mg/kg/min infusion) in the ischemic myocardium of anesthetized, open-chest pigs. Ischemia was obtained by completely occluding the left anterior descending coronary artery near its origin. Vulnerability to fibrillation was assessed by electrical fibrillation threshold (EFT), measured with diastolic impulses of 100 msec duration delivered at a rate of 180 beats/minute. Diltiazem did not oppose the rise in EFT induced by flecainide in the absence of ischemia (6.8 +/- 1.2 to 9.9 +/- 0.9 mA, p<0.001). It limited the fall in EFT observed under the dual influence of ischemia and flecainide (4.2 +/- 0.9 vs 1.3 +/- 0.6 mA, p<0.001). By reducing calcium entry into myocardial fibers, diltiazem delayed ischemic depolarization, as evidenced by reduced shortening of the monophasic action potential duration from 215 +/- 7 to 200 +/- 4 msec, instead of 178 +/- 6 (p<0.001), and reduced lengthening of intraventricular conduction time from 33 +/- 5 to 43 +/- 4 msec, instead of 53 +/- 4 (p<0.01). Therefore, diltiazem is likely to prevent the loss and even the reversal of the antifibrillatory properties of flecainide due to myocardial ischemia in dosages that do not adversely affect myocardial contractility or atrioventricular conduction to a large extent.

Background: The opinions on the efficacy of magnesium as an antiarrhythmic drug vary considerably. The action of magnesium on vulnerability to fibrillation was therefore investigated in anaesthetized, open-chest pigs under different conditions as regards plasma concentration, heart rate and myocardial perfusion., Methods: Vulnerability to fibrillation was assessed by electrical fibrillation threshold (EFT), measured with 100-ms duration diastolic impulses. These stimuli were delivered to the heart normally perfused, at a usual (90 and 120 beats/min) or accelerated (180 beats/min) rate. Vulnerability to fibrillation was also assessed at the high rate (180 beats/min) in the heart made ischaemic by complete occlusion of the left anterior descending coronary artery near its origin. EFT was then measured at the end of occlusion periods which were of increasing duration (30, 60, 90, 120 s). Monophasic action potential (MAP) duration, intraventricular conduction time, left ventricular dP/dt max (LVdP/dt max) and mean blood pressure were concurrently measured., Results: In the absence of ischaemia, 5 mumol.kg-1.min-1 magnesium i.v. infusion, which raised plasma concentration to 1.78 +/- 0.14 mmol/L, lowered EFT, measured at the rate of 116 beats/min, from 14.0 +/- 1.1 to 6.8 +/- 1.0 mA (P < 0.001), without significant variation of the other parameters. Administered as previously or in a markedly higher dose (400 mumol.kg-1 loading dose and 10 mumol.kg-1.min-1 infusion) which raised plasma concentration up to 4.84 +/- 0.52 mmol/L, magnesium significantly influenced neither EFT nor MAP duration, reduced by the high rate (180 beats/min) to 6.2-6.7 mA and 212-220 ms respectively. Under the same conditions, at the same 180 beats/min rate, ischaemia brings about a fall of EFT, from 6.9 down to nearly 0 mA, with occurrence of fibrillation, in approximately 120 s. Magnesium failed to slow this fall and to delay the onset of fibrillation. In contrast, within the minutes following the end of occlusion, magnesium increased EFT to a great extent (from 7.1 +/- 0.4 to 13.5 +/- 0.7 mA, P < 0.001), with a significant prolongation of MAP duration (212 +/- 6 to 234 +/- 8 ms, P < 0.01)., Conclusion: Magnesium may develop profibrillatory or antifibrillatory effects depending on plasma concentration, heart rate and myocardial perfusion.

