New-onset atrial fibrillation: sex differences in presentation, treatment, and outcome.

BACKGROUND: Although sex differences in coronary artery disease have received considerable attention, few studies have dealt with sex differences in the most common sustained cardiac arrhythmia, atrial fibrillation (AF). Differences in presentation and clinical course may dictate different approaches to detection and management. We sought to examine sex-related differences in presentation, treatment, and outcome in patients presenting with new-onset AF. METHODS AND RESULTS: The Canadian Registry of Atrial Fibrillation (CARAF) enrolled subjects at the time of first ECG-confirmed diagnosis of AF. Participants were followed at 3 months, at 1 year, and annually thereafter. Treatment was at the discretion of the patients' physicians and was not directed by CARAF investigators. Baseline and follow-up data collection included a detailed medical history, clinical, ECG, and echocardiographic measures, medication history, and therapeutic interventions. Three hundred thirty-nine women and 560 men were followed for 4.14+/-1.39 years. Compared with men, women were older at the time of presentation, more likely to seek medical advice because of symptoms, and experienced significantly higher heart rates during AF. Compared with older men, older women were half as likely to receive warfarin and twice as likely to receive acetylsalicylic acid. Compared with men on warfarin, women on warfarin were 3.35 times more likely to experience a major bleed. CONCLUSIONS: Anticoagulants are underused in older women with AF relative to older men with AF, despite comparable risk profiles. Women receiving warfarin have a significantly higher risk of major bleeding, suggesting the need for careful monitoring of anticoagulant intensity in women.

Randomized crossover comparison of DDDR versus VDD pacing after atrioventricular junction ablation for prevention of atrial fibrillation. The atrial pacing peri-ablation for paroxysmal atrial fibrillation (PA (3)) study investigators.

BACKGROUND: Some clinical data suggest that atrial-based pacing prevents paroxysmal atrial fibrillation (AF). This study tested the hypothesis that DDDR pacing compared with VDD pacing prevents AF after atrioventricular (AV) junction ablation. METHODS AND RESULTS: Patients were randomized to DDDR pacing (n=33) or to VDD pacing (n=34) after AV junction ablation and followed every 2 months for 6 months. Patients then crossed over to the alternate pacing mode and were followed for an additional 6 months. Primary analysis included the time to first recurrence of sustained AF (duration >5 minutes), total AF burden, and the development of permanent AF. The time to first episode of AF was similar in the DDDR group (0.37 days, 95% CI 0.1 to 1.3 days) and the VDD pacing group (0.5 days, 95% CI 0.2 to 1.7 days, P=NS). AF burden increased over time in both groups (P<0.01). At the 6-month follow-up, AF burden was 6.93 h/d (95% CI 4. 37 to 10.96 h/d) in the DDDR group and 6.30 h/d (95% CI 3.99 to 9.94 h/d) in the VDD group (P=NS). Twelve (35%) patients in the DDDR group and 11 (32%) patients in the VDD group had permanent AF within 6 months of ablation. Within 1 year of follow-up, 43% of patients had permanent AF. CONCLUSIONS: DDDR pacing compared with VDD pacing does not prevent paroxysmal AF over the long term in patients in the absence of antiarrhythmic drug therapy after total AV junction ablation. Many patients have permanent AF within the first year after ablation.

Propafenone-mexiletine combination for the treatment of sustained ventricular tachycardia.

OBJECTIVES: The purpose of this study was to explore the efficacy of combined therapy with propafenone and mexiletine for control of sustained ventricular tachycardia. BACKGROUND: Combination antiarrhythmic drug therapy may enhance efficacy and lead to control of ventricular arrhythmias in some patients. Few reports have studied the combination of class IB and class IC drugs. Thus, this study was designed to investigate a combination of mexiletine and propafenone in patients with refractory ventricular tachycardia. METHODS: Sixteen patients with sustained ventricular tachycardia had their clinical arrhythmia induced by programmed stimulation. Procainamide and propafenone alone failed to prevent reinduction of tachycardia in all. Mexiletine was subsequently added to propafenone and programmed stimulation was repeated. RESULTS: With combination therapy ventricular tachycardia was noninducible in three patients (19%). A fourth who had presented with polymorphic ventricular tachycardia had slow bundle branch reentry (cycle length 500 ms) induced. In the other 12, tachycardia cycle length increased from 262 +/- 60 ms at baseline to 350 +/- 82 ms with propafenone and to 390 +/- 80 ms with propafenone plus mexiletine (p less than 0.0001 compared with baseline). Hemodynamic deterioration requiring defibrillation occurred in six patients at baseline study, in five taking propafenone and in two taking both drugs. CONCLUSIONS: The combination of propafenone and mexiletine is effective in suppressing the induction of ventricular tachycardia in some patients refractory to procainamide and propafenone alone. In those in whom ventricular tachycardia could still be induced, the rate was slower and hemodynamically tolerated.

