Proarrhythmic effects of antiarrhythmic drugs in patients with malignant ventricular arrhythmias evaluated by electrophysiologic testing.

The provocation or worsening of arrhythmias by antiarrhythmic regimens was evaluated in patients with malignant ventricular arrhythmias undergoing electrophysiologic studies. In 314 patients with sustained or nonsustained ventricular tachycardia or ventricular fibrillation, 801 drug studies were performed using a standard protocol of programmed electrical stimulation. The criteria for proarrhythmia were: 1) initiation of sustained ventricular tachyarrhythmia in a patient in whom only nonsustained tachycardia was induced at baseline; 2) conversion of a sustained tachycardia that could be terminated by programmed electrical stimulation at baseline to one that required cardioversion for termination during drug therapy; 3) initiation of a sustained tachyarrhythmia by a less aggressive mode of stimulation than was required at baseline; and 4) development of spontaneous or incessant ventricular tachycardia. Proarrhythmia criterion 1 occurred during 20 (18%) of 118 studies and at least once in 15 (28%) of 54 patients. Criterion 2 was met during 39 (7%) of 578 studies and at least once in 29 (13%) of 220 patients. Criterion 3 was achieved during 135 (20%) of 687 studies in patients with sustained ventricular tachyarrhythmias at baseline. Criterion 4 occurred during 9 (1%) of 801 drug studies. In 40 patients in whom well tolerated ventricular tachycardia was initiated with fewer extrastimuli during drug study than at baseline, the drug was continued and the patients were followed up. The recurrence rate of tachycardia was the same in these patients as in 73 patients followed up on regimens on which the number of extrastimuli required for initiation was not reduced.(ABSTRACT TRUNCATED AT 250 WORDS)

Electrophysiologic testing in patients at high risk for sudden cardiac death. I. Nonsustained ventricular tachycardia and abnormal ventricular function.

Nonsustained ventricular tachycardia, although usually asymptomatic, is associated with a high risk of sudden cardiac death in patients with depressed left ventricular function. To test the vulnerability of such patients to symptomatic and potentially life-threatening arrhythmias, complete electrophysiologic studies were performed in 58 patients with clinically documented nonsustained ventricular tachycardia (greater than or equal to three complexes but less than 15 seconds of self-terminating ventricular tachycardia by 24 hour ambulatory electrocardiographic [Holter] or telemetric monitoring) and abnormal left ventricular function (ejection fraction less than 50% by radionuclide angiography). All patients had nonsustained ventricular tachycardia in the absence of antiarrhythmic drugs, acute ischemia, long QT syndrome, recent infarction or electrolyte abnormalities. The stimulation protocol for each patient included the introduction of single, double and triple ventricular extrastimuli at three cycle lengths (sinus, 600 and 450 ms) and two right ventricular sites (apex and outflow tract). A sustained ventricular tachyarrhythmia was induced in 23 patients (40%) and a nonsustained ventricular tachycardia in 14 patients (24%). Induction of sustained tachycardia correlated with the presence of akinesia or aneurysm, or both, by radionuclide angiography, but not with ejection fraction or presence or absence of coronary artery disease. These results indicate that: 1) patients with clinical nonsustained ventricular tachycardia and chronic left ventricular dysfunction have a high incidence of inducible sustained ventricular tachycardia or ventricular fibrillation; and 2) electrophysiologic testing may allow further substratification of risk of sudden cardiac death in high risk patients with nonsustained ventricular tachycardia.

Utility of ambulatory electrocardiographic monitoring for predicting recurrence of sustained ventricular tachyarrhythmias in patients receiving amiodarone.

