Predictors of early and late recurrence of atrioventricular accessory pathway conduction after apparently successful radiofrequency catheter ablation.

The correlation between electrophysiologic parameters and recurrence in 239 patients who underwent successful catheter ablation for an accessory pathway mediated tachycardia was analysed. Pathway conduction recurred in 15 patients (6.3%) after a mean follow-up of 7.3 months. Recurrence was most common in patients with right free wall pathways (17.1%). Accessory pathway conduction resumed in 18.9% of patients with decremental ventriculo-atrial (VA) conduction post-ablation compared with those patients without VA conduction (3.4%) (P < 0.001). Recurrence was common also in patients with repeated return of accessory pathway conduction during the ablation procedure (40% vs. 1.3%, P < 0.01). The patients in whom these observations are made should be monitored closely for recurrence of accessory pathway conduction post-ablation.

Influence of implantable cardioverter-defibrillators on the long-term prognosis of survivors of out-of-hospital cardiac arrest.

BACKGROUND: Survivors of out-of-hospital cardiac arrest not associated with acute myocardial infarction are at high risk for recurrent cardiac arrest and sudden cardiac death. The impact of the implantable cardioverter-defibrillator on long-term prognosis in these patients is uncertain. METHODS AND RESULTS: Three hundred thirty-one survivors of out-of-hospital cardiac arrest (age, 56 +/- 13.7 years) underwent electrophysiologically guided therapy. Implantable defibrillators were placed in 150 patients (45.3%), and 181 patients (54.7%) received pharmacological and/or surgical therapy alone. Left ventricular ejection fraction was 35.2 +/- 16.6% in defibrillator recipients and 45.3 +/- 18.2% in nondefibrillator patients. Median patient follow-up was 24 months in the defibrillator group and 46 months in the nondefibrillator group. In a proportional hazards model, the independent predictors of total cardiac mortality were left ventricular ejection fraction of less than 0.40 (relative risk, 4.55; 95% confidence interval, 2.44 to 8.33; P = .0001), absence of an implantable defibrillator (relative risk, 2.70; confidence interval, 1.41 to 5.00; P = .017), and persistence of inducible sustained ventricular tachycardia (relative risk, 1.84; 95% confidence interval, 0.97 to 3.49; P = .045). The 1- and 5-year probabilities of survival free of cardiac mortality in patients with left ventricular ejection fraction of less than 0.40 were 94.3% and 69.6% with a defibrillator and 82.1% and 45.3% without a defibrillator, respectively. For patients with left ventricular ejection fraction of 0.40 or more, the 1- and 5-year probabilities of survival free of cardiac mortality were 97.7% and 94.6% with a defibrillator and 95.4% and 86.9% without a defibrillator, respectively. CONCLUSIONS: In survivors of out-of-hospital cardiac arrest, the implantable defibrillator is associated with a reduction in cardiac mortality, particularly in patients with impaired left ventricular function.

Prospective evaluation of day-to-day reproducibility of upright tilt-table testing in unexplained syncope.

To evaluate the day-to-day reproducibility of upright tilt-table testing, 109 patients with unexplained syncope prospectively underwent testing on 2 consecutive days using a uniform protocol. Results of testing on 2 separate days were concordant in 69 of 109 patients (63%), and discordant in 40 of 109 patients (37%). Thirty-six of 109 patients (33%) had vasodepressor syncope on 1 or both days of testing. Nineteen of 30 patients (63%) with vasodepressor responses on the first day did not reproduce this response during the second day of testing. An additional 6 patients with an initial negative tilt test had a vasodepressor response on the second day. Only 11 of 36 patients (31%) had reproducible vasodepressor responses on both days of testing. Patients with reproducible vasodepressor responses had a significantly higher mean number of preceding clinical syncopal events than patients with 2 normal tests (p < 0.02) or nonreproducible results (p < 0.04). In addition, these patients had a significantly longer duration of clinical symptoms relative to patients with 2 tests that yielded negative results (p < 0.008) and nonreproducible results (p < 0.01). The elapsed time between the most recent clinical event and the performance of tilt-table testing was not significantly different among the 3 groups, and did not appear to influence the outcome of testing. These data show that vasodepressor responses elicited by upright tilt-table testing show day-to-day variability in many patients, a finding that may limit the interpretation of initial and follow-up test results.

Low energy conversion of atrial fibrillation in the sheep.

