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.

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.

Role of endogenous opioids and catecholamines in vasovagal syncope.

Head-up tilt testing demonstrates vasovagal mechanisms as a cause for syncope, but the pathophysiology underlying this condition remains unclear. The aim of this study was (i) to measure plasma beta-endorphins, adrenocorticotrophic hormone, cortisol, catecholamines, and brain natriuretic peptide during head-up tilt, and (ii) to assess the effect of naloxone infusion during head-up tilt in subjects with reproducible vasovagal syncope. During the assessment of unexplained syncope, 71 subjects underwent a total of 93 tilt tests (60-70 degrees head upwards for 40-45 min or until syncope occurred) during which frequent blood sampling was performed. Subjects with a positive tilt test (n = 56) (mean duration to syncope 23.6 min) showed a larger rise in beta-endorphin levels prior to syncope (baseline 4.7 +/- 2.2 vs syncope onset 6.9 +/- 3.2 pmol.l-1, P = 0.0001) than those with a negative test (n = 37) (baseline 3.9 +/- 3.9 vs end of test 4.9 +/- 2.3 pmol.l-1, P = 0.03). During tilting, adrenocorticotrophic hormone, cortisol, and noradrenaline increased; adrenaline and brain natriuretic peptide remained unchanged; and these responses were similar in positive and negative test groups. Naloxone (2.6 mg.kg-1 i.v. bolus followed by 20 micrograms.kg-1.min-1 infusion), administered in a double-blind fashion during head-up tilt in nine subjects, failed to modify either the time to syncope or the vasodepressor response. Thus, endogenous opioids appear not to be an important trigger for vasovagal syncope, and other pathophysiological mechanisms should be considered.

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.

Effects of the new class III antiarrhythmic drug dofetilide on the atrial and ventricular intracardiac monophasic action potential in patients with angina pectoris.

The class III antiarrhythmic drug dofetilide is known to prolong action potential duration by specific blockade of the delayed rectifier potassium channel Ik. As dofetilide is likely to be used in the treatment of atrial arrhythmias it is important to determine the relative sensitivity of the atrium and ventricle in man. Twelve male patients underwent monophasic action potential and refractory period recordings from the high right atrium and right ventricular septum. The patients received either 8 micrograms.kg-1 dofetilide or placebo intravenously. The mean QTc was prolonged by 11% (SD 5%, P < 0.00001) in the active group; the mean monophasic action potential increased by 31% (SD 15%, P < 0.0005) in the atrium and 27% (SD 9%, P < 0.00005) in the ventricle; the mean effective refractory period increased by 30% (SD 16%, P < 0.0005) in the atrium and 20% (SD 6%, P < 0.0001) in the ventricle. No significant change occurred in the placebo group. There was no significant difference in effect between the two chambers. The change in QTc did not accurately reflect acute changes in refractory period or monophasic action potential duration. This has important implications for the use of QT prolongation to assess the acute effect of class III drugs.

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.

Pre-dosing antibody levels and efficacy of thrombolytic drugs containing streptokinase.

OBJECTIVE: To evaluate the influence of pretreatment streptokinase resistance titre and the concentration of IgG antibodies to streptokinase on the efficacy of thrombolytic drugs containing streptokinase in restoring coronary patency in acute myocardial infarction. DESIGN: Comparative observational study. SETTING: City general hospital. PATIENTS: One hundred and twenty four previously unexposed patients presenting within six hours of onset of acute myocardial infarction. INTERVENTIONS: Streptokinase, 1.5 MIU as intravenous infusion over 60 minutes (60 patients), or anistreplase, 30 units as intravenous injection over five minutes (64 patients). MAIN OUTCOME MEASURES: Pretreatment streptokinase resistance titre and concentration of IgG antibodies to streptokinase were measured in 96 and 124 patients respectively and coronary patency assessed angiographically at 90 minutes and 24 hours. RESULTS: Pretreatment streptokinase resistance titre and concentrations of IgG antibodies to streptokinase were low and skewed towards higher values. Those patients with coronary occlusion at 24 hours had a significantly higher median streptokinase resistance titre (100 v 50 streptokinase IU ml-1, P = 0.02). There were trends towards a higher streptokinase resistance titre in those patients with coronary occlusion at 90 minutes (50 v 20 streptokinase IU ml-1, P = 0.06) and higher concentrations of IgG antibodies to streptokinase in those with coronary occlusion at both 90 minutes and 24 hours (1.53 v 0.925, P = 0.03; 1.65 v 1.04 micrograms streptokinase binding ml-1, P = 0.06). Coronary patency rates were similar in the two treatment groups. CONCLUSIONS: In the range measured in previously unexposed patients the streptokinase resistance titre has a small, but significant, negative influence on the efficacy of streptokinase and anistreplase. This effect should be considered if retreatment with streptokinase or anistreplase is proposed.

Increase in plasma beta endorphins precedes vasodepressor syncope.