The prognostic implications of changes in ventricular ectopic activity on serial 24 hour ambulatory electrocardiographic (Holter) recordings were prospectively evaluated in 107 patients with a history of sustained ventricular tachyarrhythmias treated with amiodarone for at least 30 days. Twenty-seven patients (25%) had insufficient ventricular ectopic activity (less than 10 ventricular premature complexes/h and no repetitive forms) on baseline Holter recordings for serial statistical analysis. In 53 (66%) of the remaining 80 patients, serial 24 hour Holter monitor recordings showed efficacy of treatment, defined as a 75% decrease in ventricular premature complexes, a 95% decrease in ventricular couplets and absence of ventricular tachycardia. During a mean follow-up period of 14.2 +/- 9.9 months, 34 (32%) of the 107 patients had recurrence of a sustained ventricular tachyarrhythmia. Holter recording correctly predicted nine recurrences and correctly identified 37 patients who did not experience a recurrence. Holter efficacy failed to predict recurrence of a sustained ventricular tachyarrhythmia in 16 patients, and 18 patients remained free of recurrence despite failure to achieve Holter efficacy. The positive predictive value of Holter monitoring efficacy was 33% and the negative predictive value was 70%; however, these differences were not statistically significant by chi-square analysis. Similar results were obtained using Holter recordings performed relatively early in therapy (6 weeks and 4 months). Of the 27 patients without significant ventricular ectopic activity on the baseline Holter recording, 9 had an arrhythmia recurrence despite continued infrequent ventricular premature complexes and no repetitive forms on subsequent recordings. The recurrence rate in this group (33%) was similar to the overall recurrence rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Limitations of failure of procainamide during electrophysiologic testing to predict response to other medical therapy.

To determine whether failure of procainamide to prevent initiation of ventricular tachyarrhythmias during electrophysiologic testing predicted failure of other antiarrhythmic regimens, 81 consecutive patients with coronary artery disease whose ventricular tachyarrhythmias remained inducible during procainamide administration were studied. Overall, 26 (12%) of 216 subsequent drug studies were successful and at least one effective drug regimen was identified in 22 (27%) of the 81 patients. Drug success was significantly related to the arrhythmia induced at baseline study; 7% of drug studies were successful in patients with sustained ventricular tachycardia, 24% in patients with ventricular fibrillation, and 29% in patients with nonsustained ventricular tachycardia. An effective drug regimen was found in 11 (19%) of 59 patients with sustained ventricular tachycardia, 4 (50%) of 8 patients with ventricular fibrillation and 7 (50%) of 14 patients with nonsustained ventricular tachycardia. In patients with sustained ventricular tachycardia, failure of procainamide to suppress the arrhythmia correlated with failure of other agents used singly but not in combination. This study supports the view that when procainamide fails to prevent initiation of the arrhythmia in patients with inducible sustained ventricular tachycardia it is unlikely that other individual standard agents will be effective. However, combination regimens may suppress the arrhythmia and should be evaluated. In patients with nonsustained ventricular tachycardia, all agents should be evaluated because failure to respond to procainamide does not predict subsequent responses to other agents either alone or in combination.

Plasma norepinephrine in exercise-induced ventricular tachycardia.

The relation between plasma norepinephrine levels and the occurrence of ventricular tachycardia during exercise testing was prospectively evaluated in 17 patients. Ten patients had reproducible ventricular tachycardia exclusively during exercise or recovery, or both; 7 patients had ventricular tachycardia only during ambulatory electrocardiographic monitoring. The two groups did not differ in age, exercise duration, left ventricular ejection fraction at rest, heart rate throughout the exercise protocol, rest QTc interval, change in QTc interval during exercise, the presence of coronary artery disease or exercise-related myocardial ischemia. Furthermore, there was no difference between groups in plasma norepinephrine levels at rest, peak exercise or in the recovery period. Myocardial ischemia was detectable by thallium perfusion scan in only 2 of the 10 patients with exercise-induced ventricular tachycardia. The 10 patients with exercise-induced ventricular tachycardia underwent repeat exercise testing immediately after maximal intravenous beta-adrenergic blockade with propranolol. Although they had no change in exercise duration, ventricular tachycardia did not occur in 9 of these 10 patients. Plasma norepinephrine levels were significantly decreased compared with levels before beta-adrenergic blockade (p less than 0.0002). Thus, plasma norepinephrine levels do not distinguish patients with reproducible exercise-induced ventricular tachycardia from otherwise comparable patients. Propranolol is highly effective in abolishing this arrhythmia and this effect is associated with decreased norepinephrine levels.

