Differences in arrhythmogenicity between the canine right ventricular outflow tract and anteroinferior right ventricle in a model of Brugada syndrome

BACKGROUND: The Brugada syndrome is characterized by ST-segment elevation on the ECG, especially in the right precordial leads sensitive to the right ventricular outflow tract (RVOT). OBJECTIVES: The purpose of this study was to evaluate the hypothesis that right ventricular electrophysiologic heterogeneity caused arrhythmogenicity in the Brugada syndrome. METHODS: Action potentials (APs) were mapped on the epicardium of 14 RVOT preparations and on the transmural surfaces of 15 pairs of RVOT and right ventricular anteroinferior (RVAI) preparations isolated from canine hearts. Brugada ECG and arrhythmias were induced with pilsicainide (2.5-12.5 micromol/L), pinacidil (1.25-12.5 micromol/L), and terfenadine (2.0 micromol/L). RESULTS: Low doses of drugs elevated the J-ST segment and induced APs with both short and long action potential durations (APDs) in contiguous RVOT epicardial regions. In addition, APs in the RVOT had a larger phase 1 notch and longer APD than in RVAI. The longest APDs were in the epicardium in RVOT but in the endocardium in RVAI regions. High doses of drugs eliminated the phase 2 dome of the AP and abbreviated APDs in the epicardium but not in endocardium and reduced the epicardial heterogeneity of APs but increased the transmural gradient of APD in 14 (93%) of the RVOT preparations. In contrast, abbreviations of epicardial APDs occurred in only 4 (27%) of the RVAI preparations. Ventricular tachycardia occurred more frequently in the RVOT (47%) than in paired RVAI preparations (7%). Blocking the transient outward current reduced the heterogeneity of APs and eliminated arrhythmogenicity in all preparations. CONCLUSION: Compared with the RVAI region, the RVOT has greater electrophysiologic heterogeneity that contributes to arrhythmogenicity in this model of Brugada syndrome.     

Tyramine-Induced cardiac arrhythmias

Five out of 12 physically healthy patients with depression undergoing a tyramine pressor test developed cardiac arrhythmias. These arrhythmias occurred in drug-free patients in three out of 12 infusions following as little as 0.03 mg/kg of tyramine and after moclobemide, a reversible inhibitor of monoamine oxidase-A, in four out of 14 tyramine infusions with as little as 0.04 mg/kg of tyramine. The arrhythmias seen were independent of patient's age and occurred both before and after 30 mmHg elevations in systolic blood pressure. Electrocardiographic abnormalities and arrhythmias seen were a loss of p waves, sinus tachycardia, frequent atrial ectopic beats, atrial premature beats, Wenckebach phenomenon, junctional rhythm, ventricular ectopics, varying QRS configurations, and ventricular bigeminy. Tyramine, both oral and intravenous, caused similar reproducible changes in dogs, though not in rats, mice or guinea pigs. Practical implications are that tyramine pressor testing in humans should be performed cautiously and only with adequate cardiac monitoring and resuscitation facilities at hand. These findings suggest that a normal dietary component can induce serious cardiac arrhythmias, and that a low-tyramine diet may be of value for patients who are susceptible to cardiac arrhythmias.     

Newer aspects of antiarrhythmic drug development: Introduction

Although cardiac arrhythmias remain a serious clinical problem in many patients with heart disease, the exact role of antiarrhythmic drug therapy is currently under intense evaluation. Within the last several years it has become clear that there are significant risks as well as potential benefits associated with existing agents. Ongoing studies in large patient populations should help determine the benefit/risk ratio of traditional therapy. Regardless of the outcome of these trials, current electrophysiological dogma will have to be re-evaluated and newer concepts evolve for drug development to make further progress. The goal of this symposium is to exchange information among basic and clinical investigators so as to facilitate the emergence of novel electrophysiological concepts that will form the basis for future generations of antiarrhythmic drugs.     

Post-ischemic release of nucleosides and oxypurines in isolated rat hearts. Possible involvement of ventricular fibrillation

Summary In isolated perfused rat hearts global ischemia for 2, 5, and 15 min was produced. Depending on the duration of the ischemia, postischemic reperfusion led to the release of adenosine and its catabolites, and to more or less severe ventricular tachyarrhythmias. When ventricular fibrillation occurred, a highly significant increase in the purine release was observed compared with non-fibrillating hearts. Prevention of fibrillation by antiarrhythmic drugs decreased the purine release in a highly significant way. After only 2 min of ischemia, reperfusion did not lead to ventricular fibrillation. Electrical induction of fibrillation during the reperfusion in these hearts provoked the release of very high amounts of the purine compounds. A similar effect of electrically-induced fibrillation was also obtained in hearts without a previous ischemic period. The findings suggest that ventricular fibrillation is able to induce the release of purine derivatives from the heart.     

