Phase analysis of gated blood pool scintigraphic images to localize bypass tracts in Wolff-Parkinson-White syndrome.

The ability of radionuclide techniques to localize bypass tracts in patients with Wolff-Parkinson-White syndrome to sites around the atrioventricular (AV) ring using a three view triangulation method was investigated. In 17 patients with Wolff-Parkinson-White syndrome, phase images were generated from gated blood pool scans using the first Fourier harmonic of the time-activity curve of each pixel. In addition, the difference between left and right ventricular mean phase angles was calculated for each patient and for 13 control subjects. Bypass tracts were localized to one or more sites on a 10 site grid schematically superimposed on the AV ring (Duke grid) by electrophysiologic study in all patients and by intraoperative mapping in 7 of the 17 patients. These same 10 anatomic sites were projected onto three scintigraphic views and the site of earliest ventricular phase angle was located in each view. The 10 sites around the AV ring were divided into two anatomic groups: free wall and septal/paraseptal. Phase image locations correlated with electrophysiologic locations within one grid site in 11 of 11 patients with free wall tracts and were confirmed at surgery in 5 of the 11. In five of six patients with septal/paraseptal tracts, electrophysiologic study could not localize the bypass tract to one site, whereas phase images localized two of the five as free wall adjacent to the septum, one as paraseptal and two as true posteroseptal. One posteroseptal site was confirmed at surgery. In one patient, in whom phase image analysis and electrophysiologic study showed different sites, existence of both tracts was confirmed at surgery.(ABSTRACT TRUNCATED AT 250 WORDS)

Beta-blocker use and survival in patients with ventricular fibrillation or symptomatic ventricular tachycardia: the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial.

OBJECTIVES: To evaluate whether use of beta-adrenergic blocking agents, alone or in combination with specific antiarrhythmic therapy, is associated with improved survival in persons with ventricular fibrillation (VF) or symptomatic ventricular tachycardia (VT). BACKGROUND: The ability of beta-blockers to alter the mortality of patients with VF or VT receiving contemporary medical management is not well defined. METHODS: Survival of 1,016 randomized and 2,101 eligible, nonrandomized patients with VF or symptomatic VT followed in the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial through December 31, 1996 was assessed using Cox proportional hazards analysis. RESULTS: The 817 (28%) patients discharged from hospital receiving beta-blockers had less ventricular dysfunction, fewer symptoms of heart failure and a different pattern of medication use compared with patients not receiving beta-blockers. Before adjustment for important prognostic variables, beta-blockade was not significantly associated with survival in randomized or in eligible, nonrandomized patients treated with specific antiarrhythmic therapy. After adjustment, beta-blockade remained unrelated to survival in randomized or in eligible, nonrandomized patients treated with amiodarone alone (n = 1142; adjusted relative risk [RR] = 0.96; 95% confidence interval [CI] 0.64-1.45; p = 0.85) or a defibrillator alone (n = 1347; adjusted RR = 0.88; 95% CI 0.55 to 1.40; p = 0.58). In contrast, beta-blockade was independently associated with improved survival in eligible, nonrandomized patients who were not treated with specific antiarrhythmic therapy (n = 412; adjusted RR = 0.47; 95% CI 0.25 to 0.88; p = 0.018). CONCLUSIONS: Beta-blocker use was independently associated with improved survival in patients with VF or symptomatic VT who were not treated with specific antiarrhythmic therapy, but a protective effect was not prominent in patients already receiving amiodarone or a defibrillator.

Nitrate therapy for angina pectoris. Current concepts about mechanism of action and evaluation of currently available preparations.

Nitrates are presently used in the therapy for angina pectoris. They have both direct coronary vascular and indirect systemic effects; each appears to contribute to their anti-anginal efficacy. The various nitrate preparations, including the newer preparations recently made clinically available, have varying utilities in the relief of acute ischemic pain or for anginal prophylaxis. Nitrate tolerance and dependence are proved phenomena, yet their impact on the clinical usage of nitrates is not clearly defined. The utility of nitrates, including intravenous nitroglycerin, in the treatment of unstable angina and vasospastic angina is well documented. Their efficacy compared with that of calcium channel blockers is still being investigated. The reported adverse effects of nitrates are few, despite their many years of usage in clinical medicine.