OBJECTIVES: In this study, the feasibility, efficacy and safety of low energy internal atrial cardioversion were investigated in a sheep model. The relation between the level of energy used for atrial defibrillation and the probability of successful cardioversion was examined. BACKGROUND: Atrial fibrillation is a common clinical arrhythmia that frequently recurs after termination with high energy external cardioversion. In some patients with drug-refractory and poorly tolerated atrial fibrillation, an automatic implantable cardioverter may prove useful by providing rapid restoration of sinus rhythm. METHODS: In 16 pentobarbital-anesthetized sheep, a right atrial spring electrode was implanted percutaneously and a left thoracic cutaneous patch electrode was placed on the thorax. Sustained atrial fibrillation was induced by rapid atrial pacing and terminated by biphasic cathodal shocks synchronized to the R wave of the surface electrocardiogram (ECG). RESULTS: During 768 defibrillation attempts in 16 sheep, the percent of successful cardioversion attempts increased in a dose-response manner, reaching a plateau at the average energy level of 5 J. With greater than or equal to 1.5 and greater than or equal to 2.5 J energy levels, cardioversion was achieved, respectively, in greater than 50% and greater than 80% of attempts. Ventricular fibrillation occurred in 18 (2.4%) of 768 cardioversion attempts; in all 18 cases, the shock was poorly synchronized with the ECG R wave. CONCLUSIONS: Low energy cardioversion of atrial fibrillation to sinus rhythm is feasible with use of a right atrial spring/cutaneous patch electrode configuration. The percent of successful cardioversion attempts depends on the level of energy output, and there is a risk of ventricular fibrillation if cardioversion is poorly synchronized with ventricular depolarization.

Electrophysiologic response to moricizine in patients with sustained ventricular arrhythmias.

OBJECTIVE: To assess the short-term efficacy and safety of moricizine in patients receiving electrophysiologically guided therapy for sustained ventricular arrhythmias refractory to treatment with class IA antiarrhythmic agents. DESIGN: Uncontrolled clinical trial. SETTING: Referral-based teaching medical center. PATIENTS: Twenty-one patients (18 of whom had coronary artery disease) with a mean left ventricular ejection fraction of 32% +/- 11% who presented with sustained ventricular tachycardia (13 patients), syncope (4 patients), or cardiac arrest (4 patients). INTERVENTIONS: Moricizine, 743 +/- 85 mg daily. MEASUREMENTS: Electrophysiologic testing in the drug-free state and after administration of moricizine unless sustained arrhythmias occurred. MAIN RESULTS: Sustained ventricular tachycardia was inducible in the absence of antiarrhythmic drugs in 20 patients and was not suppressed by moricizine in any patient. Four patients had six episodes of spontaneous ventricular tachycardia while receiving moricizine. A probable proarrhythmic response occurred in four patients. CONCLUSION: In patients with compromised left ventricular function caused by coronary artery disease in whom class IA antiarrhythmics were ineffective, moricizine was ineffective in suppressing sustained ventricular arrhythmias and resulted in proarrhythmic effects in some patients.

Lack of plasma interleukin-1 beta or tumor necrosis factor-alpha elevation during unfavorable hemodialysis conditions.

Plasma interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) were determined by ELISA in 17 healthy controls, 23 HD patients, 10 continuous ambulatory peritoneal dialysis patients, and 15 chronic renal failure patients, as well as in 2 HD patients experiencing pyrogenic reactions. Another group of 10 chronic HD patients were dialyzed for 2.5 h, 5 with first-use Cuprophan membranes and 5 with first-use high-flux cellulose triacetate membranes. The mean bacterial and endotoxin concentrations of the dialysate used for HD treatments during the study period were 18,440 +/- 530 CFU/mL (mean +/- SEM) and 976 +/- 205 pg/mL, respectively. Blood specimens were obtained intradialysis and postdialysis for cytokine assay and were incubated to augment cytokine production. There was no difference in plasma IL-1 beta or TNF-alpha concentrations among the healthy controls, continuous ambulatory peritoneal dialysis patients, chronic renal failure patients, or HD patients. Neither cytokine increased significantly during or after HD. Two patients experiencing pyrogenic reactions had plasma TNF-alpha concentrations of 537 and 413 pg/mL, compared with matched controls of 6 and 0 pg/mL. Il-1 beta concentration did not differ from controls. We conclude that: (1) plasma IL-1 beta and TNF-alpha are not chronically elevated in chronic renal failure, continuous ambulatory peritoneal dialysis, or HD patients; (2) HD with new Cuprophan or cellulose triacetate membranes and high concentrations of dialysate endotoxin and bacteria does not cause elevation of circulating IL-1 beta or TNF-alpha; and (3) pyrogenic reactions might be mediated by TNF-alpha.