Acylated streptokinase--plasminogen complex in patients with acute myocardial infarction.

BRL 26921 is the p- anisoyl derivative of the primary streptokinase-human plasminogen complex in which the acyl group is specifically located at the catalytic centre of the enzyme. Doses of BRL 26921 ranging from 5 mg to 25 mg were given intravenously or into a coronary artery to 12 patients with acute myocardial infarction. The complex was well tolerated and produced no serious bleeding. Coronary artery reperfusion was demonstrated angiographically in three patients. In most patients, fibrinogen, plasminogen, alpha 2 antiplasmin and alpha 2 macroglobulin levels fell and the level of fibrinogen degradation products increased acutely post treatment indicating systemic fibrinolytic activation. The degree of this activation was variable but was profound in some. It appeared to be dose related and modified by the presence of streptokinase antibodies. BRL 26921 appears less "selectively" thrombolytic in patients than had been expected from animal models.

Placebo-controlled evaluations of propafenone for atrial tachyarrhythmias.

This review summarizes the results of placebo-controlled trials of propafenone, a class IC antiarrhythmic drug, in patients with supraventricular tachycardia, atrial fibrillation (AF), and atrial flutter. Success rates for cardioversion from AF or flutter to sinus rhythm of 9-93% have been obtained with intravenous propafenone. The duration of arrhythmia is an important factor in the degree of success. The use of a single oral dose has also been reported to be effective in a number of studies. Several placebo-controlled studies have confirmed the effectiveness of propafenone in the long-term suppression of both suproventricular tachycardia and AF and flutter. These reported trials have shown consistent benefit with propafenone compared with placebo in preventing arrhythmia recurrence. The adverse side effect profile for propafenone has also been reviewed with particular reference to the potential for proarrhythmia. The rate of side effects is dose-dependent and tends to be higher in patients with underlying structural heart disease. Overall propafenone has been shown to be an effective antiarrhythmic drug with an acceptable side effect profile for the acute and long-term treatment of supraventricular arrhythmias.

Electrophysiologic assessment of antiarrhythmic drug efficacy for ventricular tachyarrhythmias associated with dilated cardiomyopathy.

To determine the benefit of serial electrophysiologic drug testing in patients with ventricular tachyarrhythmias related to dilated cardiomyopathy, programmed ventricular stimulation was performed in 38 patients. In the baseline study, sustained ventricular tachycardia (VT) was induced in 18 patients, ventricular fibrillation in 7 and nonsustained VT in 13. The patients underwent a total of 84 trials of drug therapy (mean 2.3 +/- 1.4 trials/patient). Complete success (induction of fewer than 6 repetitive responses) was recorded in 19 trials and partial success (induction of at least 6 but no more than 15 repetitive responses) in 7. Potential proarrhythmic effects were observed in 9 trials. Overall, at least 1 successful regimen was identified for 20 patients (53%). During a mean follow-up of 21 +/- 13 months, there were no arrhythmia recurrences or episodes of sudden death among patients discharged with a drug regimen determined to be effective by serial drug testing. In comparison, among patients taking regimens that failed to prevent arrhythmia induction, there were 3 arrhythmia recurrences and 2 sudden deaths (p less than 0.05). Serial electrophysiologic drug testing provides an effective method of identifying successful medical therapy for patients with ventricular arrhythmia related to dilated cardiomyopathy.

Proarrhythmic responses during electrophysiologic testing.

Antiarrhythmic drugs may worsen ventricular arrhythmias in certain patients. This effect, termed proarrhythmia, aggravation or provocation of arrhythmia, can be investigated with either noninvasive or invasive techniques. Using electrophysiologic study, 160 patients with ventricular tachycardia or ventricular fibrillation were evaluated during treatment with 432 different antiarrhythmic regimens. Proarrhythmic responses were noted in 68 drug trials (16%), and at least 1 event was observed in 51 patients (32%). Nonsustained ventricular tachycardia was converted to sustained ventricular tachycardia in 17% of these studies. Hemodynamically stable ventricular tachycardia was converted to an arrhythmia that required cardioversion for termination in 5% of the studies. Ventricular tachyrhythmia was more easily induced in 12% of trials. These proarrhythmic responses were not related to changes in QRS duration, QT interval or JT interval measured at baseline or to changes produced by antiarrhythmic drugs.

