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1.
Mech Ageing Dev ; 166: 48-54, 2017 09.
Article in English | MEDLINE | ID: mdl-28705548

ABSTRACT

INTRODUCTION: The left ventricular hypertrophy (LVH)-ventricular arrhythmias relationship associated with arterial hypertension and aging remains controversial. We aimed to assess the age-dependency of ventricular arrhythmias in spontaneously hypertensive rats (SHRs) and the corresponding ventricular structural and molecular remodeling. MATERIALS AND METHODS: Ventricular arrhythmias were quantified using 24-h radiotelemetry ECG monitoring in eight SHRs and four Wistar-Kyoto (WKY) rats at 14 (young), 24 (adult), and 48 (aging) weeks of age. Left ventricular histology and mRNA expressions of 89 proarrhythmogenic genes were assessed in six additional groups (n=4 each) of young, adult, and aging SHRs and WKYs. RESULTS: Regardless of their age, SHRs presented more premature ventricular contractions (PVCs) than age-matched WKYs (p<0.01). The arrhythmogenicity peak occurred in adult SHRs; ventricular tachycardias only occurred in adult SHRs. Among the SHRs, LV thickness, interstitial fibrosis, and the number of deregulated genes increased with age. Kcnj11 expression was deregulated in adult, but not in young or aging SHRs. DISCUSSION: This study confirms the presence of higher ventricular ectopy in SHRs than in age-matched WKYs. LVH appeared to be an adaptive, antiarrhythmic process. Myocardial energetic changes with advancing age, as reflected by Kcnj11 expression changes, could underlie this age-dependency of ventricular arrhythmias.


Subject(s)
Aging/metabolism , Arrhythmias, Cardiac/metabolism , Gene Expression Regulation , Hypertension/metabolism , Hypertrophy, Left Ventricular/metabolism , Potassium Channels, Inwardly Rectifying/biosynthesis , Ventricular Remodeling , Aging/pathology , Animals , Arrhythmias, Cardiac/pathology , Arrhythmias, Cardiac/physiopathology , Hypertension/pathology , Hypertension/physiopathology , Hypertrophy, Left Ventricular/pathology , Hypertrophy, Left Ventricular/physiopathology , Male , Rats , Rats, Inbred SHR , Rats, Inbred WKY , Risk Factors
2.
Resuscitation ; 84(3): 384-90, 2013 Mar.
Article in English | MEDLINE | ID: mdl-22940600

ABSTRACT

OBJECTIVE: Heart rate reduction (HRR) has shown a beneficial impact on the prevention of ventricular fibrillation, which could be explained by increased myocardial blood flow and preservation of mitochondrial structure. Here, we assessed the HRR impact on time to onset of ventricular fibrillation (TOVF) and myocardial metabolic energy status. METHODS AND RESULTS: An acute myocardial ischaemia was induced in pigs until ventricular fibrillation onset and TOVF was then measured. High-energy phosphates were measured in ventricular samples from the ischaemic region by nuclear magnetic resonance. Saline, ivabradine (IVA, a selective heart rate-lowering agent) and propranolol (PROPRA, a 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.


Subject(s)
Benzazepines/administration & dosage , Energy Metabolism/drug effects , Myocardial Ischemia/complications , Myocardium/metabolism , Propranolol/pharmacology , Resuscitation/methods , Ventricular Fibrillation/prevention & control , Animals , Anti-Arrhythmia Agents/pharmacology , Cyclic Nucleotide-Gated Cation Channels , Disease Models, Animal , Ivabradine , Male , Myocardial Ischemia/drug therapy , Swine , Ventricular Fibrillation/metabolism , Ventricular Fibrillation/physiopathology
3.
J Trace Elem Med Biol ; 26(2-3): 170-3, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22664334

ABSTRACT

The involvement of psychotropic drugs in sudden deaths has been highlighted. The objective of this work was to establish a link between selenium levels in heart tissue, psychotropic treatment and sudden death. Selenium levels were measured by electrothermal atomic absorption spectroscopy post-mortem in heart, brain and liver. Histological examination evidenced dilated cardiomyopathy in 45% of cases, left ventricular hypertrophy in 36%, and ischemic coronaropathy in 18%. A significant reduction of myocardial selenium levels compared to controls was seen in patients treated with neuroleptic drugs or meprobamate. No changes in brain or liver selenium levels were seen. These results suggest that selenium deficiency can facilitate sudden death in patients on psychotropic drugs. The reduced activity of glutathione peroxidase due to selenium deficiency can result in augmented oxidative stress in myocardial cells and myocardiopathy leading to sudden death.