Experimental studies have shown the limitation by calcium antagonists of the propensity to fibrillation secondary to the occlusion of a large coronary artery. However, this capacity, studied in the acute phase of infarction, is less obvious and still under debate. Ischemia was therefore produced in anesthetized, open-chest pigs by complete occlusion of the left anterior descending coronary artery according to two modes, either near its origin during brief but increasing periods (30, 60, 120, 180 s, etc) or half-way from this origin for a much longer time (60 min). The time course of vulnerability to fibrillation was monitored by ventricular fibrillation threshold (VFT), measured by trains of diastolic stimuli of 100 ms. Verapamil was administered in a 50 micrograms/kg dose followed by 2 micrograms/kg/min infusion. 1) In the case of brief proximal occlusions under pacing at a constant high rate (180 beats/min), verapamil slowed the decline of VFT from 6-8 mA to nearly 0 mA. VFT was 4.4 +/- 0.4 mA after 60 s ischemia, whereas it had already fallen to 1.8 +/- 0.3 mA (p < 0.001) in the absence of the drug. Accordingly, the onset of spontaneous fibrillation which depends on the decrease in VFT to about 0 mA was prolonged from 2-3 to 6-9 min. Bradycardia, concurrently produced by verapamil, is a factor which enhances these alterations. 2) In the case of a persistent midportion occlusion of the artery under sinus rate, fibrillations were similarly delayed by verapamil from 14-25 to 23-49 min after occlusion, but they were more numerous. VFT was lowered to critical values later, but also for a longer time. The period propitious to fibrillation was prolonged because the return of VFT to higher values reflecting hypoexcitability subsequent to the first cell injury was substantially delayed. Consequently, calcium antagonists should often prevent ventricular fibrillation when transient ischemia disappears before VFT falls to the vicinity of 0 mA. In contrast, a real benefit could not be expected from these drugs when ischemia is persistent since they then only delay fibrillations, the number of which is increased.

1. In the last decade, a number of clinical observations have questioned the efficacy of certain class I antiarrhythmic drugs against ischaemia-induced ventricular fibrillation. The effects of three drugs of this class, disopyramide (Ia), lignocaine (Ib) and flecainide (Ic) on the vulnerability to fibrillation during experimental ischaemia were investigated. 2. The study was carried out in anaesthetized, open-chest pigs (n = 8 for each of the drugs, in addition to the control group, n = 6). Vulnerability to fibrillation was evaluated by measuring electrical fibrillation threshold (EFT) by means of stepwise increased intensity of wide (100 ms) diastolic impulses applied to the ischaemic tissue at a 180 beats min-1 rate. Monophasic action potential (MAP) duration and conduction time in the ischaemic region were also measured. 3. EFT determinations were performed before and during periods of ischaemia induced by complete occlusion of the left anterior descending coronary artery near its origin. Ischaemic periods of increasing duration (30, 60, 90, 120, 150 s) were induced to determine the electrophysiological changes, of EFT especially, leading to fibrillation. 4. In the absence of ischaemia, all three drugs, administered by intravenous route (1 mg kg-1 plus 0.04 mg kg-1 min-1) increased EFT to a similar extent (from approximately 7 to 10 mA), despite a 25% prolongation of conduction time. 5. During ischaemia, none of the drugs prevented the fall in EFT towards 0 mA, resulting in spontaneous fibrillation. After 30 s of ischaemia, they no longer had any capacity for raising EFT and, after 60, 90 and 120 s of ischaemia, the decrease in EFT was exacerbated. This accelerated reduction in EFT shortened the time to onset of fibrillation (after 120 s of ischaemia, 62.5% of fibrillations with flecainide instead of 12.5 under control conditions, 75% instead of 25 with lignocaine and 50% instead of 25 with disopyramide). The reduction in MAP duration due to ischaemia was also significantly accelerated (at 60 s, 178 +/- 5 ms instead of 192 +/- 4 with flecainide, 175 +/- 3 ms instead of 194 +/- 5 with lignocaine and 180 +/- 5 ms instead of 196 +/- 3 with disopyramide) and the slowing of conduction was made worse (prolongation of conduction time by 70% instead of 50). 6. In conclusion, the antifibrillatory properties normally manifested by these drugs are first suppressed, then inverted by ischaemia, depending on oxygen debt varying with severity and duration of ischaemia.