Enhanced cardiac effect of digoxin during quinidine treatment.

Quinidine causes an increase in the serum digoxin concentration. Three patients were studied to determine if the increase in serum concentration is paralleled by an increase in the cardiac effect of digoxin. Each patient's clinical condition and serum digoxin concentration were stable when quinidine administration was begun. In all three patients, serum digoxin concentrations increased significantly after beginning quinidine, and decreased when quinidine was discontinued. While taking quinidine, all three patients had ECG findings that suggested enhanced digitalis effect and one patient had clinical evidence of an increased hemodynamic effect. These effects paralleled the increases in serum digoxin concentration. Our findings suggest that the increase in serum digoxin concentration, which occurs after beginning quinidine, is associated with an increase in the effect of digoxin on the heart.

Drug choices in the treatment of atrial fibrillation.

When considering therapy for atrial fibrillation (AF), the dominant issues are rate control, anticoagulation, rhythm control, and treatment of any underlying disorder. Drug choices for rate control include beta-blockers, verapamil and diltiazem, and digitalis as first-line agents, with consideration of other sympatholytics, amiodarone, or nonpharmacologic approaches in resistant cases. Anticoagulation may be accomplished with aspirin or warfarin, with the latter preferred in all older or high-risk patients. Antiarrhythmic drug therapy may be used (1) to produce cardioversion (most effective with ibutilide or class IC agents in recent onset AF); (2) to facilitate electrical conversion (class III agents); (3) to prevent early reversion after cardioversion; (4) to maintain sinus rhythm during chronic therapy; and/or (5) to facilitate conversion of fibrillation to flutter, which may then be amenable to termination or prevention with antitachypacing or ablative techniques. Antiarrhythmic drug selection for AF is guided by efficacy considerations (most drugs are similar), by convenience, cost, and discontinuation considerations; and, most importantly, by safety considerations. When possible, agents with serious organ toxicity potential and proarrhythmic risk should be avoided as first-line choices. In structurally normal hearts, class IC antiarrhythmic drugs are least proarrhythmic and least organ toxic (when considered together). In normal hearts, sotalol, dofetilide, and potentially azimilide also appear to have attractive profiles. Amiodarone has low proarrhythmic risk but can produce bradyarrhythmias and toxicity. In hypertrophied hearts, the risk of torsade de pointes with class III/IA agents is enhanced, whereas in ischemia or conditions with impaired cell contact, whether functionally (as by ischemia) or anatomically (as by fibrosis, infiltration, etc), proarrhythmic risk with class I antiarrhythmic drugs (sustained ventricular fibrillation/flutter) is greatly increased. The class I drugs should be avoided in these circumstances. Additional issues to consider are where to initiate therapy (in- or outpatient), what follow-up protocols to use, and whether to limit therapy to proprietary drugs or to allow generic formulation substitution. Each of these considerations is detailed in this article.

Formulation substitution and other pharmacokinetic variability: underappreciated variables affecting antiarrhythmic efficacy and safety in clinical practice.

The process of treating a patient with an antiarrhythmic drug only begins when a physician chooses the drug to be employed. In the given patient, not only must the drug be chosen, but so must the dose, the formulation, and the method of follow-up. Choosing the proper dose requires an understanding of clinical trial efficacy and safety data for the agent chosen in a population of patients resembling the individual to be treated. It also requires a detailed understanding of pharmacologic principles of drug kinetics (e.g., absorption, distribution, metabolism, and excretion) that might affect the dose needed for the specific patient. The physician must be familiar with subsequent changes in clinical circumstances that might indicate a need for a change in dose or drug. Many circumstances determining drug pharmacokinetics are not under the immediate control of physicians, such as genetic patterns, organ function, and disease circumstances. One, however, is-or should always be-the selection of the drug formulation used. Although generic versions of innovator drugs exist for many agents and often are clinically acceptable, most physicians are unaware of the meager degree of testing that is necessary for the release of a generic drug, and the wide range of attained serum levels that are called bioequivalent by the US Food and Drug Administration (FDA) when one formulation is compared with another. In patients with cardiac arrhythmias, arrhythmia recurrence, proarrhythmia, and death have been reported in association with antiarrhythmic drug formulation substitution. Despite their reported bioequivalence, the generic agents involved were clearly not therapeutically equivalent. Accordingly, this article was written to educate physicians further about the above-noted important pharmacokinetic variables that can affect a patient's outcome when an antiarrhythmic drug is employed, and to provide information on the generic drug approval process and guidelines for the use of formulation substitution.

