Dofetilide reduces the frequency of ventricular arrhythmias and implantable cardioverter defibrillator therapies.

BACKGROUND: Patients with an implanted cardioverter defibrillator (ICD) and ventricular arrhythmias leading to ICD therapies have poor clinical outcomes and quality of life. Antiarrhythmic agents and catheter ablation are needed to control these arrhythmias. Dofetilide has only been approved for the treatment of atrial fibrillation. The role of dofetilide in the control of ventricular arrhythmias in patients with an ICD has not been established. OBJECTIVE: Evaluate the safety and efficacy of dofetilide in a consecutive group of patients with an ICD and recurrent ventricular tachycardia (VT) and/ or ventricular fibrillation (VF) after other antiarrhythmic drugs have failed to suppress these arrhythmias. METHODS: We studied 30 patients (age 59 ± 11; 5 women) with symptomatic VT or VF and ICDs for secondary prevention of sudden cardiac death. These patients had an average of 1.8 ± 4.5 episodes of VT/VF per month despite antiarrhymic therapy. Twenty-one patients (70%) had recurrent appropriate ICD therapies prior to initiation of dofetilide, and 9 (30%) VTs below the programmed detection rate of the ICD. Twenty-three patients (77%) had coronary artery disease. Mean ejection fraction was 30 ± 14% and 26/30 (87%) had congestive heart failure. All patients had previously failed 2 ± 1 antiarrhythmic drugs including amiodarone (n = 19) and sotalol (n = 10). RESULTS: During the first month of treatment, 25 patients (83%) had complete suppression of VT/VF and of the 21 patients with ICD therapies 16 (76%) had no therapies during the first month of treatment. During a follow-up period of 32 ± 32 months, dofetilide reduced the monthly episodes of VT/VF from 1.8 ± 4.5 to 1.0 ± 3.5 (P = 0.006). Monthly ICD therapies decreased from 0.9 ± 1.4 to 0.4 ± 1.7 (P = 0.037). In 9 patients that presented with slow VTs under the ICD detection zone, dofetilide reduced monthly VT/VF episodes from 0.7 ± 0.6 to 0.1 ± 0.1 (P = 0.01) and 6 (67%) had no further ICD therapies. Dofetilide was discontinued in 13 patients (43%) after 24 ± 30 months due to failure to control VT/VF (n = 7), placement of a left ventricular assist device (n = 3), catheter ablation (n = 1), heart transplantation (n = 1), and left ventricular restoration surgery (n = 1). There were 7 documented deaths (2 patients died suddenly; 3 patients of progressive heart failure; and 2 of non-cardiac causes). CONCLUSIONS: In patients with an ICD and ventricular arrhythmias, dofetilide decreases the frequency of VT/VF and ICD therapies even when other antiarrhythmic agents, including amiodarone, have previously been ineffective. Recurrences still occur in some patients requiring catheter ablation, mechanical support, or heart transplantation.

The circadian pattern of cardiac autonomic modulation in a middle-aged population.

OBJECTIVES: To examine the circadian pattern of cardiac autonomic modulation (CAM) and its attributes in general population. METHODS: We obtained 24-h beat-to-beat RR data using a high resolution 12-lead Holter ECG in a community-dwelling sample of 115 non-smokers. We performed heart rate variability (HRV) analysis on the normal RRs from each 5-min segment to obtain time-specific HRV indices: high (HF; 0.15-0.40 Hz) and low (LF; 0.04-0.15 Hz) frequency powers, standard deviation of RR intervals (SDNN), and the square root of the mean of the sum of the squared differences of the adjacent RR intervals (RMSSD). For each individual, we fit the segment-specific HRV data to a cosine periodic function, and estimated 3 individual-level cosine function parameters to quantify the circadian variation: the mean (M), amplitude (A), and acrophase (θ). We then used a random-effects meta-analysis to summarize the M, A, and θ, and their 95% confidence intervals (CI). RESULTS: The mean age was 56 (SD 8) years, with 63% female and 76% white. The averages of M, A and θ (95%CI) of log HF were 3.59 (3.43-3.76) ms(2), 0.61 (0.54-0.68) ms(2), and 3:10 (2:25-3:55) AM, respectively, and that of RMSSD were 22.3 (20.5-24.1) ms, 6.5 (5.4-7.5) ms, 3:45 (2:55-4:35) AM, respectively. Older age is associated with lower mean of HRV. Males have higher oscillation amplitude than females. The acrophase of LF/HF was earlier in females than in males, and in younger individuals than in older individuals. CONCLUSIONS: The circadian pattern of CAM can be quantified by 3 cosine parameters of HRV, which are correlated with age and gender.

Direct Oral Anticoagulants in Patients with Atrial Fibrillation and Bioprosthetic Valves-A Systematic Review and Meta-analysis.