Antiarrhythmic drug efficacy for ventricular tachyarrhythmias associated with coronary artery disease as assessed by electrophysiologic studies.

The efficacy and proarrhythmic potential of antiarrhythmic agents were evaluated. Programmed ventricular stimulation was performed in 160 consecutive patients with coronary artery disease during a baseline study and 432 subsequent drug studies. The tachyarrhythmias induced during baseline studies were sustained ventricular tachycardia (121 patients), ventricular fibrillation (16 patients), and symptomatic nonsustained ventricular tachycardia (23 patients). Regimens were completely successful if fewer than 6 repetitive ventricular responses were inducible during therapy and partially successful if no more than 15 repetitive ventricular responses were inducible. Procainamide and quinidine were the most successful single agents, with overall success rates of 24% and 35%, respectively. Either procainamide or quinidine combined with mexiletine was the most successful combination (overall success of 23%). Each anti-arrhythmic regimen showed a proarrhythmic potential. The incidence of proarrhythmic effects ranged from 4 to 13%, with no significant difference between regimens. In 13% of patients at least 1 regimen produced a proarrhythmic effect. Patients treated with an antiarrhythmic regimen that prevented induction of arrhythmia had significantly fewer arrhythmia recurrences than patients treated with a regimen that failed to prevent it. In conclusion, identification of an effective drug regimen is possible in 38% of patients with lethal ventricular arrhythmias, proarrhythmic effects occur in a significant number of patients during electrophysiologic testing of antiarrhythmic regimens, and the clinical outcome in patients in whom ventricular arrhythmias are not inducible with ventricular stimulation have a better prognosis than those in whom arrhythmias continue to be inducible on therapy.

Efficacy of combination therapy with mexiletine and a type IA agent for inducible ventricular tachyarrhythmias secondary to coronary artery disease.

The efficacy of combination therapy using a type IA agent (quinidine or procainamide) and a type IB agent (mexiletine) in suppressing inducible sustained ventricular tachyarrhythmias was studied in 23 patients undergoing serial drug testing with programmed stimulation. All patients had coronary artery disease (CAD) with previous myocardial infarction and abnormal left ventricular function (mean ejection fraction 35%). Fifty-five percent of the patients presented with syncope or cardiac arrest. In 19 patients therapy had failed during empiric trials of 1 to 3 antiarrhythmic agents. All 23 patients had inducible sustained ventricular tachyarrhythmias (18 had uniform morphology sustained ventricular tachycardia (VT) and 5 had ventricular fibrillation [VF]) during control electrophysiologic study, and therapy had failed with a type IA agent and mexiletine alone. The combination therapy of mexiletine and the type IA agent prevented induction of any ventricular tachyarrhythmias in 8 of 23 patients. In 15 patients, the combination significantly prolonged the tachycardia cycle length and reduced the symptoms associated with the induced arrhythmia. Patients more likely to respond to the combination had shorter cycle lengths and polymorphic configuration of the control-induced arrhythmia. The increased efficacy of the combination therapy could not be attributed to higher plasma drug levels for the combination, as there was no significant difference in plasma levels for each drug when given alone or in combination. Thus, the increased efficacy most likely reflects a synergistic electropharmacologic effect of the 2 agents.(ABSTRACT TRUNCATED AT 250 WORDS)

Usefulness of electrophysiologic testing in evaluation of amiodarone therapy for sustained ventricular tachyarrhythmias associated with coronary heart disease.