Subject(s)
Antipsychotic Agents/adverse effects , Autopsy , Death, Sudden/etiology , Selenium/deficiency , Adult , Female , Humans , Male , Middle Aged
4.
Am J Physiol Heart Circ Physiol ; 303(3): H386-92, 2012 Aug 01.
Article in English | MEDLINE | ID: mdl-22661510

ABSTRACT

Experimental models of unprovoked atrial tachyarrhythmias (AT) in conscious, ambulatory animals are lacking. We hypothesized that the aging, spontaneously hypertensive rat (SHR) may provide such a model. Baseline ECG recordings were acquired with radiotelemetry in eight young (14-wk-old) and eight aging (55-wk-old) SHRs and in two groups of four age-matched Wistar-Kyoto (WKY) rats. Quantification of AT and heart rate variability (HRV) analysis were performed based on 24-h ECG recordings in unrestrained rats. All animals were submitted to an emotional stress protocol (air-jet). In SHRs, carbamylcholine injections were also performed. Spontaneous AT episodes were observed in all eight aging SHRs (median, 91.5; range, 4-444 episodes/24 h), but not in young SHRs or WKY rats. HRV analysis demonstrated significantly decreased low frequency components in aging SHRs compared with age-matched WKY rats (P < 0.01) and decreased low/high frequency ratios in both young (P < 0.01) and aging (P = 0.01) SHRs compared with normotensive controls. In aging SHRs, emotional stress significantly reduced the number of arrhythmic events, whereas carbamylcholine triggered AT and significantly increased atrial electrical instability. This study reports the occurrence of unprovoked episodes of atrial arrhythmia in hypertensive rats, and their increased incidence with aging. Our results suggest that autonomic imbalance with relative vagal hyperactivity may be responsible for the increased atrial arrhythmogenicity observed in this model. We also provide evidence that, in this model, the sympatho-vagal imbalance preceded the occurrence of arrhythmia. These results indicate that aging SHRs may provide valuable insight into the understanding of atrial arrhythmias.


Subject(s)
Aging , Autonomic Nervous System/physiopathology , Heart Rate , Hypertension/complications , Tachycardia, Supraventricular/etiology , Age Factors , Animals , Autonomic Nervous System/drug effects , Blood Pressure , Carbachol/administration & dosage , Cholinergic Agonists/administration & dosage , Disease Models, Animal , Electrocardiography, Ambulatory , Heart Rate/drug effects , Hypertension/physiopathology , Injections, Subcutaneous , Male , Phenotype , Rats , Rats, Inbred SHR , Rats, Inbred WKY , Stress, Psychological/complications , Stress, Psychological/physiopathology , Sympathetic Nervous System/physiopathology , Tachycardia, Supraventricular/physiopathology , Tachycardia, Supraventricular/prevention & control , Telemetry , Time Factors , Vagus Nerve/physiopathology
5.
Resuscitation ; 82(8): 1092-9, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21561702

ABSTRACT

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.