Oral anticoagulation is recommended for patients with atrial fibrillation and an elevated stroke risk. Direct oral anticoagulants (DOACs) are generally preferred over vitamin K antagonists. Nonetheless, there controversy persists regarding whether DOACs should be used in patients with atrial fibrillation and bioprosthetic valves. Therefore, we conducted this systematic review and meta-analysis to assess the safety and efficacy of DOACs compared to warfarin in this patient population. We performed a systematic search of the MEDLINE and PubMed Central databases for relevant articles. The incidence rate and risk ratio (RR) of all-cause mortality, cardiovascular mortality, ischemic stroke/systemic thromboembolism, hemorrhagic stroke/intracranial bleeding, major bleeding, and minor bleeding were calculated. A total of eight studies were included, including 5,300 patients (stratified as 1,638 patients in the DOAC arm and 3,662 patients in the warfarin arm). There was no significant difference in the rate of stroke/systemic thromboembolism [RR: 0.85; 95% confidence interval (CI): 0.43-1.69], all-cause mortality (RR: 0.77; 95% CI: 0.53-1.11), or cardiovascular death (RR: 0.81; 95% CI: 0.40-1.63) between DOACs and warfarin. Major bleeding and hemorrhagic stroke/intracranial bleeding were similar between both treatment arms (RR: 0.61; 95% CI: 0.35-1.06 and RR: 0.27; 95% CI: 0.06-1.13, respectively). In conclusion, DOACs are safe and effective in patients with atrial fibrillation and bioprosthetic valves. Future large-scale randomized studies are warranted to confirm this observation.

Oral Anticoagulation Use in High-Risk Patients Is Improved by Elimination of False-Positive and Inactive Atrial Fibrillation Cases.

BACKGROUND: Multiple registries have reported that >40% of high-risk atrial fibrillation patients are not taking oral anticoagulants. The purpose of our study was to determine the presence or absence of active atrial fibrillation and CHA2DS2-VASc (Congestive heart failure, Hypertension, Age ≥75 y, Diabetes mellitus, prior Stroke [or transient ischemic attack or thromboembolism], Vascular disease, Age 65-74 y, Sex category) risk factors to accurately identify high-risk atrial fibrillation (CHA2DS2-VASc ≥2) patients requiring oral anticoagulants and the magnitude of the anticoagulant treatment gap. METHODS: We retrospectively adjudicated 6514 patients with atrial fibrillation documented by at least one of: billing diagnosis, electronic medical record encounter diagnosis, electronic medical record problem list, or electrocardiogram interpretation. RESULTS: After review, 4555/6514 (69.9%) had active atrial fibrillation, while 1201 had no documented history of atrial fibrillation and 758 had a history of atrial fibrillation that was no longer active. After removing the 1201 patients without a confirmed atrial fibrillation diagnosis, oral anticoagulant use in high-risk patients increased to 71.1% (P < .0001 compared with 62.9% at baseline). Oral anticoagulant use increased to 79.7% when the 758 inactive atrial fibrillation patients were also eliminated from the analysis (P < .0001 compared with baseline). In the active high-risk atrial fibrillation group, there was no significant difference in the use of oral anticoagulants between men (80.7%) and women (78.8%) with a CHA2DS2-VASc ≥2, or in women with a CHA2DS2-VASc ≥3 (79.9%). CONCLUSIONS: Current registries and health system health records with unadjudicated diagnoses over-report the number of high-risk atrial fibrillation patients not taking oral anticoagulants. Expert adjudication identifies a smaller treatment gap than previously described.

A Quarter of a Century Later: What is Dofetilide's Clinical Role Today?

Dofetilide is a class III antiarrhythmic agent approved by the Food and Drug Administration for the conversion of atrial fibrillation and atrial flutter and maintenance of sinus rhythm in symptomatic patients with persistent arrhythmia. Drug trials showed neutral mortality in post-myocardial infarction patients and those with heart failure. This is a review of postmarket data, including real-world efficacy and safety in a variety of populations. Dofetilide has been used off-label with success in patients with paroxysmal atrial fibrillation and atrial flutter, as well as atrial tachycardia and ventricular tachycardia. The real-world acute conversion rate of atrial fibrillation and atrial flutter is higher than that reported in clinical trials. Dofetilide has an acceptable safety profile when initiated (or reloaded) under hospital monitoring and dosed according to creatinine clearance. Dofetilide is well tolerated and a good choice for patients with acceptable renal function and a normal QT interval, especially if atrioventricular nodal blockade needs to be avoided.

Efficacy and safety of dofetilide in patients with atrial fibrillation and atrial flutter.

BACKGROUND: Dofetilide, an I(Kr) blocker has been demonstrated to be effective in terminating persistent atrial fibrillation and flutter (AF/AFL), and in maintaining sinus rhythm after direct current cardioversion (CV). It is not known, however, whether pharmacological conversion with dofetilide predicts maintenance of sinus rhythm. In addition, there is limited information comparing the efficacy of dofetilide in persistent versus paroxysmal AF/AFL. METHODS AND RESULTS: Eighty consecutive patients with AF/AFL (51 persistent, 29 paroxysmal) admitted for initiation of dofetilide were studied. Termination of persistent AF/AFL occurred in 61% of patients while 39% required CV. After 21 +/- 19 months of follow-up, 37% of patients with persistent AF/AFL were free of recurrence. Acute conversion with dofetilide did not predict long term efficacy. Dofetilide was more effective in maintaining sinus rhythm in patients with AFL (65%) than in those with AF (25%) (p < 0.05). Dofetilide was more likely to maintain sinus rhythm in patients with persistent than paroxysmal AF/AFL (37 vs. 14%; p < 0.05). Torsades de Pointes developed in two patients despite careful dosing and monitoring of QT changes. CONCLUSIONS: Dofetilide is more effective in patients with persistent than in those with paroxysmal AF/AFL. Importantly, short-term response does not necessarily predict long-term efficacy. Significant proarrhythmia can occur even with careful in-hospital monitoring.

