Mexiletine: Its Role in the Management of Chronic Ventricular Arrhythmias

Mexiletine is a class IB anti arrhythmic agent structurally similar to lidocaine but with the advantage of a high bioavailability and relatively long half-life, making it useful for long-term oral therapy of ventricular arrhythmias. Mexiletine can be used orally or intravenously. Orally, it has a high bioavailability, reaching peak plasma concentration between 2 and 4 hours after administration. The steady-state therapeutic plasma concentration ranges from 0.5 to 2.5 fig/ml. These levels are obtained by doses of 200–300 mg every 6–8 hours. It is mostly metabolized by the liver and its metabolism and excretion are not significantly affected by renal failure. Mexiletine has very few deleterious drug interactions; more importantly, it does not affect digoxin blood levels. Its efficacy in controlling ventricular arrhythmias has been widely studied. The reported success rate varies from 84% to 52%. In our study of patients with symptomatic and refractory ventricular arrhythmias, the success rate with mexiletine was 55% initially and 33% at one year. Mexiletine appears to be most useful in combination with other anti arrhythmic agents such as propranolol, quinidine, procainamide, or amiodarone. Mexiletine has very few cardiac side effects. It was found not to have significant negative inotropic effects even in patients with congestive heart failure. Its major side effects, however, include gastric intolerance. Other less common side effects include central nervous system manifestations. Like all other antiarrhythmics, it can potentially aggravate ventricular arrhythmias in about 10% of patients but in most cases the proarrhythmic effect is not Clin cally significant.     

Propafenone: A New Anti arrhythmic for Treatment of Chronic Ventricular Arrhythmias

Propafenone is a new anti arrhythmic agent with primarily membrane-stabilizing action. Three U.S. controlled double-blind cross-over studies demonstrated the efficacy of propafenone in suppressing ventricular premature complexes (VPCs), including repetitive forms: 67–83% of patients had greater than 80% reduction of VPCs, 62% achieved greater than 90% reduction of couplets and 80%–100% achieved 200% abolition of ventricular tachycardia runs. Other studies showed that propafenone is effective in controlling ventricular arrhythmias refractory to conventional anti arrhythmic agents. Propafenone is at least as effective as these agents. Long-term sustained efficacy of propafenone was shown in some preliminary studies. Because of the variation in individual response to the drug, therapy should be individualized for each patient. Propafenone is well tolerated: side effects of propafenone are few and involve mostly the cardiac conduction system. Propafenone would be a significant addition to the anti arrhythmic armamentarium.     

Ventricular Tachycardia/Ventricular Fibrillation Ablation in the Setting of Ischemic Heart Disease

Recurrent ventricular tachycardia (VT) in the setting of coronary artery disease is frequently a life-threatening electrophysiologic emergency. Even in patients with an implantable defibrillator, recurrent VT is frequently accompanied by repeated and disabling shock therapy. Catheter ablative therapy offers the ability to provide immediate control of recurrent VT. Long-term elimination of VT should be anticipated in most patients. This article reviews the strategies, tools, techniques, and expected outcome for catheter ablation of stable and unstable ventricular arrhythmias in the setting ischemic heart disease.     

Long-Term Clinical Effects and Side Effects of Mexiletine in Patients with Ventricular Arrhythmias

In an investigation designed to study the nature and prevalence of side effects during long-term therapy and the degree of correlation between side effects and the drug serum level, starting in 1975, mexiletine was given to 12 patients for 4 to 128 months with a mean of 56.2 months. The patients were followed according to a strict protocol for the first 18 months of treatment and then returned to routine care. In August 1983, 5 patients had been taking mexiletine for 74 and 96 months (mean 85 months). At the latest follow-up in April 1986, two patients were still on mexiletine therapy after 117 and 128 months of medication, respectively. A third patient died of probable digitalis intoxication just prior to follow-up, having then been on mexiletine for 118 months, Mexiletine was well tolerated and no serious side effects were seen. In particular, there was no rise in antinuclear factor titer. The serum level of mexiletine was easily maintained within the therapeutic range. The cerebral side effects correlated closely with the drug level; the gastrointestinal with the amount of mexiletine per dose. It is concluded that mexiletine can be administered for a long time as a safe alternative to other anti arrhythmic drugs.     