Implications of the Electrophysiologic Study versus Electrocardiographic Monitoring trial for controlling ventricular tachycardia and fibrillation.

The Electrophysiologic Study versus Electrocardiographic Monitoring (ESVEM) trial had 2 objectives. The first was to determine the accuracy of noninvasive versus invasive means of predicting the efficacy of drug treatment for ventricular tachycardia/ventricular fibrillation (VT/VF). A second objective was to determine the relative efficacies of 7 antiarrhythmic drugs used in the treatment of ventricular tachyarrhythmias. ESVEM was the first opportunity to compare prospectively the efficacy, safety, and tolerability of a variety of antiarrhythmic drugs in the same patient population. No significant difference was observed between suppression of spontaneous ventricular arrhythmias on Holter monitoring and suppression of inducible ventricular arrhythmias by electrophysiologic study (EPS) in terms of the ability to predict the success of drug therapy. There was also no difference in predictive accuracy if patients in the electrophysiologic limb showed suppression by Holter monitoring in addition to suppression by EPS. Sotalol was more effective than the other 6 antiarrhythmic drugs, all class I agents, in preventing death and recurrence of arrhythmia. Efficacy compared with placebo, however, was not evaluated. In the EPS limb, sotalol was also statistically more likely to achieve an efficacy prediction than any of the sodium channel blocking drugs. Amiodarone was not used in ESVEM. It has been suggested that these conclusions, which differ from those of other, less controlled, invasive and noninvasive studies, might be because of the particular efficacy criteria used in the ESVEM protocol. Retrospective analyses of the ESVEM data were performed using more rigid efficacy criteria than were used in the original ESVEM analysis: a greater degree of ectopy suppression was required for Holter monitoring, and more stringent efficacy definitions were required in the stimulation protocol of the EPS limb. Results from the retrospective analyses and other studies support the initial ESVEM conclusions. In patients with both spontaneous and inducible sustained ventricular tachyarrhythmias as well as frequent spontaneous premature ventricular contractions, therapy with sotalol (guided by either Holter monitoring or EPS) is a reasonable initial strategy because of its superior initial long-term efficacy and better acute and long-term tolerability compared with sodium channel blocking drugs.

Selecting an antiarrhythmic agent for atrial fibrillation should be a patient-specific, data-driven decision.

Selecting an antiarrhythmic agent for atrial fibrillation (AF) should be a patient-specific decision. When possible, it should be based on sound rationale and available clinical data. This article details many of the thought processes that must go into this decision process and offers some suggested algorithmic starting points based on these considerations. With a patient's first episode of AF, termination is appropriate, but antiarrhythmic therapy should usually be withheld in order to assess the recurrence pattern. However, if severe hemodynamic or ischemic intolerance would make recurrence a serious risk, or if an early symptomatic recurrence is highly likely, antiarrhythmic therapy would be appropriate. Acute AF may terminate spontaneously or may be terminated iatrogenically. The latter may be achieved by direct current or pharmacologic approaches. The risks, benefits, and optimum utility of these approaches are addressed in the article. Infrequent recurrences may be treated with cardioversion; frequent or severely symptomatic episodes are best treated with attempts at suppression with chronic antiarrhythmic drug administration. Since the therapeutic efficacy of maintaining sinus rhythm is similar for the currently available agents, the drug selection process should be based in large part on safety and convenience considerations. The factors underlying this selection process and one suggested algorithm for drug choice are provided in this article.

