Propafenone in the treatment of patients with malignant ventricular tachyarrhythmias.

This study was conducted to determine the value of propafenone in patients with resistant malignant ventricular arrhythmias. Forty patients with either sustained ventricular tachycardia (n = 34) or primary ventricular fibrillation (n = 6), who had failed an average of four previous drug trials, were studied prospectively. The mean age was 68 years. Thirty-five had had a previous infarction, and left ventricular ejection fractions ranged from 14 to 57% (mean 36%). Noninvasive evaluation, consisting of ambulatory monitoring and exercise testing, was used to guide therapy in 12 patients, and invasive electrophysiological study was employed in the other 28. The initial daily dose was 450 mg, and electrocardiographic intervals were used to titrate the dose upward to a maximum of 900 mg per day or to tolerance. Five of the 12 noninvasively studied patients had complete abolition of ventricular tachycardia salvos. Only five of the 28 patients were rendered noninducible, but another four had adequate rate slowing with good hemodynamic tolerance of their arrhythmias. In an additional six patients, the addition of a second antiarrhythmic drug produced supplemental rate slowing. Side effects occurred in 30 patients and necessitated drug withdrawal in 13. The most serious adverse effects were congestive heart failure (in eight patients, and three withdrawn) and proarrhythmia (in four patients, and all withdrawn). The 20 patients with an adequate response were discharged on propafenone. During a mean follow-up of 12 months, there have been three cardiac deaths, one of which was sudden, and three recurrences of sustained ventricular tachycardia. Efficacy and side effects did not correlate with dose or degree of increase in electrocardiographic intervals.(ABSTRACT TRUNCATED AT 250 WORDS)

Effectiveness of propranolol added to a type I antiarrhythmic agent for sustained ventricular tachycardia secondary to coronary artery disease.

The effect of adding propranolol to procainamide, quinidine, propafenone or disopyramide was prospectively evaluated in 37 patients, all with prior infarction and inducible ventricular tachycardia (VT). After showing that VT remained inducible during therapy with a type I drug, 23 patients received intravenous propranolol. The ventricular effective refractory period, prolonged by the type I agent, was further increased by propranolol. The cycle length of the VT also increased after the type I drug and propranolol exaggerated this effect. Seven of the 23 patients were rendered noninducible after propranolol and another 10 manifested a greater than 100 ms increase in induced VT cycle length. In the other 14 patients, propranolol was infused immediately after the basal study. If VT remained inducible, testing was repeated after a type I drug was added. The ventricular effective refractory period, as well as the VT cycle length, increased after propranolol and was further prolonged after the addition of a type I agent. Seven of these 14 patients were rendered noninducible, 3 with propranolol alone and 4 others with the combination, and in 4, the VT cycle length was prolonged by greater than 100 ms. A total of 17 patients were discharged on either propranolol alone (3 patients) or on an effective combination (14 patients). During a mean follow-up of 20 months, 1 patient died suddenly, 2 had recurrence of well-tolerated VT and 9 remain on therapy. Thus, propranolol has a demonstrable antiarrhythmic effect in the invasive laboratory and may supplement the antiarrhythmic efficacy of conventional type I antiarrhythmic drugs.

Acute electrophysiologic effects and antiarrhythmic/antifibrillatory activity of intravenous amiodarone in a chronic feline infarction model.