BACKGROUND: Endogenous opioids have a tonic inhibitory effect on sympathetic tone and have been implicated in the pathophysiology of vasodepressor syncope. Plasma beta endorphin concentrations increase after vasodepressor syncope induced by exercise or by fasting. AIMS: To take frequent samples for plasma beta endorphin estimation during tilt testing, and to determine whether plasma beta endorphin increased before the start of syncope. PATIENTS: 24 patients undergoing tilt testing for investigation of unexplained syncope. SETTING: Tertiary referral centre. METHODS: Blood samples were obtained during 70 degrees head up tilt testing. Plasma beta endorphin concentrations were estimated by radioimmunoassay (mean(SD) pmol/l). RESULTS: Patients with a positive test showed a rise in beta endorphin concentrations before syncope (baseline 4.4(1.5) v start of syncope 8.5(3.1), p < 0.002). In contrast, patients with a negative test showed no change in beta endorphin concentrations (baseline 3.4(1.0) v end of test 4.5(2.3), NS). After syncope all patients showed a large secondary increase in beta endorphins (32.3(18.6)). CONCLUSION: An increase in plasma beta endorphins precedes vasodepressor syncope. This finding supports a pathophysiological role for endogenous opioids.

Increase in plasma beta endorphins precedes vasodepressor syncope.

BACKGROUND: Endogenous opioids have a tonic inhibitory effect on sympathetic tone and have been implicated in the pathophysiology of vasodepressor syncope. Plasma beta endorphin concentrations increase after vasodepressor syncope induced by exercise or by fasting. AIMS: To take frequent samples for plasma beta endorphin estimation during tilt testing, and to determine whether plasma beta endorphin increased before the start of syncope. PATIENTS: 24 patients undergoing tilt testing for investigation of unexplained syncope. SETTING: Tertiary referral centre. METHODS: Blood samples were obtained during 70 degrees head up tilt testing. Plasma beta endorphin concentrations were estimated by radioimmunoassay (mean(SD) pmol/l). RESULTS: Patients with a positive test showed a rise in beta endorphin concentrations before syncope baseline 4.4(1.5) v start of syncope 8.5(3.1), p < 0.002). In contrast, patients with a negative test showed no change in beta endorphin concentrations (baseline 3.4(1.0) v end of test 4.5(2.3), NS). After syncope all patients showed a large secondary increase in beta endorphins (32.3(18.6)). CONCLUSION: An increase in plasma beta endorphins precedes vasodepressor syncope. This finding supports a pathophysiological role for endogenous opioids.

Failure to reproduce the in vitro cardiac electrophysiological effects of naloxone in humans.

1. Opioid receptor antagonists such as naloxone have shown antiarrhythmic activity in animal models of coronary artery occlusion. Studies have indicated that these effects are stereospecific but both isomers of naloxone prolong action potential duration and refractoriness in guinea-pig and rabbit isolated ventricular myocardium (Class III effect). 2. This study was performed to identify whether this Class III effect of naloxone could be reproduced in human myocardium in vivo. Twenty patients with coronary artery disease received intravenous racemic naloxone (1-40 micrograms kg-1 min-1). Surface electrocardiographic parameters were measured and refractory periods were determined during fixed rate pacing by programmed stimulation. 3. The corrected QT interval during sinus rhythm (SR-QTc) was prolonged by 5(3)% (P = 0.06) at a dose of 20 micrograms kg-1 min-1 and by 9(10)% at 40 micrograms kg-1 min-1 (P = 0.03). These small changes were lost at higher paced heart rates. No significant effects on atrial, atrioventricular nodal or ventricular refractoriness were seen. 4. Plasma naloxone concentrations well into the micromolar range were achieved with both of the higher doses of naloxone administered. Plasma beta-endorphin concentrations invariably increased following naloxone infusion. There was no statistical relationship between peak plasma naloxone concentrations and the absolute or percent prolongation of SR-QTc. 5. It seems unlikely that racemic naloxone would have any clinical utility as an antiarrhythmic agent. Racemic naloxone may enhance cardiac adrenergic nerve activity and this receptor mediated effect may have prevented the demonstration of any nonreceptor mediated prolongation of cardiac refractoriness. Studies with the individual stereoisomers of naloxone would be of interest.

Assessment by general practitioners of suitability of thrombolysis in patients with suspected acute myocardial infarction.

OBJECTIVE: To assess the clinical ability of general practitioners to decide to give thrombolytic therapy to patients with suspected myocardial infarction and to assess the contribution of the electrocardiograph (ECG) to this decision-making process. SETTING: 7 practices on the North side of Glasgow and the coronary care unit of Stobhill General Hospital. SUBJECTS: 137 patients presenting with chest pain who required direct admission to the coronary care unit. MAIN OUTCOME MEASURES: Agreement between the general practitioner's clinical decision to give thrombolytic therapy with or without reference to the ECG and the prescription of thrombolytic therapy in the coronary care unit. RESULTS: The predictive accuracy of the general practitioner's assessment of the necessity for thrombolytic therapy was 71.5%. The ECG had no impact on the accuracy of this decision and there were problems with the recording and interpretation of the ECG. Clinical decision making was altered in six cases by the ECG: wrongly in four. CONCLUSION: The diagnostic accuracy among general practitioners would result in some patients who did not have acute myocardial infarction being given thrombolytic therapy. In this study the ECG did not contribute towards diagnostic accuracy. Substantial improvement in both the recording and interpretation of ECGs is needed before thrombolytic agents can be routinely prescribed at home.