Objectives: To investigate the role of ventricular and atrial beta-adrenoceptor activation by isoprenaline in the genesis of rhythm disorders and risk of fibrillation in the healthy or ischaemic heart., Methods: The study was performed in anaesthetized, open-chest pigs. Electrical fibrillation threshold (EFT) of the ventricles was measured with trains of diastolic stimuli of 100 ms duration synchronized with respect to the R-waves and delivered to the myocardium by a subepicardial electrode introduced into the area which could be subjected to ischaemia. Monophasic action potential (MAP) and effective refractory period (ERP) were recorded in the same area. Ischaemia was obtained by complete occlusion of the left anterior descending coronary artery near its origin during increasing periods (30, 60, 90, 120, 150, 180, 240 s)., Results: At a rate varying according to the action exerted by isoprenaline on the sinus rate, EFT decreased by about 30% in the healthy heart during the infusion of 0.5 micrograms/kg/min isoprenaline under the influence of the acceleration of cardiac beats. In the ischaemic heart, sinus tachycardia accelerated the fall in EFT and the reduction in MAP duration and resulted sooner in spontaneous ventricular fibrillation. During ventricular pacing at a constant rate of 200 beats/min, isoprenaline raised EFT by nearly 80% in the absence of ischaemia, but this rise was abolished by ischaemia, at least of no-flow type., Conclusion: Tachycardia produced by activation of atrial adrenoceptors decreases EFT in the healthy heart and aggravates its fall in the ischaemic heart. Ventricular adrenoceptor activation counteracts the EFT fall related to tachycardia in the healthy heart, but not in the ischaemic heart. Therefore, the protection against ischaemic fibrillation due to beta-blockers would be essentially attributable to their action on the sinus nodes.

Calcium antagonists may reduce propensity to ventricular fibrillation, by altering the balance between coronary blood flow and metabolic demand, and thus may substantially prolong time to occurrence of fibrillations. This delay in the onset of fibrillation should be sufficient to prevent sudden death in the case of transitory episodes of myocardial ischemia. Therefore, this study was based on the determination of time to onset of fibrillation in an animal model of transitory ischemia. This model was achieved by the complete, but transitory occlusion of the left anterior descending coronary artery near its origin under ventricular pacing at a constant high rate (180 beats/min), in anesthetized, open-chest pigs. Amlodipine was preferred to another calcium antagonist for this study because it is among the least negatively inotropic of these drugs. It was intravenously infused at 0.02 mg.kg-1.min-1. Time to fibrillation was prolonged from 87 +/- 10 to 146 +/- 16 s (p < 0.05) with the 0.30 mg/kg dose and to 201 +/- 22 s (p < 0.05) with the 0.60 mg/kg dose, without serious impairment of blood pressure or left ventricular dP/dtmax in the absence of ischemia. Concurrently, amlodipine significantly limited the shortening of monophasic action potential duration (200 +/- 4 vs. 172 +/- 6 ms), the lengthening of conduction time (43 +/- 2 vs. 53 +/- 2 ms), and the alterations of ST segments and T waves induced by 60 s ischemic depolarization. Consequently, amlodipine might reduce the incidence of sudden death by lengthening time to onset of fibrillation beyond the duration of the ischemia, when transitory.

Calcium antagonists have been reported to counteract the increase by ischemia of vulnerability to ventricular fibrillation. This ability might be especially of interest in the prevention of sudden death subsequent to a major, but transitory, inadequacy between myocardial oxygen requirements and available coronary blood flow produced by exercise, emotion, etc., because death is then not related to irreversible damage of myocardial fibers. This study has been undertaken to examine the protective effect of a calcium antagonist on an animal model of this type of ischemia. This model used complete, but transient occlusion of the left anterior descending coronary artery near its origin during pacing at a constant high rate (180 beats/min) in anesthetized, open-chest pigs, most often resulting in fibrillation within 1-2 minutes after a progressive fall of the electrical fibrillation threshold. Amlodipine was the preferred calcium antagonist for this study because it is only moderately negatively inotropic. The results of the preventive administration of amlodipine was assessed by the time to onset of fibrillation. Amlodipine 0.30 mg/kg prolonged this time by 50-100% (p < 0.05) without appreciable impairment of blood pressure or myocardial contractility. Concurrently, amlodipine delayed the shortening of the monophasic action potential duration, the lengthening of conduction time, and the alterations of ST segments and T waves linked to ischemic depolarization. Consequently, when given experimentally before the occurrence of major, but transitory ischemia, amlodipine protected against fibrillation. Similarly, in clinical settings it ought to delay sudden death that may occur as a result of a major but transitory inadequacy between myocardial oxygen requirements and available coronary blood flow.