In animal studies, amiodarone has substantial and immediate antiarrhythmic/antifibrillatory action during acute myocardial ischemia. The magnitude of this effect is discordant with the minor degree of prolongation of ventricular action potential duration (APD) and refractoriness which occurs immediately after acute drug administration. However, amiodarone's early onset of antiadrenergic activity and inhibition of inward slow calcium channel currents may be important when arrhythmogenesis is dependent on increased sympathetic tone. Because ventricular arrhythmia substrate may differ in acute and chronic ischemic heart disease, we investigated the acute electrophysiologic and antiarrhythmic/antifibrillatory effects of intravenously (i.v.) administered amiodarone in nine chronically infarcted cats. Amiodarone caused significant decreases (-17%) in mean heart rate (HR) and increases (+10%) in mean ventricular effective refractory period (ERP), which occurred promptly after drug administration. Increases in mean ventricular fibrillation (VF) threshold also occurred (11 +/- 3.4 and 12.5 +/- 2.4 mA for right and left ventricular sites before drug as compared with 45.5 +/- 13.2 and 42 +/- 13.9 mA after drug). Despite these changes, no significant reduction in the incidence of malignant ventricular arrhythmias induced by programmed stimulation was noted (63% of animals with arrhythmia induced before drug were still inducible after drug). In addition, no change in the increased degree of mean dispersion of refractoriness between infarcted and normal myocardial sites occurred following amiodarone (22.8 +/- 3.9 ms before vs. 30.2 +/- 2.5 ms after drug). In chronic myocardial infarction without superimposed acute ischemia, early onset of amiodarone's antiadrenergic and calcium channel blocking activities may play only a minor role in preventing ventricular arrhythmias inducible by programmed stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of beta-adrenergic blockade on vulnerability to ventricular fibrillation and inducibility of ventricular arrhythmia in short- and long-term feline infarction models.

Previous investigation, predominantly in the short-term canine model, has documented a potent antifibrillatory effect of beta-adrenergic blockade. To determine whether the protection afforded by beta blockade is species- and model-specific, we studied 23 chloralose-anesthetized cats. Eight animals were studied over a short term and underwent serial determinations of the ventricular fibrillation (VF) threshold prior to and 1 minute after occlusion of the left anterior descending coronary artery (LAD) and immediately following reperfusion of a 10-minute occlusion. Beta-blocking doses of intravenous propranolol (P) (0.5 mg/kg) attenuated the fall in VF threshold during acute ischemia. Increasing the dose of P to 1 mg/kg did not provide further protection, nor did P protect against reperfusion VF. The other 15 animals underwent a preliminary surgical procedure during which the LAD was completely and irreversibly occluded (nine animals) or in which a sham procedure was performed (six animals). Two weeks later, we measured ventricular refractoriness at several left ventricular sites, ventricular inducibility using programmed electrical stimulation, and VF thresholds both before and after administration of intravenous P (1 mg/kg). Ventricular refractory periods in the infarcted zones were significantly increased compared with normal sites and with values obtained in sham-operated animals. In addition, VF thresholds in the infarcted animals were lower than those obtained in the sham-operated group. Before treatment, a reproducible sustained ventricular tachyarrhythmia was induced by means of programmed stimulation in seven of the nine chronically infarcted animals but in none of the sham-operated animals (p less the 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of thromboxane inhibition on vulnerability to ventricular fibrillation in the acute and chronic feline infarction models.

Inhibition of the enzyme that synthesizes thromboxanes may protect against the development of ventricular fibrillation (VF) during acute myocardial ischemia. This study was carried out to test this hypothesis with a new thromboxane synthetase inhibitor, and to extend the studies to alternative animal models of myocardial infarction. In a series of acute experiments, 19 cats were pretreated with 10 mg/kg of U-63557A (a dose that produced greater than 75% reduction in thromboxane B2 [TxB2] levels) or saline before abrupt left anterior descending coronary artery occlusion. Seven of the nine control animals suffered spontaneous VF associated with a 77% fall in VF threshold compared with the treated animals, of which 2 of 10 had spontaneous VF and in which VF threshold fell by only 45% (p less than 0.025). Despite a similar extent of TxB2 inhibition in another set of nine animals, U-63557A failed to protect against a fall in VF threshold during coronary reperfusion. Finally, chronic changes in VF threshold and inducibility of sustained ventricular tachycardia by programmed stimulation were assessed in a group of eight animals. The lowering of VF threshold and inducibility of ventricular tachycardia seen in the control state were not influenced by treatment with U-63557A. Thus protection against infarct-related VF by TxB2 inhibition is a property shared by more than one pharmacologic agent. Arrhythmias generated by reperfusion or induced in a more chronic setting may not be thromboxane-dependent. These results have important implications for the planning of studies designed to assess the antiarrhythmic potential of drugs that inhibit thromboxane synthesis.