希氏-浦肯野系统和室性心律失常

近期研究提示希氏-浦肯野系统与室性心律失常的发生关系密切。作为左室的特殊传导组织,希氏-浦肯野系统的解剖与电生理特点,使其在正常或病理情况下易于参与折返型心律失常形成。目前资料提示浦肯野系统病变是短联律间期室性早搏相关心律失常和儿茶酚胺敏感性多形性室性心动过速的原因。随着对希氏-浦肯野系统与室性心律失常关系的认识,导管消融可作为此类心律失常的治疗途径。     

Ablation of Ventricular Arrhythmias in Arrhythmogenic Right Ventricular Dysplasia

VT Ablation in Right Ventricular Dysplasia. Arrhythmogenic right ventricular dysplasia (ARVD) is a genetically determined myocardial disease characterized by fibrofatty replacement of the right ventricular wall. Ventricular tachyarrhythmias can be seen in the early stages of the disease, which is one of the most important causes of sudden death in young healthy individuals. Radiofrequency (RF) catheter ablation is an option for the treatment of medically refractory ventricular arrhythmias and it has shown to successfully abolish recurrent ventricular tachycardias (VT) as well as reduce the frequency in defibrillator therapies. However, variable acute and long‐term success rates have been reported. The current mapping and ablation techniques include activation and entrainment mapping during tolerated VT and substrate ablation using 3‐dimensional electroanatomic mapping systems. This article aims at providing a comprehensive review of RF catheter ablation of ventricular arrhythmias in the context of ARVD. (J Cardiovasc Electrophysiol, Vol. 21, pp. 473‐14, April 2010)     

Propagation of Electrical Activity in Ischemic and Infarcted Myocardium as the Basis of Ventricular Arrhythmias

Impulse Propagation in Ischemia. The disturbances in impulse propagation in the heart with regional ischemia and the heart with chronic infarction, which underlie the initiation and perpetuation of arrhythmias, are briefly reviewed. Evidence is presented that reentry is responsible for ventricular tachycardia in both conditions. During acute ischemia, reentrant excitation is characterized by unstable functional reentrant circuits, the properties of which are determined by the changes in transmembrane action potential. Tachycardia is caused by a single unstable reentrant circuit. Fibrillation ensues when a single circuit is broken up into many independent reentrant wavelets. In contrast, ventricular excitation during sustained monomorphic tachycardia in hearts with a healed infarct is characterized by stable reentrant circuits determined by the architecture of surviving myocardial cell bundles within the infarct. In acutely ischemic myocardium, conduction velocity is reduced to about half of the value in normal myocardium, due to the reduced action potential amplitude and upstroke velocity. After about 5–10 minutes ischemic cells become inexcitable at resting membrane potentials of -50 to -60 mV. An important characteristic of ischemic cells is the dependence of the action potential upstroke on cycle length mainly because of the markedly prolonged recovery from inactivation of the fast Na⁺ current in partially depolarized cells. Changes in transmembrane potentials do not occur homogeneously throughout the ischemic zone, and small differences in resting potential (associated with small differences in local K⁺ accumulation) of depolarized cells result in large local differences in refractory periods. The time dependence of refractoriness explains why an increase in sinus rate, or a single premature beat, may produce conduction block at certain sites, and allow conduction in adjacent areas, thus setting the stage for reentry. A decrease in electrical cell-to-cell coupling, which also is a factor in decreasing conduction velocity, only occurs after 15–20 minutes of ischemia. Its role in the type 1B arrhythmias, which coincide with the period when uncoupling begins, remains to be elucidated. The cellular electrophysiology of myocardial cells surviving in the subendocardium of infarcts in human hearts is close to normal. Conduction slowing may be caused by “zigzag” conduction along small bundles that are separated by fibrous tissue, and that merge and divide over small distances. (J Cardiovasc Electrophysiol, Vol. 3, pp. 77–87, February 1992)     

Ventricular Tachycardia in Patients with Impaired Left Ventricular Function: The Role of Propafenone

The combined occurrence of left ventricular dysfunction and -ventricular tachyarrhythmias portends a high annual mortality. Anti arrhythmic drugs can ameliorate ventricular arrhythmia and may reduce the risk of sudden cardiac death. We administered propafenone to 15 patients with ventricular tachyarrhythmias and left ventricular ejection fractions 40%. Propafenone significantly reduced isolated ventricular premature depolarizations, couplets, and ventricular tachycardia on ambulatory monitoring. Propafenone eliminated all exercise provocable ventricular tachycardia. Propafenone additionally abolished ventricular tachycardia inducible by programmed stimulation in 4 of 7 patients. In 8 patients studied before and during therapy, there was no significant change in left ventricular ejection fraction as determined by nuclear ventriculography. Propafenone was discontinued in 4 patients due to side effects. Seven patients receiving continuing propafenone therapy remain alive with only one patient suffering arrhythmia recurrence. Propafenone is an effective drug for the management of ventricular tachyarrhythmias and may be used for patients with impaired left ventricular function.     