Subject(s)
Benzazepines/pharmacology , Heart Rate/drug effects , Myocardial Ischemia/complications , Ventricular Fibrillation/etiology , Ventricular Fibrillation/prevention & control , Animals , Disease Models, Animal , Dose-Response Relationship, Drug , Heart Conduction System/drug effects , Heart Conduction System/physiopathology , Ivabradine , Mitochondria, Heart/drug effects , Mitochondria, Heart/ultrastructure , Muscle Cells/drug effects , Muscle Cells/ultrastructure , Myocardial Ischemia/physiopathology , Positron-Emission Tomography , Swine , Ventricular Fibrillation/physiopathology
6.
J Forensic Leg Med ; 17(8): 437-8, 2010 Nov.
Article in English | MEDLINE | ID: mdl-21056880

ABSTRACT

Sudden cardiac deaths constitute a major health problem. Most cases are attributed to cardiomyopathies, coronary artery diseases and functional dysregulations. Sudden death in an adult due to a primitive cardiac tumor is a rare occurrence. In the following, we present a case of an adult male who died from an undiagnosed cystic atrio-ventricular node tumour six years after having a pace maker fitted. We focus on the postmortem diagnosis to underline the importance of a systematic histological examination of the cardiac conduction tissue in forensic pathology.


Subject(s)
Atrioventricular Node/pathology , Death, Sudden/etiology , Heart Neoplasms/pathology , Mesothelioma/pathology , Adult , Forensic Pathology , Humans , Male , Pacemaker, Artificial
7.
Int J Cardiovasc Imaging ; 26(4): 373-83, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20052618

ABSTRACT

The present study investigated whether IVUS could serve as a reliable reference in validating MDCT characterization of coronary plaque against a histological gold standard. Twenty-one specimens were postmortem human coronary arteries. Coronary cross-sections were imaged by 40 MHz IVUS and by 64-slice MDCT and characterized histologically as presenting calcified, fibrous or lipid-rich plaques. Plaque composition was analyzed visually and intra-plaque MDCT attenuation was measured in Hounsfield Units (HU). 83 atherosclerotic plaques were identified. IVUS failed to characterize calcified plaque accurately, with a positive predictive value (ppv) of 75% versus 100% for MDCT. Lipid-rich plaque was even less accurately characterized, with ppv of 60 and 68% for IVUS and MDCT respectively. Mean MDCT attenuation was 966 +/- 473 HU for calcified plaque, 83 +/- 35 HU for fibrous plaque and 70.92 HU +/- 41 HU for lipid-rich plaque. No significant difference in mean MDCT attenuation was found between fibrous and lipid-rich plaques (P = 0.276). In vivo validation of MDCT against an IVUS reference thus appears to be an unsuitable and unreliable approach: 40 MHz IVUS suffers from acoustic ambiguities in plaque characterization, and 64-slice MDCT fails to analyze plaque morphology and components accurately.


Subject(s)
Coronary Angiography/methods , Coronary Artery Disease/diagnosis , Coronary Vessels , Tomography, X-Ray Computed , Ultrasonography, Interventional , Aged , Cadaver , Coronary Artery Disease/diagnostic imaging , Coronary Artery Disease/pathology , Coronary Vessels/diagnostic imaging , Coronary Vessels/pathology , Humans , Middle Aged , Predictive Value of Tests , Reproducibility of Results
8.
Cardiovasc Toxicol ; 9(2): 64-9, 2009 Jun.
Article in English | MEDLINE | ID: mdl-19484391

ABSTRACT

Further to our previous observation of post-mortem cardiac lesions after sudden death in several athletes with a history of anabolic steroid abuse, this study was intended to reproduce these lesions in rabbits administered testosterone oenanthate, a prototypic anabolic steroid abused by athletes, and to provide evidence for the protective effects of trimetazidine and dexrazoxane that are used as antianginal and cardioprotective drugs, respectively. Groups of six rabbits each were administered saline, testosterone, or a combination of testosterone and either trimetazidine or dexrazoxane for 3 months. Histologic cardiac lesions including necrosis, misshapen cell nuclei, interstitial and endocardial fibrosis, lymphocytic infiltrates, and vascular dystrophies were observed in testosterone-treated rabbits. In contrast, no significant lesions were observed in the animals treated with testosterone combined with either trimetazidine or dexrazoxane. This is the first study providing evidence for testosterone cardiotoxicity following sub-chronic exposure in laboratory animals. In addition, these results suggest the protective role of trimetazidine and dexrazoxane.