Electrophysiologic effects of left ventricular hypertrophy in the intact cat.

Electrophysiologic abnormalities have been described in isolated, hypertrophied left ventricular tissue removed from animals exposed to a chronic pressure load. However, changes in electrical properties of intact hypertrophied hearts have not been described. To study this question, 15 cats underwent supraventricular aortic banding and five underwent a sham procedure. After ten weeks, the animals were anesthetized and instrumented using paired transmural plunge electrodes and endocardial quadripolar pacing catheters. Measurement of pacing threshold, refractoriness, inducibility of ventricular arrhythmias (using programmed electrical stimulation), and vulnerability to ventricular fibrillation (ventricular fibrillation threshold) were made in both groups. Mean left ventricular mass was significantly greater in the banded compared with sham-operated animals (2.5 +/- 0.9 v 2.1 +/- 0.5 g/kg body weight; P less than .05). Pacing thresholds and refractory periods measured at multiple left and right ventricular sites were similar in both groups, and there was no difference in the extent of site-to-site differences in refractoriness (dispersion). Six banded but no sham animals had inducible ventricular tachycardia or fibrillation using programmed stimulation. Furthermore, left ventricular mass was significantly greater in animals with inducible arrhythmias compared with those noninducible (P less than .05). Ventricular fibrillation thresholds, measured in milliamperes (mA), in the banded animals were significantly lower in the left ventricle (13.5 +/- 1.3 mA) than in the right (21.7 +/- 3.2 mA; P less than .05) and was also lower than the thresholds obtained in either the left or right ventricle of the sham-operated animals (18.3 +/- 1.9 mA and 20.1 +/- 1.1 mA, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Diagnosis and treatment of cardiac rhythm disorders in the elderly.

The elderly patient is susceptible to a variety of cardiac rhythm disturbances that may or may not cause symptoms. It is incumbent on the physician who cares for geriatric patients to have a familiarity with the diagnostic criteria for each of these arrhythmias and with the drugs and devices that are used to treat them. This includes the potential adverse effects of therapy and methods to counter them. Even more important is a sense of when to intervene, which is based, in large measure, on a knowledge of "normal variation" in the aged.

Safety and efficacy of amiodarone. The low-dose perspective.

Amiodarone has been reported to be a remarkably safe and effective drug in the European and South American experience but American investigators have published conflicting data. Since this disparity may be explained by a different dosing schedule, we prospectively evaluated the safety and efficacy of a low dose regimen in a group of 68 patients with cardiac arrhythmia resistant to conventional therapy, of whom 57 had manifested either ventricular tachycardia or fibrillation. All were loaded either intravenously (17) or orally, and maintained on an oral dose of 200 to 600 mg/day (mean daily dose 317 +/- 114 mg) and followed for 4 to 58 months (22 +/- 11). Results indicated that amiodarone was a safe and effective antiarrhythmic drug when used in lower doses.

Effect of antiarrhythmic drugs on defibrillation threshold: case report of an adverse effect of mexiletine and review of the literature.

Antiarrhythmic agents can influence defibrillation threshold (DFT). Basic research suggests that some class I drugs may have deleterious effects by raising defibrillation energy requirements. Evaluation of this problem in man has been limited to reports of patients who were more difficult to cardiovert or defibrillate after treatment with amiodarone and class IC agents. In the present report, mexiletine appeared to be the probable cause of an important elevation of DFT in a patient undergoing replacement of a malfunctioning automatic implantable cardioverter/defibrillator (AICD). This report and the accompanying literature review suggest that more information at both the basic and clinical levels is required. Retesting of device efficacy in terminating induced arrhythmia in the laboratory appears prudent in patients who require antiarrhythmic drug therapy subsequent to AICD implantation.

Role of permanent pacemakers in the pharmacologic therapy of patients with reentrant tachyarrhythmias.