The prognostic importance of electrophysiologic studies in patients with sustained ventricular tachyarrhythmias treated with amiodarone was prospectively studied in 100 consecutive patients. Sustained ventricular tachycardia (VT)/ventricular fibrillation (VF) was inducible in all patients before amiodarone therapy. After amiodarone administration 2 groups of patients were identified. In group 1 patients the ventricular tachyarrhythmia was no longer inducible and in group 2 patients the arrhythmia remained inducible. In group 1, no recurrent arrhythmia occurred during a follow-up of 18 +/- 10 months. In group 2, 38 of 80 patients (48%) had arrhythmia recurrence during a follow-up of 12 +/- 9 months. The difference between group 1 and 2 could not be explained by clinical variables, amiodarone doses or plasma concentrations, or electrocardiographic variables. In patients in whom cardiovascular collapse or other severe symptoms where noted during electrophysiologic study after amiodarone treatment, recurrences caused sudden death (n = 12). However, in patients in whom the induced arrhythmia produced moderate symptoms, the recurrent arrhythmia was nonfatal VT (n = 26). Electrophysiologic testing provides clinical guidance and predicts prognosis in patients treated with amiodarone as it does for the evaluation of other antiarrhythmic agents.

Electrophysiological effects of felodipine in combination with metoprolol.

The combined use of some beta-adrenoceptor blocking agents with calcium channel blockers may cause adverse pharmacodynamic drug interactions: hypotension, heart block or even asystole may be precipitated. The electrophysiological effects of combined administration of intravenous metoprolol 10mg and the vasodilating calcium antagonist felodipine (0.1 mg/kg/bodyweight) were assessed in an open study by invasive methods. Following metoprolol, the heart rate was reduced from 69 +/- 24 to 60 +/- 16 beats/min (mean +/- SD, p less than 0.05) with a minor prolongation of the sinus node recovery time. The A-H interval was increased from 94 +/- 25 to 109 +/- 16 msec (p less than 0.005) and the H-V interval was unchanged. The effective refractory period of the atrioventricular node was prolonged from 327 +/- 54 to 361 +/- 62 msec (p less than 0.01) with a minor prolongation of the effective refractory period of the ventricular Purkinje fibres. Systolic and diastolic blood pressures showed a mean reduction of 11 (p less than 0.001) and 6mm Hg (p less than 0.05), respectively. Following felodipine, the changes in heart rate and effective refractory periods of the atrioventricular node and ventricular Purkinje fibres returned towards control values. No further prolongation of the A-H interval resulted and further blood pressure changes were minor. The absence of adverse haemodynamic or electrophysiological effects suggests that this combination of agents may be safely used.

Bacterial endocarditis involving a subaortic membrane.

A subaortic membrane predisposes to bacterial endocarditis usually affecting the aortic valve and left ventricular outflow tract. Endocarditis involving the subaortic membrane itself has been described twice only; once at operation and once at postmortem. The case of a man with vegetations involving a subaortic membrane that were detected preoperatively and the echocardiographic appearances of these findings are reported.

Coronary artery spasm leading to life threatening arrhythmias.

A 39 year old woman sustained life threatening arrhythmias associated with coronary artery spasm. On both occasions she was attending hospital outpatient clinics and was successfully resuscitated. Electrocardiography performed during further episodes of pain suggested that spasm could occur in either the right or left coronary artery.

Use of fax facility improves decision making regarding thrombolysis in acute myocardial infarction.

BACKGROUND: Electrocardiography is the fundamental investigation for decision making regarding thrombolytic treatment in acute myocardial infarction (MI). Increasing the accuracy of ECG analysis by input from consultant staff may assist in management decisions in patients with suspected MI. AIMS: To evaluate a system whereby out of hours ECGs can be faxed to the consultant to aid in decision making regarding thrombolytic treatment. METHODS: 112 patients with suspected MI were assessed on admission by the senior house officer (SHO) who faxed to a cardiology consultant the ECG trace and a predesigned form with information on: clinical assessment of the patient; interpretation of the ECG; and views regarding administration of thrombolytic treatment including choice of agent. The consultant reviewed the information and communicated his views to the SHO. Subsequent diagnosis was recorded in all patients and the forms were analysed in regard to areas of agreement and disagreement between the SHO and the consultant. RESULTS: A diagnosis of MI was confirmed in 52 of the 112 patients (46.4%). The consultant agreed with the SHO's decision on thrombolysis in 98 patients (87.5%). The reason for disagreement in the remaining 14 patients (12.5%) was SHO misinterpretation of the ECG (10 patients) and clinical assessment (four patients). Eight patients were saved unnecessary thrombolytic treatment and four received it when they otherwise would not have. Additionally the choice of thrombolytic agent was changed in six patients from streptokinase to tissue plasminogen activator. CONCLUSION: The use of fax machine assists in decision making with regard to thrombolytic treatment and provides support to junior doctors in what can be a difficult, yet critical decision.