High success rate of atrioventricular node ablation with radiofrequency energy.

Radiofrequency current was introduced as an alternative energy source for transcatheter ablation of cardiac arrhythmias to avoid the complications associated with direct current shocks. Initial use of radiofrequency current for complete ablation of the atrioventricular (AV) node yielded only moderate success rates, presumably because of the small size of electrodes and difficulty in localizing the AV node. The use of a larger 4-mm tip electrode for delivery of radiofrequency current and a method to better localize the AV node were prospectively studied in 32 patients undergoing catheter ablation of the AV node. There were 21 men and 11 women with a mean age of 62 +/- 12 years. Complete AV block was achieved immediately in 31 patients (97%) and it persisted in 28 patients (88%) during a mean follow-up period of 12 +/- 6 months. Three patients who had return of AV condition required no drug therapy for control of ventricular rate during atrial fibrillation. The number of radiofrequency pulses used to achieve complete AV block ranged from 1 to 5 (mean 1.9 +/- 1.1). In greater than 50% of the cases, only one radiofrequency pulse was required. The mean power and duration of radiofrequency pulses were 21.2 +/- 4.5 W and 33 +/- 15 s, respectively. All patients developed a stable junctional escape rhythm within 45 min of successful ablation. The QRS configuration was unchanged in 30 patients. One patient had a new right bundle branch block after ablation. There were no complications related to the ablation procedure.(ABSTRACT TRUNCATED AT 250 WORDS)

"Nodoventricular" accessory pathway: evidence for a distinct accessory atrioventricular pathway with atrioventricular node-like properties.

Two patients are described with recurrent pre-excited tachycardia and electrophysiologic characteristics typically ascribed to a nodoventricular accessory connection. The accessory pathway in each case demonstrated rate-dependent prolongation of conduction time and a low right ventricular insertion site; it was associated with a left bundle branch block configuration during pre-excitation. Intraoperatively, the pathway was demonstrated to originate at the anterior right atrioventricular (AV) anulus and not at the AV node. These data suggest that a "typical" nodoventricular pathway, by electrophysiologic criteria, may in fact be an AV pathway with AV node-like conduction properties and a distal right ventricular insertion site.

Progression to chronic atrial fibrillation after pacing: the Canadian Trial of Physiologic Pacing. CTOPP Investigators.

OBJECTIVES: This study examined the effect of physiologic pacing on the development of chronic atrial fibrillation (CAF) in the Canadian Trial Of Physiologic Pacing (CTOPP). BACKGROUND: The role of physiologic pacing to prevent CAF remains unclear. Small randomized studies have suggested a benefit for patients with sick sinus syndrome. No data from a large randomized trial are available. METHODS: The CTOPP randomized patients undergoing first pacemaker implant to ventricular-based or physiologic pacing (AAI or DDD). Patients who were prospectively found to have persistent atrial fibrillation (AF) lasting greater than or equal to one week were defined as having CAF. Kaplan-Meier plots for the development of CAF were compared by log-rank test. The effect of baseline variables on the benefit of physiologic pacing was evaluated by Cox proportional hazards modeling. RESULTS: Physiologic pacing reduced the development of CAF by 27.1%, from 3.84% per year to 2.8% per year (p = 0.016). Three clinical factors predicted the development of CAF: age > or =74 years (p = 0.057), sinoatrial (SA) node disease (p < 0.001) and prior AF (p < 0.001). Subgroup analysis demonstrated a trend for patients with no history of myocardial infarction or coronary disease (p = 0.09) as well as apparently normal left ventricular function (p = 0.11) to derive greatest benefit. CONCLUSIONS: Physiologic pacing reduces the annual rate of development of chronic AF in patients undergoing first pacemaker implant. Age > or =74 years, SA node disease and prior AF predicted the development of CAF. Patients with structurally normal hearts appear to derive greatest benefits.