Prolonging survival by reducing arrhythmic death: pharmacologic therapy of ventricular tachycardia and fibrillation.

Antiarrhythmic drug therapy of sustained ventricular tachyarrhythmias is undertaken to reduce arrhythmic symptoms, recurrences, and mortality. Ideally, reduction of arrhythmic death will reduce total mortality as well, although this may not hold true in the presence of competing risk. Whether, in fact, antiarrhythmic therapy actually reduces arrhythmic death remains uncertain in the absence of any placebo-controlled trials. Nonetheless, the following conclusions can be drawn from the Electrophysiologic Study versus Electrocardiographic Monitoring (ESVEM) trial, the Cardiac Arrest Study Hamburg (CASH), and the Cardiac Arrest in Seattle: Conventional versus Amiodarone Drug Evaluation (CASCADE) study, as well as a beta blocker study by Steinbeck et al: (1) class I antiarrhythmics are less effective than amiodarone or sotalol for the prevention of recurrent sustained ventricular tachycardia/ventricular fibrillation; (2) sympathetic inhibition as a component of the antiarrhythmic regimen may strongly contribute to mortality reduction; and (3) the respective roles of antiarrhythmic drugs, implantable devices, and the concurrent use of both are in a state of flux, awaiting results of randomized controlled clinical trials.

Generic antiarrhythmics are not therapeutically equivalent for the treatment of tachyarrhythmias.

The consequences of antiarrhythmic drug formulation substitution were assessed by survey of 130 experts on arrhythmias. Fifty-four arrhythmia recurrences, 7 proarrhythmic events, and 3 deaths resulting from generic substitution are reported, thus raising serious concerns about both antiarrhythmic drug substitution and the adequacy of the generic drug approval process.

Importance of beta blockade in the therapy of serious ventricular arrhythmias.

Beta blockers have traditionally been considered relatively poor antiarrhythmic agents for patients with ventricular arrhythmias. This view is based on the observations that beta blockers are less effective in suppressing spontaneous ventricular ectopy or inducible ventricular arrhythmias than are the class I and class III agents. However, there are convincing data that beta blockers can have a clinically important antiarrhythmic effect and prevent arrhythmic and sudden death. Beta blockers have multiple potential effects that can contribute to a therapeutic antiarrhythmic action, including an antiadrenergic/vagomimetic effect, a decrease in ventricular fibrillation threshold, and prevention of a catecholamine reversal of concomitant class I/III antiarrhythmic drug effects. Postinfarction trials, recent congestive heart failure studies, and observations in patients who are at risk for sustained ventricular arrhythmias all suggest a potent antiarrhythmic effect of beta blockade.

Effects of digoxin on sinus nodal function before and after vagal blockade in patients with sinus nodal dysfunction: a clue to the mechanisms of the action of digitalis on the sinus node.

To increase the limited knowledge of the effects of digitalis on sinus nodal function in patients with sinus nodal dysfunction and to initiate an investigation into the mechanisms underlying its effects, 34 patients with sinus nodal dysfunction were studied. Twenty patients underwent determination of sinus cycle length, estimated sinoatrial conduction time and maximal corrected sinus recovery time before and after the administration of 0.75 mg of intravenous digoxin. For the group, sinus cycle length did not change, sinoatrial conduction time increased insignificantly and maximal corrected sinus recovery time shortened; however, individual variation occurred. The effects of acute digitalization appeared to predict the effects of chronic digitalis administration on sinus nodal function in the eight patients who subsequently continued to take digoxin. Fourteen patients received digoxin after vagal blockade with atropine. After vagal blockade, digoxin lengthened sinus cycle length, sinoatrial conduction time and maximal corrected sinus recovery time. The effects of digoxin administered after atropine could be antiadrenergic, direct, or both, and are opposite to those induced by atropine alone. Because these effects are similar to those of vagotonia yet are not apparent when the vagi are unblocked, digoxin may have direct excitatory, adrenergic or previously unrecognized vagolytic effects on sinus nodal function in man and their manifestation may be dependent on heart rate or autonomic tone.