Improved pacemaker technology has permitted application in more diverse groups of patients. A more recently described subset appears to be those with reentrant tachycardias treatable with antiarrhythmic drugs. Here, pacing offers the ability both to test the efficacy of a drug regimen and to provide adjunctive "fail-safe" therapy for those with episodic breakthrough. With the advent of more sophisticated devices, especially those with cardioversion/defibrillation capability, we anticipate a growing interest in these applications which will undoubtedly benefit patients.

Nitrous oxide anesthesia in patients with ischemic chest discomfort: effect on beta-endorphins.

Relief of discomfort during acute myocardial ischemia is usually accomplished with a narcotic analgesic. Because these medications may cause unpleasant symptoms and exert a possibly adverse hemodynamic effect, the availability of alternative analgesic medication would be advantageous. Nitrous oxide is a commonly used potent analgesic gas. Nitrous oxide has been used to relieve ischemic discomfort during myocardial infarction. The current study was undertaken to corroborate that data in a randomized, blinded, cross-over study and to begin to explore a mechanism for the analgesic effect. Twelve patients with typical ischemic chest discomfort and a suspected myocardial infarction were included in the study. Each patient received a 30-minute inhalation treatment of 30% nitrous oxide/70% oxygen and 30 minutes of 30% room air/70% oxygen. Patients were blinded to their treatment and were randomized to receive nitrous oxide first, then room air, or vice versa. A semiquantitative assessment of the severity of chest discomfort was made before, during, and at the conclusion of each treatment together with a measurement of plasma beta-endorphin levels using a venous blood sample. Eleven of the 12 patients reported a significant reduction in the intensity of their chest discomfort during the nitrous oxide inhalation, but none had pain relief during the control period. Beta-endorphin levels fell to a greater extent during the inhalation of nitrous oxide than during the control period (51% versus 26%; P less than .05). No significant adverse effects were noted and most patients slept during the nitrous oxide inhalation. It is concluded that nitrous oxide anesthesia is a superior method of pain relief in patients with ischemic heart disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of calcium-binding additives on ventricular fibrillation and repolarization changes during coronary angiography.

Ventricular fibrillation during coronary angiography with Renografin-76 (meglumine sodium diatrizoate) has been attributed to the calcium-binding additives sodium citrate and sodium ethylenediaminetetraacetic acid (EDTA), which may produce repolarization changes manifested as prolongation of the QT interval. Angiovist-370 is a newer form of meglumine sodium diatrizoate that contains calcium EDTA as its additive and thus has a decreased calcium-binding effect. Eight hundred sixteen patients were prospectively randomized to receive either Renografin-76 or Angiovist-370. Ventricular fibrillation occurred in 10 of 410 patients receiving Renografin-76 and in 0 of 406 patients given Angiovist-370 (p less than 0.0005). Clinical data were analyzed without knowledge of other data in the 10 patients treated with Renografin-76 who had ventricular fibrillation (Group I), 103 randomly selected patients who also received Renografin-76 but had no ventricular fibrillation (Group II) and 108 randomly selected patients given Angiovist-370 (Group III). Of several variables examined, only the QT interval differentiated patients receiving Renografin-76 and Angiovist-370. The mean corrected QT interval (QTc interval) before coronary angiography was slightly but not significantly (p = 0.7) higher in Group I than in Groups II and III. Ten seconds after the first left coronary artery injection it was more prolonged in Groups I and II (0.552 and 0.561 second, respectively) than in Group III (0.448 second) (p less than 0.00005). Similarly, 10 seconds after the first right coronary artery injection it was significantly longer in Groups I and II (0.545 and 0.544 second) than in Group III (0.477 second) (p less than 0.00005).(ABSTRACT TRUNCATED AT 250 WORDS)

Electrophysiology of beta blockers in supraventricular arrhythmias.