How useful is thyroid function testing in patients with recent-onset atrial fibrillation? The Canadian Registry of Atrial Fibrillation Investigators.

BACKGROUND: Patients with recent-onset atrial fibrillation often undergo routine thyroid function screening to rule out thyroid disease as a cause of atrial fibrillation. METHODS: Patients with recent (< 3 months) onset of documented atrial fibrillation or flutter were enrolled in the Canadian Registry of Atrial Fibrillation from outpatient clinics, emergency departments, and hospital wards across Canada. Seven hundred twenty-six patients underwent baseline thyroid function screening and were assessed for presence of clinical thyroid disease. Serum thyrotropin level (TSH) was measured in 707 patients (97%), and thyroxine level (T4) in 407 patients (56%). RESULTS: A TSH level less than 0.1 mU/L was present in 5 patients (0.7%). A TSH level less than normal but more than 0.1 mU/L was present in 34 patients (4.7%). No patient had definite hypothyroidism (TSH > 20 mU/L), but 56 patients (7.7%) had an elevated TSH level that was less than 20 mU/L. During 1.7 years of follow-up, only 7 patients were found to have clinical hyperthyroidism, and 11 patients (1.5%) had hypothyroidism. Logistic regression analysis showed that palpitations (odds ratio, 4.9; 95% confidence interval, 1.7-14.0) and asymptomatic presentation (odds ratio, 5.5; 95% confidence interval, 1.9-16.2) were risk factors for low TSH level, and increasing age (odds ratio, 1.32 every 10 years; 95% confidence interval, 1.01-1.66) was a risk factor for high TSH level. The positive predictive value of palpitations and asymptomatic presentation for low TSH level were 9% and 8%, respectively. CONCLUSIONS: An abnormal TSH level is common in patients with recent-onset atrial fibrillation. However, clinical thyroid disease is uncommon. Routine TSH screening of patients who have atrial fibrillation has a low yield and may be better applied to those patients at higher risk of having undiagnosed clinical thyroid disease.

Effect of pacing cycle length and autonomic blockade on sinus node refractoriness.

Sinus node (SN) refractoriness can be measured indirectly by observing the return responses after the introduction of progressively earlier atrial premature beats. The SN effective refractory period (ERP) is defined as the longest premature interval resulting in an interpolated atrial return response. In the present study, SNERP was analyzed in 71 subjects--51 control persons and 20 patients with evidence of SN dysfunction. SNERP could be measured in 40 of 51 control subjects and was shown to prolong at shorter basic pacing cycle lengths. At a basic cycle length of 600 ms, SNERP was 330 +/- 40 ms, whereas at 500 ms it was 350 +/- 50 ms (p less than 0.05). At a basic cycle length of 600 ms, SNERP was measured in 31 control subjects and 7 patients with SN dysfunction. The values of 330 +/- 40 and 520 +/- 20 ms, respectively, in these 2 groups suggested that this method can be used to differentiate patients with SN dysfunction (p less than 0.001). In 12 control subjects, SNERP was measured before and after partial autonomic blockade with propranolol and atropine. SNERP shortened from 360 +/- 40 to 320 +/- 40 ms (p less than 0.05). It shortened with atropine and prolonged with propranolol. Thus, SNERP prolongs with a shorter basic pacing cycle length and is affected by autonomic manipulation, in a fashion analogous to the atrioventricular node.

Effect of basic pacing cycle length on sinus node refractoriness in the rabbit.

