Electrophysiological, haemodynamic, and mitochondrial alterations induced by levobupivacaine during myocardial ischemia in a pig model: protection by lipid emulsions?

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.

Effects of amlodipine and perindoprilate on the structure and function of mitochondria in ventricular cardiomyocytes during ischemia-reperfusion in the pig.

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.

Fluoxetine blocks Nav1.5 channels via a mechanism similar to that of class 1 antiarrhythmics.

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.

Determinants of torsades de pointes in older patients with drug-associated long QT syndrome: a case-control study.

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.

Protective effects of ranolazine and propranolol, alone or combined, on the structural and functional alterations of cardiomyocyte mitochondria in a pig model of ischemia/reperfusion.

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.

Ivabradine but not propranolol delays the time to onset of ischaemia-induced ventricular fibrillation by preserving myocardial metabolic energy status.

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 ß-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.

Involvement of neuroleptic drugs in selenium deficiency and sudden death of cardiac origin: study and human post-mortem examination.

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.

Sudden death of cardiac origin and psychotropic drugs.

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.

Mexiletine differentially restores the trafficking defects caused by two brugada syndrome mutations.

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 ß(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.

Chronic oral amiodarone but not dronedarone therapy increases ventricular defibrillation threshold during acute myocardial ischemia in a closed-chest animal model.

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.

Heart rate reduction with ivabradine increases ischaemia-induced ventricular fibrillation threshold: role of myocyte structure and myocardial perfusion.

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.

5-Fluorouracil-induced Tako-Tsubo-like syndrome.

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.

Experimental intracameral injection of vancomycin microparticles in rabbits.

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.

Cardiac lesions induced by testosterone: protective effects of dexrazoxane and trimetazidine.

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.

Heart lesions associated with anabolic steroid abuse: comparison of post-mortem findings in athletes and norethandrolone-induced lesions in rabbits.

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.

Ivabradine induces an increase in ventricular fibrillation threshold during acute myocardial ischemia: an experimental study.

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.

Trimetazidine protective effect against ischemia-induced susceptibility to ventricular fibrillation in pigs.

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 impact of acute myocardial ischemia on the ventricular defibrillation threshold during chronic oral azimilide therapy.

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.

The effects of ropivacaine at clinically relevant doses on myocardial ischemia in pigs.

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.

Cardiotoxicity of 5-fluorouracil in 1350 patients with no prior history of heart disease.

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).