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 Nav1.5 encoded by the SCN5A gene plays a critical role in cardiac excitability and the propagation of action potentials. Nav1.5 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. Nav1.5 mutations that cause BrS result in a loss of channel function. Our aim was to functionally characterize two novel Nav1.5 mutations (A124D and V1378M) in BrS patients. Wild-type (WT) and mutant Nav1.5 channels were expressed in tsA201 cells in the presence of the β1-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

Vagal stimulation after acute coronary occlusion: The heart rate matters

Background: There is a well documented causal link between autonomic imbalance and cardiac elec­trical instability. However, the mechanisms underlying the antiarrhythmic effect of vagal stimulation are poorly understood. The vagal antiarrhythmic effect might be modulated by a decrease in heart rate. Methods: The proximal anterior interventricular artery was occluded in 16 pigs by clamping under general anaesthesia. Group 1: heart rates remained spontaneous (n = 6; 12 occlusions); Group 2: heart rates were fixed at 190 bpm with atrial electrical stimulation (n = 10; 20 occlusions). Each pig received two occlusions, 30 min apart, one without and one with vagal stimulation (10 Hz, 2 ms, 5–20 mA). The antiarrhythmic effect of vagal activation was defined as the time to the appearance of ventricular fibrillation (VF) after occlusion. Results: In Group 1, vagal stimulation triggered a significant decrease in basal heart rate (132 ± 4 vs. 110 ± 17 bpm, p < 0.05), and delayed the time to VF after coronary occlusion (1102 ± 85 vs. 925 ± ± 41 s, p < 0.05). In Group 2, vagal stimulation did not modify the time to VF (103 ± 39 vs. 91 ± 20 s). Analyses revealed that heart rate and the time to VF were positively linearly related. Conclusions: Maintaining a constant heart rate with atrial electrical stimulation in pigs prevented vagal stimulation from modifying the time to VF after acute coronary occlusion

Parodontopathies (causes ou conséquences de diverses pathologies organiques)

LYON1-BU Santé Odontologie (693882213) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Les macrolides sont-ils cardiotoxiques ?

LYON1-BU Santé Odontologie (693882213) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Effets cardiaques de la trimetazidine (revue de la littérature)

Les maladies cardiovasculaires et en particulier les cardiopathies ischémiques (CPI) sont un problème de santé publique majeur. Leur coût pour la société reste très important malgré un arsenal thérapeutique très vaste. La trimetazidine (TMZ) est l un des traitements les plus anciens des CPI dont l utilisation semble actuellement dénigrée. Nous avons donc voulu évaluer ses effets en recherchant les différentes études relatives à cette molécule. De cette revue de la littérature nous avons dégagé plusieurs éléments. La TMZ reste assez fréquemment prescrite (un peu plus de 13%). Mais surtout de nombreuses études révèlent son effet bénéfique dans la récupération post-ischémique puis dans la récidive angineuse. De plus de nouveaux travaux notent une diminution du risque de fibrillation d origine ischémique. Cependant, ces études récentes sont réalisées sur de petites cohortes. Il semble donc indispensable de poursuivre des études de plus grande ampleur pour confirmer ou infirmer ces résultats.The cardiovascular diseases and especially ischemic heart disorders (IHD) are a major problem of public health. Their cost for the society remains very important in spite of a very large therapeutic armory. Trimetazidine (TMZ) is one of the most ancient treatments of IHD use of which seems currently denigrated. We therefore wanted to assess its effects by searching different studies relating to this molecule. Of this study of literature we cleared several elements. TMZ remains rather often prescribed (a little more than 13 %). But especially many studies reveal his advantageous effect in post-ischemic recovery and in the repetition of angina. Moreover, new studies note a reduction of the risk of fibrillation induced by ischemia. However, these recent studies are accomplished on small cohorts. So it seems necessary to order larger studies to confirm or to preempt these results.GRENOBLE1-BU Médecine pharm. (385162101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Antiagrégants plaquettaires et art dentaire

LYON1-BU Santé (693882101) / SudocSudocFranceF

Les allergies des patients aux produits et matériaux utilisés en art dentaire

LYON1-BU Santé Odontologie (693882213) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Ischaemia-induced loss or reversal of the effects of the class I antiarrhythmic drugs on vulnerability to fibrillation

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