The effects of three quinidine-like drugs, disopyramide, lidocaine and flecainide were investigated in anaesthetized, open-chest pigs on vulnerability to ventricular fibrillation under normal conditions and under myocardial ischaemia conditions. Vulnerability to fibrillation was evaluated by electrical ventricular fibrillation threshold (VFT), measured with 100 ms duration diastolic impulses the intensity of which was increased by steps of 1.0 or 0.5 mA. Impulses were delivered at the rate of 180 beats · min(-1). The ventricles were subjected to pacing at the same rate before the VFT determination, particularly throughout periods of ischaemia of increasing duration (30, 60, 90, 120, 150 s), separated by appropriate intervals for reproducibility of the results. Monophasic action potential (MAP) duration and conduction time were monitored in the ischaemic area under pacing. Ischaemia was obtained by complete occlusion of the left anterior descending coronary artery near its origin. The three drugs were i.v. administered in clinical dose range (1.00 mg · kg(-1) plus 0.04 mg · kg(-1) · min(-1)). In the absence of ischaemia, they increased almost equally VFT (from about 7 to 10 mA), despite 25% prolongation of conduction time. But, none of them was able to impede the increasingly marked fall of VFT caused by ischaemia: at 30 s, they had already lost any capacity for raising VFT and, beyond this time, they even aggravated its fall which led to spontaneous fibrillation when VFT approached 0 mA. The faster fall of VFT shortened time to onset of fibrillation (20 24 fibrillations for the three drugs at 150 s as against 12 24 in control period), the ischaemia-induced reduction of MAP duration (by 20%) being also hastened and slowing of conduction enhanced, given the addition of the depressant effects of ischaemia and drugs on conduction. Consequently, the antifibrillatory properties normally manifested by the studied drugs are first suppressed, then inverted by ischaemia.

Results obtained in the prevention of ventricular fibrillation secondary to myocardial ischaemia are unexpected. Profibrillatory properties might be manifested by Class I antiarrhythmic drugs, normally antifibrillatory. Clear antifibrillatory properties might be manifested by calcium channel blockers, the antifibrillatory effects of which are normally questionable. Therefore, the action of a Class I antiarrhythmic drug, flecainide, and of a calcium channel blocker, verapamil, on the vulnerability to ischaemic ventricular fibrillation was assessed in anaesthetized, open-chest pigs by ventricular fibrillation threshold. Ventricular fibrillation threshold was determined with trains of diastolic stimuli of 100 msec duration, delivered at a rate of 180 beats/min (near that of the ventricular tachycardia), by a subepicardial electrode inserted into the area that could be subjected to ischaemia. Before determining this threshold, ventricles were paced at the same rate, particularly during the ischaemic periods. Ischaemia was produced by complete occlusion of the left anterior descending coronary artery, either at its origin or half-way from it, over increasing periods. The monophasic action potential and conduction time were recorded in the ischaemic area. Before ischaemia, flecainide was adapted to rais the ventricular fibrillation threshold, in spite of a lengthening of the conduction time. Verapamil was devoid of any influence on these parameters. The antifibrillatory effect of flecainide disappeared with ischaemia, which reduced the ventricular fibrillation threshold down to near 0 mA, with triggering of the spontaneous fibrillation at this level: this reduction was no longer counteracted and even hastened by flecainide, becomes finally profibrillatory. Verapamil, on the contrary, delayed the fall in ventricular fibrillation threshold, maintained far from 0 mA, with prevention of fibrillation, unless the occlusion was maintained over a much longer period. Verapamil similarly delayed the shortening of the monophasic action potential duration and the lengthening of the conduction time, preceding fibrillation and leading to it. Consequently, ischaemic depolarization is apparently responsible for the loss of antifibrillatory activity in a sodium blocker, such as flecainide, and the development of antifibrillatory activity in a calcium blocker, since the sodium channel is activated only at high potentials, whereas the calcium channel is activated at lower potentials.