Subject(s)
Cardiotonic Agents/therapeutic use , Heart Diseases/prevention & control , Razoxane/therapeutic use , Testosterone/toxicity , Trimetazidine/therapeutic use , Animals , Female , Heart Diseases/chemically induced , Heart Diseases/pathology , Male , Rabbits
9.
Exp Toxicol Pathol ; 61(4): 317-23, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19027274

ABSTRACT

Among 15,000 forensic post-mortem examinations performed on the coroner's order over a 24-year period (January 1981-December 2004) in the area of Lyon, France (population: 2,000,000), 2250 cases of unexpected cardiac sudden death were identified retrospectively according to WHO criteria. Of these, 108 occurred during recreational sport and 12 occurred in athletes. In the latter category, a history of anabolic steroid abuse was found in 6 cases, whereas pre-existing ordinary cardiac lesions were observed in the 6 remaining cases. To shed light on the possible role of anabolic steroids in the induction of cardiac lesions, an experimental study was conducted in rabbits that were treated orally with norethandrolone 8mg/kg/day for 60 days, and sacrificed at day 90. The histopathological examination of the heart from treated animals showed coronary thrombosis associated with left ventricle hypertrophy in 3 cases, and lesions analogous to toxic or adrenergic myocarditis in all other treated animals. These findings were very similar to those observed after cardiac sudden death in the 6 athletes with a history of anabolic steroid abuse. In addition, elevated caspase-3 activity in the heart of treated rabbits as compared to controls suggests that apoptosis is involved in the induction of norethandrolone-induced cardiac lesions. These results confirm the cardiotoxic potential of anabolic steroid abuse.


Subject(s)
Anabolic Agents/adverse effects , Death, Sudden, Cardiac/etiology , Heart Diseases/chemically induced , Myocardium/pathology , Norethandrolone/adverse effects , Sports , Adult , Animals , Death, Sudden, Cardiac/pathology , Female , Forensic Pathology , Heart Diseases/pathology , Humans , Male , Middle Aged , Rabbits , Retrospective Studies , Young Adult
10.
J Cardiovasc Pharmacol ; 52(6): 548-54, 2008 Dec.
Article in English | MEDLINE | ID: mdl-19034029

ABSTRACT

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.


Subject(s)
Anti-Arrhythmia Agents/pharmacology , Benzazepines/pharmacology , Heart Conduction System/drug effects , Myocardial Ischemia/drug therapy , Ventricular Fibrillation/prevention & control , Action Potentials , Acute Disease , Animals , Disease Models, Animal , Dose-Response Relationship, Drug , Female , Heart Conduction System/physiopathology , Heart Rate/drug effects , Ivabradine , Male , Mitochondria, Heart/drug effects , Mitochondria, Heart/enzymology , Myocardial Ischemia/complications , Myocardial Ischemia/physiopathology , Succinate Dehydrogenase/metabolism , Sus scrofa , Time Factors , Ventricular Fibrillation/etiology , Ventricular Fibrillation/physiopathology , Ventricular Function, Left/drug effects , Ventricular Pressure/drug effects
11.
Cardiovasc Drugs Ther ; 22(1): 29-36, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18157622

ABSTRACT

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.


Subject(s)
Myocardial Ischemia/complications , Trimetazidine/pharmacology , Vasodilator Agents/pharmacology , Ventricular Fibrillation/prevention & control , Animals , Coronary Vessels/pathology , Disease Models, Animal , Electric Stimulation , Female , Heart Rate , Homeostasis/drug effects , Lipid Peroxidation/drug effects , Male , Malondialdehyde/blood , Swine , Ventricular Fibrillation/etiology
12.
J Anesth ; 20(4): 341-3, 2006.
Article in English | MEDLINE | ID: mdl-17072705

ABSTRACT

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.


Subject(s)
Amides/pharmacology , Anesthetics, Local/pharmacology , Myocardial Contraction/drug effects , Myocardial Ischemia/physiopathology , Ventricular Fibrillation/chemically induced , Animals , Female , Male , Monitoring, Physiologic , Ropivacaine , Swine , Ventricular Fibrillation/physiopathology
13.
Bull Cancer ; 93(3): E27-30, 2006 Mar 01.
Article in English | MEDLINE | ID: mdl-16567310

ABSTRACT

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).