Parenteral Antiarrhythmics for Life-Threatening Ventricular Arrhythmias

Parenteral Antiarrhythmics for Ventricular Arrhythmias. The acute management of life-threatening ventricular tachyarrhythmias often includes the use of parenteral antiarrhythmics. There are a number of agents currently available for this purpose. They are used to suppress inducible monomorphic ventricular tachycardia during programmed electrical stimulation, they terminate spontaneous sustained ventricular tachycardia, and prevent ventricular fibrillation in the setting of an acute myocardial infarction. Serious adverse reactions include proarrhythmia, hypotension, severe bradyarrhythmias, and precipitation of congestive heart failure. A comparative evaluation of intravenous antiarrhythmics is difficult due to inherent differences in the choice of agents for study, protocol design, patient population, defined endpoints, and serum drug levels. Likewise, the reported adverse reaction rates vary from 0.4% to 75%. To understand the difficulties in clinical decision-making in this problem area, particularly drug selection, we present here a review of pertinent clinical trials evaluating parenteral drug efficacy and adverse effects.     

Value of Programmed Ventricular Stimulation in Patients with Congenital Heart Disease

INTRODUCTION: The role of programmed ventricular stimulation (VSTIM) for risk stratification in congenital heart disease is unclear. We analyzed the results of VSTIM in selected congenital heart disease survivors at a single center to determine whether it improved the ability to predict a serious outcome. METHODS AND RESULTS: Between July 1985 and September 1996, 140 primary VSTIM studies were performed on 130 patients (median age 18.1 years, range 0 to 51). Tetralogy of Fallot (33 %), d-transposition of the great arteries (25 %), and left ventricular outflow tract obstruction (12%) accounted for the majority of patients. Indications included spontaneous ventricular tachycardia (VT) of > or = 3 beats (72%) and/or symptoms (68%). Sustained VT was induced in 25% of the studies, and nonsustained VT in 12%. Atrial flutter or other supraventricular tachycardia was documented in 32% and bradyarrhythmias in 26%. By univariate analysis, mortality was increased in patients with positive VSTIM versus negative VSTIM (18% vs 7%, P = 0.04). Using multivariate analysis, positive VSTIM was associated with a sixfold increased risk of decreased survival and a threefold increased risk of serious arrhythmic events, allowing up to 87% sensitivity in predicting mortality. However, 7 (33%) of 21 patients with documented clinical VT had false-negative studies. CONCLUSION: VSTIM in a large, selected group of congenital heart disease patients identified a subgroup with significantly increased mortality and sudden arrhythmic events. Failure to induce VT was a favorable prognostic sign, but the frequency of false-negative studies was high. Frequent supraventricular tachycardia further complicated risk stratification. Although VSTIM appears to be a reasonable tool for evaluation of this population, a larger, multicenter trial is recommended to clarify its utility.     

Antiarrhythmic Drug Therapy for Ventricular Arrhythmias: Current Perspectives

Antiarrhythmic Drug Therapy. Pharmacologic therapy for ventricular arrhythmias has undergone a remarkable change recently. Recognition of the importance of underlying structural heart disease on prognostic implications of ventricular arrhythmias has resulted in the refinement of the clinical classification of these arrhythmias. With refinement of techniques of risk stratification, it is now possible to identify patients with ventricular arrhythmias at high risk for sudden death. Retrospective analyses of prior antiarrhythmic drug trials and new data from prospective randomized trials are now available and can more directly define the risks and benefits of antiarrhythmic therapy. Prevention of sudden death, reduction in total mortality, or improvement in symptoms remain the only benefits of antiarrhythmic drugs. With inclusion of total mortality as the major endpoint for assessment of pharmacologic interventions in high-risk patients, the potential for excess mortality due to antiarrhythmic agents is now recognized. The pharmacologic diversity of newly released antiarrhythmic agents and others under development has resulted in a re-evaluation of the traditional classification of these drugs. Multiple ongoing clinical trials will define the risks and benefits of antiarrhythmic therapy and other nonpharmacologic interventions in patients with ventricular arrhythmias.     