Purpose: Cardiac disorders, cardiac arrest and ventricular fibrillation in the most severe cases, have been observed after the administration of dantrolene to patients treated by verapamil for coronary artery disease. This study was designed to examine the interaction of dantrolene with amlodipine, a dihydropyridine., Methods: In 12 anaesthetized, open-chest pigs, the effects of the interaction have been studied on heart rate, atrioventricular conduction, monophasic action potential duration, intraventricular conduction time, left ventricular dP/dt max and mean blood pressure. The study was performed with normal coronary circulation and ischaemia of a large area of the left ventricule, obtained by complete occlusion of the left anterior descending coronary artery near its origin, under pacing at a constant high rate, 180 beats.min-1. The drugs were injected iv, amlodipine 0.4 mg.kg-1 first and dantrolene 3.0 mg.kg-1 20 min later in six animals and the order was reversed in the other animals., Results: Sinus rate and atrioventricular conduction were not affected by amlodipine, but were slowed by dantrolene added (145 +/- 9 to 131 +/- 7 beats.min-1, P < 0.01 and 150 +/- 15 to 180 +/- 20 msec, P < 0.01). In contrast, amlodipine or amlodipine plus dantrolene did not change MAP duration or conduction time in the normal heart. Similarly, they did not alter the maximal variations due to ischaemia, but delayed them, while prolonging the time to onset of fibrillation (111 +/- 8 to 343 +/- 33 sec. P < 0.001 with amlodipine alone, 289 +/- 11 to 323 +/- 16 sec, P < 0.05 with dantrolene). Left ventricular dP/dt max was lowered from 1670 +/- 86 to 1532 +/- 50 mmHg.sec-1 (P < 0.001) and mean blood pressure from 79 +/- 4 to 70 +/- 3 mmHg (P < 0.01) by amlodipine, but dantrolene did not enhance and even counteracted these effects. Finally, potassium plasma concentration did not increase above 5.1 +/- 0.2 mmol.L-1 under the dual influence of amlodipine and dantrolene., Conclusion: In usual clinical doses, dantrolene may be safely administered concurrently with amlodipine.

The prevention of ventricular fibrillation raises a special problem when related to myocardial ischaemia, since class I antiarrhythmic drugs are then ineffective and may even behave as profibrillatory agents: the usual antifibrillatory properties of these drugs which are inhibitors of sodium channel, activated at high potentials, disappear with the disappearance of the role of sodium channel caused by ischaemic depolarization. Calcium channel then replacing sodium channel, calcium channel inhibitors should tend to prevent ischaemic ventricular fibrillation. Therefore, vulnerability to ventricular fibrillation was assessed in open-chest pigs by the threshold for fibrillation electrically induced with impulses of 100 ms duration at the rate of 180 beats/min. Ischaemia was produced by total occlusion of the left anterior descending coronary artery near its origin. Electrical fibrillation threshold was measured at the end of ischaemic period of increasing duration (30, 60, 120, 180, 240, 360 s) under control conditions and after i.v. administration of verapamil (50 micrograms/kg loading dose and 2 micrograms/kg/min infusion). Unaffected by verapamil when coronary circulation was normal, fibrillation threshold was raised by the drug when lowered by ischaemia, increasingly with the prolongation of ischaemia responsible for depolarization of the fibres, up to 500%. The rise of fibrillation threshold resulted in a delay in the triggering of fibrillation which occurs when the fibrillation threshold (6-8 mA) falls down to the pacing threshold (0.3-0.4 mA). These experiments tend to confirm the positive results recently obtained in man with verapamil in the prevention of postinfarction sudden death, provided that myocardial contractility is not too much adversely affected. But, in these experiments, left ventricular dP/dt max was not reduced by more than 15%, even just after the loading dose and returned to its control values within a few minutes.

Because recent clinical studies have failed to show evidence of the benefit of lidocaine in the arrhythmias occurring in the early stage of myocardial infarction and have even shown an increased mortality in patients thus treated, we investigated the value of lidocaine as a protective agent against ventricular fibrillation related to myocardial ischemia in the in situ heart of anesthetized open-chest pigs subjected to transient total occlusion of the proximal left anterior descending coronary artery (LAD) under ventricular pacing at a constant high rate. Vulnerability to the fibrillatory process induced by coronary occlusion was assessed both by time to onset of ventricular fibrillation (TF) and by electrical ventricular fibrillation threshold (EFT) determined after coronary occlusions of increasing duration (30, 60, 120, 180 s). Monophasic action potential (MAP) was recorded concurrently in the nonischemic and ischemic areas. Lidocaine, even in relatively high doses (2-4 mg.kg-1), did not prolong TF, nor did it increase EFT. On the contrary, TF was significantly shortened and EFT was significantly decreased (15-30%) at the maximal concentrations of lidocaine, with return to control values in 40-60 min. Therefore, lidocaine tends to increase the risk of ischemic ventricular fibrillation (VF): It fails to control the extreme enhancement of excitability and worsens conduction disorders, even though it decreases normal conduction only slightly. Use of lidocaine against rhythm disorders in acute myocardial infarction (AMI), is at least debatable and probably contraindicated.