A comparison of rate control and rhythm control in patients with atrial fibrillation.

BACKGROUND: There are two approaches to the treatment of atrial fibrillation: one is cardioversion and treatment with antiarrhythmic drugs to maintain sinus rhythm, and the other is the use of rate-controlling drugs, allowing atrial fibrillation to persist. In both approaches, the use of anticoagulant drugs is recommended. METHODS: We conducted a randomized, multicenter comparison of these two treatment strategies in patients with atrial fibrillation and a high risk of stroke or death. The primary end point was overall mortality. RESULTS: A total of 4060 patients (mean [+/-SD] age, 69.7+/-9.0 years) were enrolled in the study; 70.8 percent had a history of hypertension, and 38.2 percent had coronary artery disease. Of the 3311 patients with echocardiograms, the left atrium was enlarged in 64.7 percent and left ventricular function was depressed in 26.0 percent. There were 356 deaths among the patients assigned to rhythm-control therapy and 310 deaths among those assigned to rate-control therapy (mortality at five years, 23.8 percent and 21.3 percent, respectively; hazard ratio, 1.15 [95 percent confidence interval, 0.99 to 1.34]; P=0.08). More patients in the rhythm-control group than in the rate-control group were hospitalized, and there were more adverse drug effects in the rhythm-control group as well. In both groups, the majority of strokes occurred after warfarin had been stopped or when the international normalized ratio was subtherapeutic. CONCLUSIONS: Management of atrial fibrillation with the rhythm-control strategy offers no survival advantage over the rate-control strategy, and there are potential advantages, such as a lower risk of adverse drug effects, with the rate-control strategy. Anticoagulation should be continued in this group of high-risk patients.

Design and synthesis of 4-substituted benzamides as potent, selective, and orally bioavailable I(Ks) blockers.

Multiple delayed rectifier potassium currents, including I(Ks), are responsible for the repolarization and termination of the cardiac action potential, and blockers of these currents may be useful as antiarrhythmic agents. Modification of compound 5 produced 19(S) that is the most potent I(Ks) blocker reported to date with >5000-fold selectivity over other cardiac ion channels. Further modification produced 24A with 23% oral bioavailability.

Arylcyclopropanecarboxyl guanidines as novel, potent, and selective inhibitors of the sodium hydrogen exchanger isoform-1.

A novel series of arylcyclopropanecarboxyl guanidines was synthesized and evaluated for activity against the sodium hydrogen exchanger isoform-1 (NHE-1). In biological assays conducted in an AP1 cell line expressing the human NHE-1 isoform, the starting cyclopropane 3a (IC(50) = 3.5 microM) shows inhibitory activity comparable to cariporide (IC(50) = 3.4 microM). Structure-activity relationships are used to optimize the affinity of various acyl guanidines for NHE-1 by screening the effect of substituents at both aryl and cyclopropyl rings. It is demonstrated that introduction of appropriate hydrophobic groups at the phenyl ring and a gem-dimethyl group at the cyclopropane ring enhances the NHE-1 inhibitory activity by up to 3 orders of magnitude (compound 7f, IC(50) = 0.003 microM). In addition, the gem-dimethyl series of analogues seem to display improved oral bioavailability and longer plasma half-life in rats. Furthermore, the lead benzodihydrofuranyl analogue 1 (BMS-284640) shows over 380-fold increased NHE-1 inhibitory activity as well as improved selectivity for NHE-1 over NHE-2 compared to cariporide.

Coexistence of type I atrial flutter and intra-atrial re-entrant tachycardia in patients with surgically corrected congenital heart disease.

OBJECTIVES: This study assessed the coexistence of intra-atrial re-entrant tachycardia (IART) and isthmus-dependent atrial flutter (IDAF) in patients presenting with supraventricular tachyarrhythmias after surgical correction of congenital heart disease (CHD). BACKGROUND: In patients with CHD, atrial tachyarrhythmias may result from IART or IDAF. The frequency with which IART and IDAF coexist is not well defined. METHODS: Both IDAF and IART were diagnosed in 16 consecutive patients using standard criteria and entrainment mapping. Seven patients had classic atrial flutter morphology on surface electrocardiogram (ECG), whereas nine had atypical morphology. RESULTS: A total of 24 circuits were identified. Three patients had IDAF only, five had IART only, seven had both, and one had a low right atrial wall tachycardia that could not be entrained. Twenty-two different reentry circuits were ablated. Successful ablation was accomplished in 13 of 14 (93%) IART and 9 of 10 (90%) IDAF circuits. There was one IART recurrence. The slow conduction zone involved the region of the right atriotomy scar in 12 of 14 (86%) IART circuits. No procedural complications and no further recurrences were seen after a mean follow-up of 24 months. CONCLUSIONS: Both IDAF and IART are the most common mechanisms of atrial re-entrant tachyarrhythmias in patients with surgically corrected CHD, and they frequently coexist. The surface ECG is a poor tool for identifying patients with coexistent arrhythmias. The majority of IART circuits involve the lateral right atrium and may be successfully ablated by creating a lesion extending to the inferior vena cava.

Reappraisal of brain tumor risk among U.S. nuclear workers: a 10-year review.