Antiarrhythmic drugs and devices for the management of ventricular tachyarrhythmia in ischemic heart disease.

Ischemic heart disease is the most frequent cardiac abnormality in patients with sustained or nonsustained ventricular tachyarrhythmias. The goals of therapy in such patients are to decrease the severity and incidence of symptoms and prolong life. In this article, we review the current views on antiarrhythmic drug therapy and an implantable cardioverter-defibrillator (ICD) in patients with ischemic heart disease. The importance of beta blockade as part of the therapy is emphasized. In addition, the superiority of sotalol and amiodarone over class I drugs, the benefits of combined treatment with amiodarone and a beta blocker, and the impact and limitations of current trials comparing the effectiveness of drug therapy with that of an ICD are all considered. Also discussed is the combined use of an antiarrhythmic drug and an ICD. In this approach sotalol is generally the agent of choice, with amiodarone the second choice.

"Paradoxical" prolongation of sinus nodal recovery time after atropine in the sick sinus syndrome.

A case of symptomatic sick sinus syndrome is presented with confirmation of sinus nodal dysfunction established by functional testing. The validity of such provocative testing and the criteria for abnormality are discussed. A newly recognized, seemingly "paradoxical" and potentially detrimental effect of atropine noted in this patient is examined. Despite an increase in sinus rate and an improvement in sinoatrial conduction time after administration of atropine, a markedly prolonged sinus recovery time after rapid atrial pacing occurred, and atrial quiescence for more than 10 seconds was seen. Possible electrophysiologic mechanisms for this phenomenon, such as decreased atriosinus entrance block, concealed sinoatrial reentry or enhanced intranodal depolarization, are discussed and potential clinic correlates are made.

Sotalol for ventricular tachyarrhythmias: beta-blocking and class III contributions, and relative efficacy versus class I drugs after prior drug failure. ESVEM Investigators. Electrophysiologic Study Versus Electrocardiographic Monitoring.

In the Electrophysiologic Study Versus Electrocardiographic Monitoring (ESVEM) trial, d,l-sotalol was associated with a lower arrhythmia recurrence and mortality than class I antiarrhythmic drugs. To further evaluate the relative efficacy of d,I-sotalol compared with class I drugs, and to assess the relative importance of its class II (beta-blocking) and class III effects, 6-year arrhythmia recurrence and mortality in patients receiving sotalol were compared with those in patients receiving class I drugs, subdivided according to whether they also received coadministered beta blockers. Relative efficacy was also determined for sotalol and for class I drugs as stratified by the presence/absence of prior drug failure. Arrhythmia recurrence was lower for the 84 patients receiving sotalol than for patients given class I agents with (n = 28) (p = 0.008) or without (n = 184) (p = 0.001) alpha beta blocker. Mortality was lower for patients taking sotalol than for those given a class I drug without alpha beta blocker (p = 0.034), but similar (p = 0.835) if alpha beta blocker was also administered. In contrast to class I drugs, which had lower efficacy rates when prior drug trials had failed, sotalol maintained its efficacy despite prior drug failures preceding or during the ESVEM trial. Both class II and III actions in the ESVEM trial were important to the clinical superiority of sotalol in the treatment of ventricular tachyarrhythmias.

Reproducibility of drug efficacy predictions by Holter monitoring in the electrophysiologic study versus electrocardiographic monitoring (ESVEM) trial. ESVEM Investigators.