The effect of basic pacing cycle length on sinus node refractoriness was investigated. In 18 rabbit right atrial preparations, the sinus node effective refractory period (SNERP) was measured at multiple basic pacing cycle lengths. In 14 experiments SNERP was measured at basic pacing cycle lengths of 400, 350 and 300 ms. The mean SNERP (+/- standard deviation) prolonged from 168 +/- 31 ms at 400 ms to 181 +/- 37 ms at 350 ms to 196 +/- 40 ms at 400 ms (p less than 0.001). To rule out the possibility that rapid stimulation might release acetylcholine and thus prolong refractoriness, 4 more experiments were conducted in the presence of atropine (2 X 10(-6) M), and similar results were obtained. The spatial orientation of refractoriness was examined in 7 experiments. At the same premature interval, shorter basic pacing cycle lengths resulted in block of the premature impulse at a greater distance from the sinus node. Therefore, in sinus node tissue refractoriness increases with shortening of basic pacing cycle length, a response similar to that of the atrioventricular node.

Nonsustained ventricular tachycardia arising from the right ventricular outflow tract.

Characteristics of left bundle branch block morphology, inferiorly directed frontal plane QRS axis and repetitive nonsustained salvos were used to define a discrete subgroup of patients with ventricular tachycardia (VT). The origin of this tachycardia was thought to be the right ventricular outflow tract. Twenty-six patients with this definition (group 1) were compared with 29 consecutive patients with all other forms of VT (group 2). When compared with patients in group 2, group 1 patients were younger (average age 37 vs 51 years, p less than 0.005), had less structural heart disease (2 of 26 vs 25 of 29 patients, p less than 0.005) and had a better prognosis (no deaths) after an average follow-up time of 28 months in comparison with 5 deaths after an average follow-up of 35 months (p less than 0.05). Induction of VT was possible using isoproterenol infusion in 14 of 20 group 1 patients, but no VT could be induced in 9 group 2 patients (p less than 0.05). Exercise stress testing induced VT in 11 of 21 group 1 patients and 2 of 9 group 2 patients (p greater than 0.05). Programmed electrical stimulation failed to induce VT in 9 group 1 patients, but did induce it in 15 of 20 group 2 patients (p less than 0.005). Successful therapy in group 1 patients was achieved by beta blockers alone (7 patients), beta blockers plus type 1A antiarrhythmic drugs (9 patients), procainamide alone (2 patients), sotalol (3 patients) and amiodarone (2 patients). Three patients were not treated.(ABSTRACT TRUNCATED AT 250 WORDS)

Efficacy of sotalol guided by programmed electrical stimulation for sustained ventricular arrhythmias secondary to coronary artery disease.

Sotalol is a class III antiarrhythmic drug with additional beta-blocker activity that has been shown to be effective in supraventricular and ventricular arrhythmias. Its long-term efficacy for ventricular arrhythmias is not as well described. Patients with documented sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) who had their clinical arrhythmia inducible at baseline electrophysiologic study received sotalol 320 to 640 mg/day. Repeat programmed stimulation was performed after a minimum of 72 hours while receiving the final dose. Of 28 patients (25 men and 3 women) whose arrhythmias were inducible at baseline, 15 had their arrhythmias suppressed with sotalol. Sotalol had greater success in suppressing arrhythmias in those with VF (8 of 9, 89%) than in those with VT (7 of 19, 37%, p < 0.01). In patients with a history of coronary artery disease but no history of myocardial infarction the arrhythmia was suppressed in 7 of 8 (88%) compared with 8 of 20 (40%, p < 0.05) patients with a history of myocardial infarction. All 15 patients in whom ventricular arrhythmias were suppressed continued to take long-term sotalol, and at a follow-up of 10.3 +/- 6.4 months none has had arrhythmia recurrence. Thus, sotalol is an effective drug for the suppression of ventricular arrhythmias as judged by programmed electrical stimulation. It appears to be more effective in patients in whom the clinical arrhythmia is VF rather than VT.

The Canadian Registry of Atrial Fibrillation: a noninterventional follow-up of patients after the first diagnosis of atrial fibrillation.