A review of cohort mortality studies among workers exposed to ionizing radiation in U.S. nuclear programs was published in this journal 10 years ago. The present review extends that investigation to include four new groups of workers at Fernald (Ohio), Rocketdyne/Atomics International (California), Mallinckrodt Chemical (Missouri), and Los Alamos National Laboratory (New Mexico). The total number of brain tumors has doubled to nearly 300, with 3.8 million person-years of observation among 140,000 U.S. white male workers. This increased risk of brain tumor is highly consistent, persistent, and stable. The sum total of these studies dwarfs the reported experience of any other comparison group. The observed increased brain tumor risk is statistically significant and has changed little since 1991 when it was estimated at 15%. Study results from 1999 and 2000 may suggest a modest growing risk of 25-30%.

Elimination of focal atrial fibrillation with a single radiofrequency ablation: use of a basket catheter in a pulmonary vein for computerized activation sequence mapping.

A focal source for atrial fibrillation (AF) may be found in the first few centimeters of the pulmonary veins. Radiofrequency (RF) ablation may be directed at this source using activation mapping, but if the responsible atrial extrasystoles are infrequent or difficult to map, elimination of the source may require complete electrical isolation of the vein with multiple RF lesions. A new three-dimensional mapping system using a 64-pole basket catheter has been developed recently. We report the use of this system for ablation of focal AF in two patients. Mapping identified foci in the left and right superior pulmonary veins. Each focus was eliminated with a single RF ablation.

Synthesis, structure proof, and biological activity of epothilone cyclopropanes.

[structure--see text] A semisynthetic route to epothilone cyclopropanes from epothilones A and B is described. Of significance, the deoxygenation of the 12, 13-epoxide to give the corresponding olefin was achieved with high efficiency. The title compounds (8, 9) were active in both tubulin polymerization and cytotoxicity assays, which is in direct contrast to a previously published report. These results provide further evidence that the role of the 12,13-epoxide of epothilones is largely conformational and argue against some of the current pharmacophore models.

Transient ST elevation after transthoracic cardioversion in patients with hemodynamically unstable ventricular tachyarrhythmia.

The significance of ST-segment elevation after resuscitation from arrhythmias not associated with ischemia was examined in a group of patients who received transthoracic shocks for hemodynamically unstable ventricular tachyarrhythmias during electrophysiologic studies. ST-segment elevation was seen in 15.4%, was transient, and was not associated with clinical evidence of myocardial infarction.

Relation between myocardial viability and abnormalities on the signal-averaged electrocardiogram in patients with low (<40%) ejection fraction and coronary artery disease.

To determine a possible mechanism for the previously observed improved outcome after bypass surgery in patients with poor ventricular function and viable myocardium, we sought to examine the relation between the extent of viability and the frequency of an abnormal signal-averaged electrocardiogram (SAECG) in patients with reduced ejection fraction and coronary artery disease. Fifty-two patients with coronary disease and ventricular dysfunction underwent quantitative redistribution thallium-201 (Tl-201) scintigraphy at rest to determine the extent of viability. The presence of late potentials was assessed by SAECG. Long-term, cardiac event-free survival was determined. Patients with greater viability (group 1, n = 23) were similar to patients with less viability (group 2, n = 29) with respect to age, gender, ejection fraction, and incidence of arrhythmia. Fewer group 1 patients had late potentials (33% vs. 65%, p = 0.05) and individual parameters were significantly more abnormal in the group 2 patients. Patients with late potentials had less viability than patients without late potentials (viability index 0.61+/-0.15 vs. 0.69+/-0.14, respectively, p = 0.05). By multivariate analysis, only the extent of viable myocardium and the left ventricular end-diastolic pressure were independent predictors of late potentials. Survival free of cardiac death or transplantation was better in patients with a normal SAECG (p<0.04) and in patients with predominantly viable myocardium (p<0.005). Thus, patients with low ejection fraction, coronary disease, and viable myocardium have a lower frequency of late potentials, suggesting reduced susceptibility to ventricular arrhythmia.

Electrophysiologic characteristics of accessory atrioventricular connections in an inherited form of Wolff-Parkinson-White syndrome.

INTRODUCTION: A familial form of Wolff-Parkinson-White syndrome (WPW) occurs in association with hypertrophic cardiomyopathy and intraventricular conduction abnormalities. This syndrome, demonstrating autosomal dominant inheritance and segregating with a high degree of penetrance but variable expressivity, has been genetically linked to chromosome 7q3. The purpose of this study is to detail the electrophysiologic characteristics of accessory atrioventricular connections (AC) in four members of a kindred with this syndrome. METHODS AND RESULTS: We clinically evaluated 32 members of a single kindred and identified 20 individuals with ventricular preexcitation, abnormal intraventricular conduction including complete AV block and/or ventricular hypertrophy. Genetic linkage analysis mapped the disease gene in this kindred to the chromosome 7q3 locus (maximum logarithm of the odds score = 6.88, theta = 0); recombination events in affected individuals reduced the genetic interval from 7 centimorgans (cM) to 5 cM. Electrophysiologic study of four individuals with preexcitation, identified seven AC (1 right sided, 3 septal, and 3 left sided). All four individuals had inducible orthodromic tachycardia; while three had multiple AC. Bidirectional conduction was demonstrated in 6 of 7 AC. Successful ablation was accomplished in 5 of 7 AC. CONCLUSION: The electrophysiologic characteristics and location of AC in family members having this complex cardiac phenotype are similar to those seen in individuals with isolated WPW. Identification of WPW in more than one family member should prompt clinical evaluation of relatives for additional findings of ventricular hypertrophy or conduction abnormalities.