Selection of antiarrhythmic therapy may be based on suppression of spontaneous ventricular arrhythmias assessed by Holter monitoring, but the implications of discordant Holter results on repeat 24-hour monitoring has not been defined. This study examines the frequency and significance of reproducible Holter suppression on two 24-hour recordings in the Electrophysiologic Study Versus Electrocardiographic Monitoring (ESVEM) trial. Repeat 24-hour Holter monitoring was obtained in patients randomized to the Holter monitor limb of the ESVEM trial, during the same hospitalization, after a drug efficacy prediction. These Holters were not used to define drug efficacy but were subsequently analyzed to determine the reproducibility of drug efficacy predictions by Holter monitoring. A repeat 24-hour Holter monitor, following the one that predicted drug efficacy, was available in 119 patients. Ninety-nine patients (83%) also had suppression that met efficacy criteria on the second Holter monitor. There were no significant differences in arrhythmia recurrence (p = 0.612) or mortality (p = 0.638) in patients with concordant Holter results (n = 99; 1-year arrhythmia recurrence = 45%; 1-year mortality = 10%) compared with those with discordant Holter results (n = 20; 1-year arrhythmia recurrence = 45%; 1-year mortality = 16%). We conclude that (1) there is discordance between the first effective Holter monitor and a repeat Holter monitor in 17% of patients, and (2) suppression of ventricular ectopic activity on 2 separate 24-hour Holter monitors does not identify a group with a better outcome, nor does failure of suppression on the second Holter monitor identify a group with a worse prognosis.

Quinidine-digoxin interaction: time course and pharmacokinetics.

The time course of the rise in serum digoxin concentration was followed in 18 patients treated with digoxin as quinidine treatment was started with a loading dose. The mean serum digoxin levels rose significantly during the first 24 hours after administration of quinidine was begun, and reached a new steady state concentration after about 48 hours. Digoxin kinetics were studied in two groups of normal volunteers: Group 1 (n = 7) received a small dose of quinidine, 800 mg/day, and group II (n = 8) received 1,600 mg/day. There was no significant mean change in the apparent volume of distribution of digoxin in either group. In group I (small dose), quinidine reduced the digoxin clearance values: total clearance by 30 percent, renal clearance by 32 percent and nonrenal clearance by 29 percent. In group II (large dose), quinidine reduced digoxin total clearance by 36 percent, renal clearance by 54 percent and nonrenal clearance by 22 percent. The reduction in digoxin volume of distribution and renal clearance during quinidine treatment were a function of the serum quinidine concentration. The change in nonrenal clearance of digoxin was independent of serum quinidine concentration.

Response to programmed ventricular stimulation: sensitivity, specificity and relation to heart disease.

This prospective study of 100 patients evaluated the sensitivity and specificity of the repetitive ventricular response and ventricular tachycardia induced by programmed electrical stimulation for identifying patients with spontaneous ventricular tachyarrhythmias. The influence of underlying heart disease on such sensitivity and specificity was also evaluated. The repetitive ventricular response was sensitive (92 percent) for detecting patients with prior spontaneous ventricular tachyarrhythmias, but lacked specificity (57 percent); the rate of false positive responses was 43 percent. Inducible ventricular tachycardia was less sensitive (65 percent) but more specific (98 percent); the rate of false positive responses was only 3 percent. Among the 100 patients, 71 had heart disease, 29 did not. The presence of underlying heart disease had no significant effect on the sensitivity and specificity of repetitive ventricular responses or ventricular tachycardia induced by programmed stimulation; it did not increase the rate of false positive responses. It is concluded that (1) ventricular tachycardia induced with programmed ventricular stimulation is an excellent basis for guiding the management of clinically significant ventricular tachyarrhythmias, regardless of underlying heart disease; and (2) the repetitive ventricular response is not useful for this purpose because of its high rate of false positive responses among patients with or without significant heart disease.

Four-contact glove probe method for rapid recording of cardiac electrograms during surgery.

A technique is presented for recording four simultaneous electrograms from the heart during operation for cardiac arrhythmias. this technique permits intraoperative maps of cardiac electrical activity to be constructed more rapidly than is possible with single-point mapping, thereby decreasing the risks to the patient and yielding more information about cardiac events.

Electrophysiologic evaluation of sinus node function.

Sinus node dysfunction can be evaluated by invasive and noninvasive means. In this article, invasive testing of sinus node function and its clinical utility are reviewed. Sinus recovery times, sinoatrial conduction times, sinus node refractory periods, and sinus node electrograms are all reviewed in detail, with regard to both theory and practice.