Proarrhythmic responses during electrophysiologic testing.

Proarrhythmia is a potentially lethal adverse effect of antiarrhythmic drugs. Underlying mechanisms and the approaches to identification are discussed. The applicability of electrophysiologic testing is considered, with particular reference to the validity of the different responses to programmed stimulation considered to be manifestations of proarrhythmia. The incidence of proarrhythmia in relation to individual antiarrhythmic agents is also reviewed.

Chemical cardioversion of atrial fibrillation with intravenous dofetilide.

We studied the effects of two active dose levels of dofetilide (8 and 12 micrograms/kg) and placebo in 16 patients with recent onset atrial fibrillation. The study was of a crossover design such that all patients received a therapeutic agent, 15 patients completed the study. Cardioversion was achieved in 2/6 patients receiving 8 micrograms/kg dofetilide and in 2/9 patients receiving 12 micrograms/kg. No patients cardioverted as a result of the placebo infusion. Two patients who cardioverted suffered episodes of torsades de pointes following the active drug. Electrical cardioversion was attempted in eight patients who remained in atrial fibrillation and was successful in six. The average duration of atrial fibrillation was 35 days in those who cardioverted and 83 days in those who did not. The compound appears to have only limited effect in cardioversion of atrial fibrillation of moderate duration.

Quantification of aortic regurgitation using continuous and pulsed wave Doppler echocardiography.

In a prospective blind study, continuous and pulsed wave Doppler echocardiography were used to predict the severity of angiographically assessed aortic regurgitation in 36 patients. High quality continuous wave spectral recordings of the regurgitant jet were obtained in 32 patients but four patients with mild aortic regurgitation had dropout of high velocity signals precluding accurate assessment. The deceleration slope of the peak to end-diastolic velocity measured by continuous wave Doppler, and pulsed wave Doppler mapping of the regurgitant jet in the left ventricle were compared with angiographic severity. The deceleration slope was significantly steeper in patients with severe rather than mild or moderate aortic regurgitation (3.65 +/- 1.04 vs. 1.89 +/- 0.42 vs. 1.52 +/- 0.59 m sec-2). A decay slope of greater than 3 m sec-2 was observed only in patients with 3+ or 4+ aortic regurgitation and a decay slope less than 1.2 m sec-2 was seen only in mild 1+ aortic regurgitation but there was considerable overlap between groups, making it difficult in individual cases to assess severity on the basis of the continuous wave deceleration slope. The pulsed wave Doppler technique was more time consuming, added little to the continuous wave Doppler assessment and underestimated severe regurgitation in almost 50% of cases. Hence, there are significant problems using either Doppler technique in quantitatively assessing aortic regurgitation.

Pacing termination of spontaneous ventricular tachycardia in the coronary care unit.

We reviewed our experience with the use of pacing techniques in the acute treatment of spontaneous ventricular tachycardia occurring outside the context of acute myocardial ischaemia. Over a consecutive 18 month period 23 patients (20 male, aged 38-76 yr) admitted to our coronary care unit experienced a total of 75 episodes of haemodynamically tolerated sustained ventricular tachycardia. Pace termination was attempted in 18 patients in a total of 58 episodes of ventricular tachycardia using a standard temporary external pacemaker. Pacing was successful in 32/58 (55%) attempts vs 13/49 (27%) with intravenous antiarrhythmic drug therapy p = 0.003. The superior success rate of pacing was apparent whether or not patients were receiving chronic antiarrhythmic drug therapy. Pace termination should be considered in the treatment of haemodynamically tolerated spontaneous ventricular tachycardias.