Enhanced release of TNF-alpha, but not IL-1 beta, from uremic blood after endotoxin stimulation.

Aberrant immunologic host defenses associated with uremia may be a cause of the high incidence of sepsis in chronic hemodialysis (CHD) patients. This investigation determined the cytokine response of blood from five nondialyzed chronic renal failure (CRF) patients, five CHD patients, and five healthy controls (HC) after in vitro stimulation with 1 ng/ml Escherichia coli 0113 endotoxin. Concentrations of the cytokines TNF-alpha and IL-1 beta were determined by ELISA and were similar in all baseline and unspiked samples. TNF-alpha concentrations in CRF and CHD spiked samples were similar to each other but significantly greater (p less than 0.01) than in HC spiked samples. IL-1 beta concentrations in CRF, CHD, and HC-spiked samples were not significantly different. We conclude that CRF and CHD patients have enhanced TNF-alpha response, which may be related to uremia and not dialysis-related factors. Uremia does not potentiate IL-1 beta release.

Determinants of acute hemodynamic and electrophysiologic effects of verapamil in humans: role of myocardial drug uptake.

To examine the relationship between myocardial verapamil content (MVC) and acute effects in humans, coronary sinus catheterization was used in 22 patients to determine myocardial uptake of verapamil after bolus intravenous (i.v.) verapamil (4 mg) injection. Verapamil-induced effects on hemodynamic and electrophysiologic parameters were measured simultaneously and correlated with MVC per unit baseline coronary sinus blood flow (MVC:F). Myocardial uptake of verapamil was rapid: peak MVC (1.2 +/- 0.2% of injected dose) occurred at 5.4 +/- 0.4 min; at 30 min, residual MVC was 71.1 +/- 3.4% of maximum. Peak MVC:F in individual patients was inversely related to the extent of coronary artery disease (p less than 0.005) but not to left ventricular (LV) systolic function. Verapamil produced significant (p less than 0.001) early reductions in arterial pressure and systemic vascular resistance (SVR); cardiac index (CI) increased, left ventricular (LV) positive dP/dt was unchanged. Verapamil prolonged (p less than 0.01) PR and AH intervals (maximum at 12-18 min) and atrioventricular (AV) nodal effective and functional refractory periods (ERP, FRP) (maximum at 30 min). In individual patients, the extent of changes in AH intervals (r = 0.69; p less than 0.05) and LV dP/dt (r = 0.62; p less than 0.05) correlated with peak MVC:F. We conclude that after i.v. injection, verapamil uptake by the human myocardium is rapid and more extensive in patients with minor coronary artery disease. Despite the hysteresis between MVC and drug effects, MCV is a determinant of inotropic and electrophysiologic effects of verapamil.

Relationship between systemic and coronary vascular responses to digoxin and concurrent drug therapy with verapamil/beta-adrenoceptor antagonists in humans.

1. In 24 patients who were undergoing coronary arteriography for the assessment of ischaemic heart disease, the relationship between the systemic and coronary vascular responses to acute intravenous digoxin administration (500 micrograms) and concurrent drug therapy with the calcium antagonist verapamil (group I) or a beta-adrenoceptor antagonist (group II) or neither of these agents (group III) was examined. 2. Systemic vascular resistance (SVR) tended to rise rapidly after digoxin injection in patients in groups II and III, and tended to decline initially in patients in group I; however, these differences were not statistically significant (variance ratio [VR] = 0.77). 3. No significant differences were observed in coronary vascular responses to acute digoxin administration between the three groups of patients (VR = 0.34). 4. For the entire group of 24 patients, no statistically significant digoxin-induced effects on resistance could be demonstrated in either the systemic or coronary circulations, although in individual patients vasoconstrictor effects were observed. 5. We conclude that acute intravenous administration of digoxin does not consistently cause systemic or coronary vasoconstriction in patients with ischaemic heart disease. Variability in vasomotor responses to digoxin is not clearly related to concurrent drug therapy with verapamil or a beta-adrenoceptor antagonist. The observation that systemic vascular resistance tends to increase in the first few minutes after digoxin injection should be addressed in future studies.

Acute myocardial uptake of digoxin in humans: correlation with hemodynamic and electrocardiographic effects.