The Canadian Registry of Atrial Fibrillation (CARAF) is a nondirected, follow-up study of 1,086 patients who are enrolled at 6 centers across Canada at the time of initial electrocardiographically documented diagnosis of atrial fibrillation (AF). Enrollment commenced in 1991 with an intended 10-year follow-up. Comprehensive baseline data, including clinical history, laboratory, and echocardiographic variables were collected. The patients were treated by their own referring physicians and CARAF did not direct their care. Detailed follow-up was performed at 3 months, 1 year, then yearly, with echocardiograms repeated every 2 years. Several studies, which evaluated patient populations, predictors of events, and cardiac structure and functioning, have been performed and are ongoing. Thyroid function was evaluated at baseline, and, of 707 patients evaluated, only 6 patients were found to be hyperthyroid. Symptoms during AF were evaluated and a profile of the types of symptoms and the predictors of symptoms was compiled. Antiarrhythmic drug use is being followed. Sotalol and propafenone were the most commonly used medications, with the use of antiarrhythmic drugs increasing with recurrence of AF. The use of anticoagulants was assessed. The overall use of warfarin was relatively low, but its use increased dramatically with the presence of various risk factors including congestive heart failure, hypertension, and previous stroke. The one risk factor that did not result in increased use of warfarin was hypertension. Therefore, CARAF was able to identify that hypertension appears to be under-recognized and undertreated in its risk for thromboembolic events. CARAF is just now reaching maturity, with the majority of patients having > or=4 years of follow-up. Therefore, extensive investigations are currently under way that will evaluate the baseline characteristics and utilize these as predictors of recurrence of AF, progression to chronicity, and the occurrence of major events such as stroke and death. A very large cohort of patients with serial echocardiograms over 4 years will permit an understanding of the progression of structural and valvular disease. Therefore, CARAF offers a unique opportunity for comprehensive, nondirected follow-up of patients from their initial diagnosis of AF.

Circadian variation of paroxysmal atrial fibrillation. PA3 Investigators. Atrial Pacing Peri-ablation for Prevention of Atrial Fibrillation Trial.

The circadian variation of paroxysmal atrial fibrillation (AF) was studied in 67 patients who received a dual-chamber pacemaker 3 months before a planned atrioventricular node ablation. A distinct circadian variation of AF was observed with 2 time peaks in initiation (1 in the early morning and 1 in the early evening hours), which was modulated by atrial pacing, the duration of AF, and the use of beta-adrenergic blocking agents.

The electrophysiologic basis and management of symptomatic recurrent tachycardia in patients with Ebstein's anomaly of the tricuspid valve.

Twenty-two patients with Ebstein's anomaly were evaluated because of recurrent tachycardia. A total of 30 accessory pathways were present in 21 of the 22 patients. Twenty-six accessory pathways were of the atrioventricular (A-V) type while four were Mahaim fibers. Multiple accessory pathways were present in eight patients. Twenty-five of the 26 accessory A-V pathways were right-sided, either in the posterior septum (12 pathways) or the posterolateral free wall (13 pathways); one patient with corrected transposition of the great arteries had a left-sided accessory A-V pathway in a lateral free wall location. Patients with accessory A-V pathways had a long minimal ventriculoatrial (V-A) conduction time during reciprocating tachycardia (192 +/- 47 ms) and usually showed a persistent complete or incomplete right bundle branch block morphology. At surgery, preexcitation was invariably localized to the atrialized ventricle. The long V-A conduction time during reciprocating tachycardia appeared to consist of late activation of the local ventricle in the region of the accessory pathway with a further delay occurring before excitation of adjacent atrium presumably due to conduction over the accessory pathway. Accessory A-V pathways were successfully sectioned with no deaths in 13 of 15 patients. On the basis of these data, certain electrocardiographic findings encountered in the study of patients with recurrent tachycardia should point to the possibility of associated Ebstein's anomaly: morphology of the surface electrocardiogram suggesting preexcitation of the right posterior septum or right posterolateral free wall as well as the combination during reciprocating tachycardia of a long V-A interval and right bundle branch block.

Cardiovascular effects of epinephrine and dipivalyl epinephrine applied topically to the eye in patients with glaucoma.

The cardiovascular effects of topical ophthalmological preparations of 2% epinephrine (EPI), 0.1% dipivalyl epinephrine (DPE), and placebo were studied in double-blind fashion in 20 patients with glaucoma. Both drugs and placebo produced a decrease in heart rate (2 +/- 3 beats/min) which, although small, was highly significant (p less than 0.001). Neither drug not placebo produced a significant effect on mean or systolic blood pressure (BP) over the group as a whole (p greater than 0.1). However, 5 of 20 patients responded to EPI with a significant rise in mean or systolic BP (defined as a change greater than mean change +/- 2 SD), whereas there were no such responses to DPE or placebo. One patient developed marked ventricular ectopy after EPI. We conclude that EPI may cause cardiovascular side effects in a high percentage of patients (25% in this study) through individual susceptibility rather than a predictable effect. DPE, a new epinephrine analogue, appears to be devoid of these effects.