beta-adrenergic blocking agents are efficacious in the treatment of patients with a variety of supraventricular tachycardias, based directly on their capacity to counter the effects of beta-adrenergic stimulation on sinus and atrioventricular nodal tissue. Specifically, beta blockers depress sinus node automaticity and inhibit atrioventricular nodal function by prolonging refractoriness and slowing conduction. Supraventricular arrhythmias that depend on these structures either for perpetuation or for conduction to the ventricles are predictably sensitive to beta blockade. These arrhythmias include sinus tachycardia, sinoatrial reentrant, atrioventricular nodal reentrant (dual pathway) and atrioventricular reciprocating (concealed bypass tract) tachycardias, as well as atrial flutter and fibrillation. beta blockers may also be used, in selected patients, to inhibit catecholamine-facilitated accessory pathway function by prolonging refractoriness. beta blockers offer particular clinical advantages, including an acceptable side-effect profile, titratable effect, varied pharmacology and reasonable concordance between efficacy of parenteral and oral dosage forms. The key element in the most effective use of these drugs appears to be an accurate arrhythmia diagnosis that allows for the most appropriate application of a reliable treatment form.

Value of electrophysiologic testing in patients with nonsustained ventricular tachycardia.

This study was undertaken to determine the value of electrophysiologic testing in 61 patients with nonsustained ventricular tachycardia (VT) (3 or more beats) on ambulatory monitoring and no history of sustained ventricular arrhythmia. The study group consisted of 38 patients with coronary artery disease (CAD), 9 with idiopathic dilated cardiomyopathy and 14 with a normal heart. Nonsustained VT (at least 3 but not more than 15 beats) was induced in 46%, sustained VT (more than 15 beats) in 15% and no VT in 39%. Sustained VT was induced more frequently in the presence of left ventricular dysfunction (p = 0.005) but was not related to the presence of CAD. Over a mean follow-up of 26 months, 10 patients died from cardiac causes (4 suddenly), including 1 patient with inducible sustained VT, 2 with nonsustained VT and 7 with no inducible VT. Inducibility was not related to survival, either as a single variable or when combined with CAD, left ventricular dysfunction or recent myocardial infarction. Left ventricular function alone was a good predictor of outcome. Of 46 patients with an ejection fraction of 35% more or in New York Heart Association functional class I or II, 3 (7%) died from cardiac causes, compared with 7 of 13 patients (54%) with an ejection fraction of less than 35% or in functional class III or IV (p = 0.0001). Thus, in patients with nonsustained VT, the incidence of sustained VT during electrophysiologic testing is low and is related to the degree of left ventricular dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)

Pacing-induced angina pectoris and induction of ventricular arrhythmias in coronary artery disease.

Ischemia caused by rapid pacing during electrophysiologic study could facilitate induction of ventricular arrhythmias. The results of extrastimulation were retrospectively analyzed in 32 patients with coronary artery disease (CAD) without a history of symptomatic arrhythmia. These patients were studied at cardiac catheterization for angina pectoris refractory to medical therapy. Eleven patients (group I) had typical angina during trains of rapid right ventricular pacing (repeated trains of 8 stimuli [mean cycle length (CL) 473 +/- 47 ms]) but were asymptomatic during slower trains (CL 800 +/- 100 ms). Twenty-one patients (group II) had no symptoms with either rapid (CL 448 +/- 51 ms) or slow (CL 688 +/- 105 ms) trains, despite comparable left ventricular function, CAD severity and medication. Effective refractory periods (S1S2) after rapid drive were shorter in group I than in group II patients (225 +/- 9 vs 240 +/- 14 ms, p less than 0.002), but refractory periods during slow pacing were similar (251 +/- 12 vs 253 +/- 17 ms, difference not significant). No patient in either group had sustained arrhythmia (more than 15 beats) induced by single and double ventricular extrastimuli, decrementally applied at the right ventricular apex. The number of extra beats provoked in group I when rapid trains caused angina (4.3 +/- 3.6) was similar to that induced by extra-stimulation after slower pacing without angina (4.4 +/- 3.5) and to that obtained with rapid or slow pacing in group II (3.1 +/- 3.3 and 2.8 +/- 2.2).(ABSTRACT TRUNCATED AT 250 WORDS)