Acute myocardial uptake of digoxin was measured at a constant paced heart rate (75 beats/min) for 30 min after an intravenous bolus injection of 500 micrograms of digoxin in 14 patients with ischemic heart disease. Myocardial digoxin content, determined by serial measurement of aortocoronary sinus digoxin concentration gradients and coronary sinus blood flow, was expressed relative to coronary sinus blood flow at rest and correlated with simultaneous hemodynamic and electrocardiographic changes. Myocardial digoxin uptake was extensive (4.1 +/- 0.7% of total injected dose at 30 min) and prolonged, with rapid initial uptake (75.3 +/- 6.6% of maximum at 3 min), followed by a variable phase of slower accumulation. Peak left ventricular positive first derivative of left ventricular pressure (dP/dt) increased progressively (p less than 0.01), with a similar time course to that of myocardial digoxin accumulation; maximal change was 18.5 +/- 4.7% at 27 min. The ratio of inotropic effect to myocardial digoxin content did not vary significantly over the period of the experiment. However, peak inotropic effects in individual patients were not significantly related to peak myocardial digoxin content. The spontaneous PR interval increased transiently, with a peak increase of 5.9 +/- 1.8% (p less than 0.05) 12 min after digoxin administration. It is concluded that after intravenous bolus administration, 1) peak effects of digoxin on atrioventricular (AV) conduction occur early, whereas positive inotropic effects increase progressively for greater than or equal to 27 min; and 2) digoxin accumulation in the human myocardium is prolonged and is a determinant of inotropic effects, but not of prolongation of AV node conduction.

Verapamil in unstable angina pectoris: failure to demonstrate a relationship between efficacy and plasma levels.

Verapamil has been shown to be effective in reducing the frequency of episodes of ischemic pain in patients with unstable angina pectoris, and to be more effective than beta-adrenoceptor antagonists in such patients. However, in many patients ischemic symptoms persist despite verapamil therapy. In a group of 33 consecutive patients admitted to the Coronary Care Unit with unstable angina pectoris and treated with verapamil and nitroglycerin, we prospectively tested the hypothesis that plasma concentrations of verapamil were a direct determinant of resolution of ischemic symptoms over the initial 72-h period of admission. During this period, improvement or resolution of symptoms occurred in 23 of the 33 patients. With patients receiving 240 to 320 mg/day of verapamil, plasma verapamil concentrations varied between 8 and 487 ng/ml, rising significantly with increasing duration of therapy. Mean plasma verapamil concentrations were somewhat greater in patients who improved than in those with ongoing or worsening symptoms, but the differences were not statistically significant. Furthermore, no correlation was found between symptomatic status and plasma concentrations of norverapamil, the active metabolite of verapamil. In one patient cardiac failure worsened, possibly attributable to an elevated plasma verapamil concentration (336 ng/ml). We conclude that in this clinical setting there is little place for routine monitoring of plasma verapamil concentrations.

Myocardial uptake of drugs and clinical effects.

The process of uptake of cardioactive drugs into the myocardium is a major determinant of the efficacy and potential toxicity of such agents. Evaluation of responses to anti-arrhythmic and positive inotropic agents is best performed with reference to their concentration in the myocardium, and the potential toxicity of drugs such as tricyclic antidepressants and anthracycline antineoplastics is likely to be related to peak myocardial drug concentrations. Although it has been appreciated for many years that even during long term drug administration the myocardial drug content may not be readily predictable on the basis of estimation of plasma drug concentrations, methodology for direct assessment of myocardial drug content has remained limited. The results of in vitro experiments, utilising tissue culture preparations of myocardial cells or isolated atria, have shed some light on the role of local factors as determinants of myocardial drug uptake. For many agents, attainment of maximal cardiac drug content in vitro is a very slow process (taking up to 3 hours), although maximal inotropic and electrophysiological effects may occur more rapidly. The prolonged time course of drug washout from these preparations also reflects their extensive and slow intracellular accumulation. Mechanical activity of the myocardium appears to accelerate drug uptake, particularly for otherwise slowly equilibrating agents, but the major determinant of the extent of drug uptake into isolated myocardial preparations is lipophilicity, perhaps reflecting the passage of drugs through the sarcolemma. In intact animals, assessment of myocardial drug content after acute drug administration has been performed utilising serial myocardial biopsy or sacrifice of animals. Studies in open-chested dogs suggest that acute accumulation of agents may be most closely predicted from the second compartment of a 3-compartment pharmacokinetic model, and that there is a variable correlation between changes in plasma and myocardial drug concentrations. For example, bretylium concentrations within the myocardium continue to increase for up to 6 hours after drug administration. Factors which may influence drug uptake into the myocardium in intact animals include ischaemia, which usually results in a delay in both drug uptake and subsequent clearance. This change can also be inferred from the time course of onset of antiarrhythmic drug effects in some models of myocardial ischaemia. Anoxia may also inhibit myocardial drug uptake.(ABSTRACT TRUNCATED AT 400 WORDS)