Subject(s)
Antimetabolites, Antineoplastic/adverse effects , Fluorouracil/adverse effects , Heart Diseases/chemically induced , Heart/drug effects , Adult , Aged , Angina Pectoris/chemically induced , Cardiac Output, Low/chemically induced , Chest Pain/chemically induced , Female , Humans , Male , Middle Aged , Myocardial Infarction/chemically induced
14.
Heart Rhythm ; 2(5): 518-22, 2005 May.
Article in English | MEDLINE | ID: mdl-15840477

ABSTRACT

OBJECTIVES: To quantify and study the distribution of innervation of the left atrium and the pulmonary veins in humans. BACKGROUND: Damage to cardiac nerves has been hypothesized as the explanation for successful radiofrequency ablation of atrial fibrillation. METHODS: From January 2003 to September 2003, histologic and quantitative studies of innervation of the left atrium and the pulmonary veins was performed in 43 consecutive necropsied adult hearts (30 men and 3 women; mean age 45.5 +/- 12.4 years). The left atrium was sectioned in 1-cm slices from left to right, with the plane of section perpendicular to the long axis of the heart. Sections of the pulmonary veins at their ostia and sections 1 cm away of this structure also were obtained. Nerve fiber density was counted manually for each case and expressed as the mean number per slice. RESULTS: Numerous epicardial nerve fibers and ganglia having distinct patterns of distribution in the left atrium were found. Nerve density was significantly higher at the ostia of the four pulmonary veins than in their distal part (7.1 +/- 2.1 vs 5.2 +/- 1.3 for left upper pulmonary vein; 6.3 +/- 1.5 vs 5.2 +/- 1.7 for right upper pulmonary vein; 7.4 +/- 2 vs 5.9 +/- 2 for left lower pulmonary vein; 6.7 +/- 1.8 vs 3.9 +/- 1.3 for right lower pulmonary vein). The left superior vein was significantly more innervated than the right inferior vein (12.3 +/- 3 vs 10.6 +/- 1.4). Gradients of innervation were found from right to left (9.8 +/- 4.6 vs 18.5 +/- 6.6, P < .05) and from the front to the rear of the atrium (17.2 +/- 6.4 vs 20.7 +/- 6.5, P < .05). The same heterogeneous distribution was observed at the myocardial level but with thinner nerve fibers, making quantification difficult. Only very thin nerve fibers were present in the endocardium. CONCLUSIONS: The human left atrium exhibits several gradients of innervation at discrete sites. These findings may have clinical implications for radiofrequency ablation of atrial fibrillation.


Subject(s)
Autonomic Nervous System/physiopathology , Heart Atria/innervation , Pulmonary Veins/innervation , Adolescent , Adult , Aged , Atrial Fibrillation/physiopathology , Atrial Fibrillation/therapy , Autonomic Nervous System/anatomy & histology , Catheter Ablation , Child , Female , Humans , Male , Middle Aged
15.
Can J Psychiatry ; 49(2): 100-5, 2004 Feb.
Article in English | MEDLINE | ID: mdl-15065743

ABSTRACT

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.


Subject(s)
Heart Diseases/complications , Mental Disorders/drug therapy , Psychotropic Drugs/adverse effects , Adult , Aged , Antipsychotic Agents/adverse effects , Antipsychotic Agents/therapeutic use , Arrhythmias, Cardiac/chemically induced , Arrhythmias, Cardiac/mortality , Arrhythmias, Cardiac/pathology , Brain/pathology , Canada , Death, Sudden, Cardiac/epidemiology , Death, Sudden, Cardiac/etiology , Death, Sudden, Cardiac/pathology , Drug Therapy, Combination , Electroencephalography/drug effects , Female , Heart Diseases/mortality , Heart Diseases/pathology , Humans , Lung/pathology , Male , Mental Disorders/mortality , Mental Disorders/pathology , Middle Aged , Myocardium/pathology , Psychotropic Drugs/therapeutic use , Retrospective Studies
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