Management of paroxysmal atrial fibrillation.

Paroxysmal atrial fibrillation is a common, poorly understood and difficult-to-treat arrhythmia. Although it tends to be treated in a similar fashion to chronic atrial fibrillation, its pathophysiology is different, and drugs commonly used for chronic atrial fibrillation may have only limited value in treating paroxysmal atrial fibrillation. A broad range of presenting clinical symptoms may be associated with this arrhythmia, and even in the asymptomatic patient, there may be a risk of serious thromboembolic events. In symptomatic patients, effective control of paroxysms with antiarrhythmic therapy can often be difficult, and the role of anticoagulation remains controversial. This review attempts to clarify these issues, by surveying the range of therapies available.

The incidence and mechanism of hypotension following thrombolytic therapy for acute myocardial infarction with streptokinase-containing agents--lack of relationship to pretreatment streptokinase resistance.

The incidence, amplitude, mechanism and relationship to prior exposure to streptococcal antigen of blood pressure changes to streptokinase-containing thrombolytic agents were investigated in 125 patients treated with either 1.5 x 10(6) IU streptokinase over 60 min or 30 U anistreplase over 5 min, within 6 h of onset of acute myocardial infarction. Twenty-one of 52 patients with anterior and 34 of 73 with inferior myocardial infarction had a hypotensive response. There were no significant differences in the incidence, duration or amplitude of hypotension between the two treatment groups. The maximum mean fall in systolic blood pressure was 16.9 mmHg (95% confidence limits, CL 12.2 to 24.5 mmHg), and the maximum mean fall in diastolic blood pressure was 13.7 mmHg (CL 10.3 to 17.1 mmHg), starting 4 min after start of therapy and resolving within 34 min. Blood pressure changes were well tolerated. Hypotension was not related to pretreatment streptokinase resistance titre, or anti-SK IgG concentration, to changes in plasma fibrinogen, B-beta 15-42 peptide, D-dimer--as indices of thrombin activation and fibrin (-ogen) breakdown--to plasma viscosity. The blood pressure changes following treatment with streptokinase-containing thrombolytic agents in acute myocardial infarction are frequent but well tolerated. The mechanism of hypotension remains unclear, but is not related to prior exposure to streptococcal antigen.

Acceleration of ventricular response to atrial flutter after intravenous adenosine.

Adenosine may be of therapeutic and diagnostic value in the emergency management of arrhythmias. It causes transient atrioventricular nodal block and thus ends paroxysmal supraventricular tachycardias that involve the atrioventricular node. Also, it may uncover underlying atrial arrhythmias by slowing the ventricular response. Its duration of action is brief and serious adverse effects have not been reported. A 12 year old patient with atrial flutter is presented, in whom intravenous adenosine was followed by acceleration of the heart rate to a potentially dangerous arrhythmia.

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.

Monitoring of streptokinase resistance titre in acute myocardial infarction patients up to 30 months after giving streptokinase or anistreplase and related studies to measure specific antistreptokinase IgG.

OBJECTIVE: To examine the induction of antistreptokinase antibodies after giving streptokinase or anistreplase to patients with acute myocardial infarction. DESIGN: Patients were randomly allocated to receive either 1.5 x 10(6) IU, streptokinase or 30U anistreplase in a double blind study. Blood samples were collected immediately before treatment and subsequently at intervals up to 30 months; plasma samples were assayed for streptokinase resistance titre (functional assay) and streptokinase binding by IgG (microradioimmunoassay). SETTING: Cardiology department in a general hospital. PATIENTS: 128 consecutive eligible patients. Samples were collected for up to one year according to a prospective design: a subsection of 47 patients was selected for intensive study over the first 14 days. After one year, all available patients (67) were sampled on one further occasion. RESULTS: Antibody responses to streptokinase and anistreplase were similar. Streptokinase resistance titres exceeded pretreatment concentrations five days after dosing, and values peaked at 14 days. By 12 months after dosing, 92% of resistance titres (n = 84) had returned to within the pretreatment range. Antistreptokinase IgG concentrations also exceeded baseline concentrations within five days and peaked at 14 days. Half of the individual values had returned to within the pretreatment range by 12 months (n = 84) and 89% by 30 months (n = 18). CONCLUSION: Although we cannot be sure of the clinical significance, because of the increased likelihood of resistance due to antistreptokinase antibody, streptokinase and anistreplase may not be effective if administered more than five days after an earlier dose of streptokinase or anistreplase, particularly between five days and 12 months, and increased antistreptokinase antibody may increase the risk of allergic-type reactions.