器质性心脏病室性心动过速的导管消融进展

器质性室性心动过速绝大多数是折返性机制。激动顺序、拖带和舒张期电位仍然有价值,而非接触式标测等新技术提供了较强大的标测手段。然而,消融的能量和效能仍然是制约成功率的主要因素。心外膜标测、盐水冲洗大头和冷凝消融具有潜在的价值。     

The Effect of Acute Versus Delayed Remote Ischemic Preconditioning on Reperfusion Induced Ventricular Arrhythmias

Remote Ischemic Preconditioning and Cardiac Arrhythmias. Introduction: The effect of remote ischemic preconditioning (RIPC) on arrhythmias in in vivo models is unknown. Our purpose was to determine effects of both acute and delayed RIPC on arrhythmias. Methods and Results: In the acute protocol anesthetized open chest rats were exposed to 5 minutes of proximal left coronary artery occlusion (CAO) and 10 minutes of reperfusion. Rats were either untreated (ischemia/reperfusion, IR group, n = 17) or received RIPC (n = 14) with 5 minutes bilateral femoral occlusions followed by 5 minutes of reperfusion times 3, started 30 minutes before CAO. At reperfusion, onset of ventricular tachycardia (VT) was delayed in RIPC group (25.7 seconds) versus IR (8.8 seconds; P = 0.04). Number of episodes of VT was 17.0 in IR versus 3.0 in the RIPC group (P = 0.01) and duration of VT was 54.1 seconds in IR versus 4.9 seconds in RIPC (P = 0.019). Number of ventricular premature complexes (VPC) was 26.0 in IR and 10.0 in RIPC rats (P = 0.04). Levels of reperfusion injury salvage kinases (RISK), that is, phospho‐Akt and phospho‐p70S6 in the risk area of IR and RIPC hearts were similarly higher compared to the nonischemic areas both at 1 and 10 minutes into reperfusion. Delayed RIPC was induced on day 1 and on day 2, myocardial IR was induced. Delayed RIPC did not affect VT or VPC. Conclusion: Acute RIPC of the lower limbs induced a powerful delay in/and reduction in IR induced ventricular arrhythmias, but without evoking the RISK pathway; a late protective phase of RIPC on arrhythmias did not occur. (J Cardiovasc Electrophysiol, Vol. 23, pp. 1374‐1383, December 2012)     

Coronary Venous Mapping and Catheter Ablation for Ventricular Arrhythmias

Catheter ablation is an effective treatment method for ventricular arrhythmias (VAs). These arrhythmias can often be mapped and targeted with ablation from the left and right ventricular endocardium. However, in some situations the VA site of origin or substrate may be intramural or epicardial in nature. In these cases, the coronary venous system (CVS) provides an effective vantage point for mapping and ablation. This review highlights situations in which CVS mapping may be helpful and discusses techniques for CVS mapping and ablation.     

Mode of Onset of Malignant Ventricular Arrhythmias in Idiopathic Ventricular Fibrillation

Mode of Onset of Idiopathic VF. Introduction : The mode of onset of malignant ventricular arrhythmias (ventricular tachycardia [VT] or ventricular fibrillation [VF] has been well described in patients with organic heart disease and in patients with the long QT syndromes. Less is known about the mode of onset of VF in patients with out-of-hospital VF who have no evidence of organic heart disease or identifiable etiology.
Methods and Results : We reviewed the ECGs of all our patients with Idiopathic VF. Documentation of the onset of spontaneous arrhythmias was available for 22 VK episodes in 9 patients (6 men and 3 women; age 41 ± 16 years). In all instances, spontaneous VF followed a rapid polymorphic VT, which was initiated by premature ventricular complexes (PVCs) with very short coupling intervals. The PVC initiating VF had a coupling interval of 302 ± 52 msec and a prematurity index of 0.4 ± 0.07. These PVCs occurred within 40 msec of the peak of the preceding T wave. Pause-dependent arrhythmias were never observed.
Concltision : Cardiac arrest among patients with idiopathic VF has a very distinctive mode of onset. Documentation of a polymorphic VT that is not pause dependent is of diagnostic value.     

Prevention of Recurrent Life-threatening Ventricular Arrhythmias by Temporary Cardiac Pacing

ABSTRACT Overdrive pacing has been applied in 26 patients to prevent frequent recurrent ventricular fibrillation (VF) and ventricular tachycardia (VT) occurring in the setting of ventricular extrasystole of 2–5 degrees graded by Lown. These patients had 3–47 recurrent attacks of VF and VT (11.4±2.4) which were not prevented with antiarrhythmic agents. Overdrive pacing was continued for 2–236 hours (21.3±3.7) and appeared to be effective in 23 (88.4%) of the 26 patients including those with prolonged QT intervals. Atrial pacing was more effective than ventricular overdriving and required stimulation at a slower rate. Antiarrhythmic therapy and overdrive pacing in combination were more effective than both used independently. Suppression of ventricular extrasystole and prevention of life-threatening arrhythmias were achieved by increasing the heart rate by 23.2±4.5 beats/min.