Clinical trials of pacing mode selection.

Current recommendations in favor of dual-chamber over single-chamber ventricular pacing for patients with sinus node dysfunction or AV conduction disorders were made largely based on observational data and expert opinions. The first randomized pacing mode selection study was relatively small and suggested survival advantage with physiologic pacing only after an extended follow-up duration of 5.5 years. Preliminary results of the first large-scale multicenter randomized pacing mode selection trial revealed only modest reduction in atrial fibrillation without survival advantage after 3 years of physiologic pacing. Two other large-scale multicenter randomized trials comparing physiologic versus ventricular pacing are currently ongoing. They may provide further scientific evidence based on which more objective recommendations can be made with respect to pacing mode selection.

Sinus node dysfunction.

The syndrome of sinus node dysfunction has become increasingly recognized as a cause of symptoms and morbidity, particularly in the elderly population. This syndrome does not represent a homogeneous disease entity. Increased investigation has shown that many pathologic conditions and pathophysiologic mechanism may lead to one of the several clinical and electrocardiographic manifestations of the sick sinus syndrome. Attempts to improve diagnostic accuracy, identify underlying mechanisms and to predict the outcome of therapy have led to the development of various diagnostic tests. However, at present these have proven of limited clinical value and the mainstay of diagnosis remains ECG monitoring. Treatment is directed at the control of symptoms with pacemaker therapy for bradyarrhythmias and combined pacemaker and antiarrhythmic drug therapy for the bradycardiatachycardia syndrome.

QT prolongation and torsades de pointes: the sole manifestation of coronary artery disease.

We describe a case of torsades de pointes as the sole manifestation of coronary artery disease, a presentation not previously reported to our knowledge.

In vitro protein binding of propafenone and 5-hydroxypropafenone in serum, in solutions of isolated serum proteins, and to red blood cells.

The binding of propafenone (PF) and 5-hydroxypropafenone (5-OH-PF) in serum and in solutions of isolated serum proteins was examined by equilibrium dialysis. Both PF and 5-OH-PF displayed pH-dependent binding in serum and in a solution of alpha-1-acid glycoprotein (AAG). PF displayed extensive binding to AAG (i.e., free fraction of 0.08 +/- 0.02), whereas the binding of 5-OH-PF to AAG was moderate (i.e., free fraction of 0.54 +/- 0.10). The removal of lipoproteins from serum did not alter the free fraction of PF but significantly increased the free fraction of 5-OH-PF compared with that in intact serum. Both PF and 5-OH-PF displayed concentration-dependent binding in a 19.3-mumol AAG solution. Concentration-independent binding was apparent in solutions of human serum albumin, high-density lipoproteins, low-density lipoproteins, and very low density lipoproteins over the PF and 5-OH-PF concentration ranges examined. By use of previously determined binding parameters (affinities and capacities), the binding model of PF provided an estimate of the free fraction in serum that was similar to the observed free fraction, although the free fraction of 5-OH-PF was overestimated. The distribution of PF and 5-OH-PF into red blood cells was extensive when buffer was used as the supernatant; however, when serum was used as supernatant, the amounts of PF and 5-OH-PF that were distributed into red blood cells decreased substantially. PF and 5-OH-PF interacted with all of the proteins examined.

Atrial fibrillation: extending basic science to clinical frontiers.

Basic research in atrial fibrillation is advancing with enormous speed, extending the boundaries from research in intact tissues, to cellular electrophysiology and to molecular biology. Never before has the need been greater for a true 'bench to bedside' approach to research. The basic researchers need to understand the potential clinical relevance of their work so that their efforts may be directed to areas of clinical impact. On the other hand, the clinician needs the aid of the basic researcher to help solve some of the vexing clinical problems. Emphasizing the need for this liaison, this paper discusses problems confronted by the clinician and suggests areas of basic research that may help answer the frustration of the clinician in dealing with patients with atrial fibrillation.