Electrophysiologic mechanisms of ventricular arrhythmias

In this work the electrophysiologic mechanisms of ventricular arrhythmias have been briefly summarized. Ventricular arrhytmias can be caused either by pacemaker activity or by reentrant excitation. Enhancement of normal automaticy can generate a parasystolic rhythm in normal fibers. Abnormal automaticity may arise fom fibers in which maximum diastolic potential has been reduced by a variety of interventions. Triggered activity is caused by either an early (EAD) or delayed (DAD) afterdepolarization and requires a prior normal action potential for initiation. While there is growing evidence that EAD-induced triggered activity plays a significant role in the Long QTU syndrome and Torsade de Pointes, no clinical arrhythmias has definitely been ascribed to DADs, although DADs have been recorded in man after acute digoxin intoxication.Ventricular arrhytmias can be also caused by reentrant excitation, which can be subdivided into reflection or circus movement reentry (CMR). In the reflection model impulses in both directions are transmitted over the same pathway. In the CMR three models can be differentiated: the ring model, which requires a fixed anatomical obstacle; the figure-eight model and the leading circle model, where functional rather than fixed anatomical obstacles are involved.Abbreviations AV atrio-ventricular - CMR circus movement reentry - DAD delayed afterdepolarization - EAD early afterdepolarization - ECG electrocardiogram - LV left ventricle - MAP monophasic action potential - MF muscle fiber - PF Purkinje fiber - RV right ventricle - TdP Torsade de Pointes     

氨乙基异硫脲对大鼠离体心脏冠脉结扎后再灌期心律失常与细胞动作电位的作用

用Langendorff方法与微电极技术研究自由基清除剂氨乙基异硫脲(AET)对离体大鼠心脏冠脉结扎后再灌期心律失常与细胞动作电位的作用。AET(0.001～1mmol/L)使室颤和室速发生率明显下降,使正常窦性心律时间增加。浓度为0.01～1mmol/L的AET可使不可逆室颤发生率下降为零。冠脉阻塞再灌损伤使缺血中心区心肌动作电位波形异常,APA,RP,V_(max)各参数下降。AET(0.1mmol/L)可使异常波形动作电位显著减少。     

Should Radiofrequency Therapy Be Performed in Every Symptomatic Patient with Supraventricular Tachycardia? (Pro Drug Position)

The indication for treatment of paroxysmal supraventricular tachycardia depends on the frequency and severity of the tachycardia attacks. If the tachycardia attacks are mildly symptomatic and occur only once or twice a year, there is no indication for either continuous drug therapy or radiofrequency oblation. The only therapeutic measure required is termination of each acute event. If symptoms occur frequently, long-term antiarrhythmic drug therapy is then indicated and will be effective for chronic prophylaxis in most individuals with a low risk of proarrhythmic events. Only in patients with severe or life-threatening symptoms or cases refractory to drug therapy would radiofrequency ablation possibly be justified.     

The effect of chronic atrial overdrive suppression pacing on the incidence of supraventricular tachyarrhythmias.

Chronic overdrive suppression pacing has been suggested as an effective adjunctive method for reducing the incidence of cardiac tachyarrhythmias. Documentation of effectiveness during prolonged monitoring is lacking, however. To assess more accurately the long-term utility of this treatment modality for medically refractory supraventricular tachyarrhythmias (SVTs), 10 patients with atrially implanted Intermedics Intertach pacemakers were randomly assigned to either a low or a high bradycardia (back-up) pacing rate. SVT counts were performed during matching follow-up periods both at the initial rate and after rate crossover. The primary antitachycardia modality of this pacemaker (P mod) provides burst pacing to terminate tachycardia episodes, and P mod counters were utilized to quantitate SVT episodes. Tachycardia termination algorithms were programmed to "no restart" and were not changed during the study. The P mod use counter, therefore, reflected the number of discrete episodes of SVTs. Pacemaker implantation diagnoses include atrial flutter, concealed bypass tract, AV nodal reentry, intraatrial reentry, and Wolff-Parkinson-White associated tachycardia. Patient age was 59 +/- 18 yrs. The average pacemaker back-up low rate was 45.7 +/- 4 versus a back-up high rate of 85.1 +/- 2 beats/min. Follow-up was for 57.4 days +/- 33 days at the low rate and 57.3 days +/- 34 days at the high rate (r = 0.99). There was no difference in SVT incidence with a P mod usage of 98.4 +/- 106 at the low rate and 100.8 +/- 94 at the high rate (p = NS). In this blinded, randomized cross-over trial, chronic atrial overdrive suppression pacing did not reduce the overall incidence of SVT episodes during prolonged monitoring.     

Effects of halothane on arrhythmias induced by myocardial ischaemia

The effect of halothane on arrhythmias induced by ischaemia was investigated in rats, isolated perfused rat hearts, and pigs. Responses to the occlusion of the left anterior descending coronary artery were determined in groups (n = 9) of chronically prepared rats treated with no halothane, 0.5, or 1.0 per cent halothane immediately after occlusion; in isolated rat hearts (n = 10) treated with no halothane, 0.5, 1.0, 2.0, or 4.0 per cent halothane for 15 min before and after occlusion; and 20–25 kg pigs (n = 11) anaesthetised with halothane or pentobarbital. The ECG, arrhythmias, blood pressure (BP), heart rate (HR) and extent of infarction were determined in each model. In pigs, left ventricular pressure, dp/dt_max and cardiac output were also measured. In chronically prepared rats, halothane anaesthesia started after occlusion was antiarrhythmic and decreased the incidence of ventricular fibrillation and resulting mortality. In isolated rat hearts, 0.5 or 1.0 per cent halothane had little effect on occlusion-induced arrhythmias. The highest concentration of halothane increased the incidence of ventricular fibrillation both before and after occlusion. Halothane decreased developed ventricular pressure in a dose-dependent manner. In acutely prepared pigs, halothane pre-treatment had no appreciable effect upon occlusion-induced arrhythmias when compared with pentobarbital anaesthesia. Thus, halothane is antiarrhythmic when treatment is initiated after occlusion in the rat but this action is not seen in isolated hearts or intact pigs. The antiarrhythmic action of halothane is, therefore, species and model dependent.