Risk of proarrhythmia with class III antiarrhythmic agents: sex-based differences and other issues.

Although men have a higher risk of atrial fibrillation compared with women, the absolute number of women with atrial fibrillation is greater. Congestive heart failure increases the risk of developing atrial fibrillation in women more than in men, and the prognosis for women with atrial fibrillation is worse than for men. The longer baseline corrected QT interval in women is well known. The mechanism is likely the result of increased circulating androgens, causing the QT interval to shorten in men after puberty. Female sex is associated with an increased risk of torsades de pointes in the setting of potassium antagonists. Class III antiarrhythmic drugs are frequently used for the treatment of atrial fibrillation in heart failure patients because of their neutral effect on mortality and their tolerance by patients with low ejection fractions. Although amiodarone and azimilide carry a low potential for producing torsades de pointes compared with sotalol and dofetilide, the prevalence of torsades de pointes in women is at least twice that in men for all these drugs. Careful monitoring of the QT interval and potassium level, as well as control of congestive heart failure, can help reduce the risk of proarrhythmia. Avoidance of polypharmacy with other potassium antagonists and unmonitored drug formulation changes are important in the management of all patients taking class III agents, but they are particularly crucial in women with additional risk factors for torsades de pointes.

Old and new antiarrhythmic drugs for converting and maintaining sinus rhythm in atrial fibrillation: comparative efficacy and results of trials.

In managing atrial fibrillation (AF), the main therapeutic strategies include rate control, termination of the arrhythmia, and the prevention of recurrences and thromboembolic events. Safety and efficacy considerations are important in optimizing the choice of an antiarrhythmic drug for the treatment of AF. Recently approved antiarrhythmics, such as dofetilide, and promising investigational drugs, such as azimilide and dronedarone, may change the treatment landscape for AF. For medical conversion of recent-onset AF, class IC antiarrhythmic drugs, administered as an oral bolus, have been demonstrated to be the most efficacious pharmacologic conversion agents. Intravenous ibutilide and oral dofetilide both have efficacies superior to placebo in controlled trials for converting persistent AF. Comparative trials in paroxysmal AF have demonstrated that flecainide, propafenone, quinidine, and sotalol are equally effective in preventing recurrences of AF. Amiodarone has been demonstrated to be more efficacious than propafenone or sotalol in the Canadian Trial of Atrial Fibrillation. In persistent AF, twice-daily dofetilide has been shown to be as or more effective than low-dose sotalol given twice daily for the maintenance of sinus rhythm in patients with AF. Trials have demonstrated that subjective adverse effects are less frequent with class IC drugs, sotalol, and dofetilide compared with such drugs as quinidine. In patients without structural heart disease, flecainide, propafenone, and D,L-sotalol are the initial drugs of choice, given their reasonable efficacy, low incidence of subjective side effects, and lack of significant end-organ toxicity. Treating AF in patients with left ventricular dysfunction can be difficult because of associated electrophysiologic derangements, potential proarrhythmic concerns, and negative inotropic effects of antiarrhythmics. Some data exist suggesting that angiotensin-converting enzyme inhibitors and angiotensin receptor blockers can prevent AF either by preventing atrial dilation and stretch-induced arrhythmias or by blocking the renin-angiotensin system. In post-myocardial infarction patients, D,L-sotalol, dofetilide, and amiodarone-and in congestive heart failure patients, amiodarone and dofetilide-have demonstrated neutral effects on survival in controlled trials. In the Congestive Heart Failure Survival Trial of Antiarrhythmic Therapy (CHF-STAT), amiodarone lowered the frequency of AF development and improved left ventricular ejection fraction over time. In CHF-STAT, there was lower mortality in patients who converted from AF to sinus rhythm. Dofetilide decreased rehospitalization for congestive heart failure in the Danish Investigations of Arrhythmia and Mortality on Dofetilide (DIAMOND) trials. Neutral effects on survival and favorable hemodynamics have positioned amiodarone and dofetilide as the antiarrhythmics of choice in patients with left ventricular dysfunction. In post-myocardial infarction patients, sotalol is an additional agent to consider for treatment of AF in this setting.

A review of clinical trials assessing the efficacy and safety of newer antiarrhythmic drugs in atrial fibrillation.

Clinical trials assessing the efficacy of anti- arrhythmic drugs for terminating atrial fibrillation have demonstrated that rate control drugs have little to no added efficacy compared to placebo; however, spontaneous conversion of recent-onset atrial fibrillation is common. Antiarrhythmic drugs such as oral dofetilide, oral bolus-flecainide and propafenone and intravenous ibutilide all have a role in terminating atrial fibrillation. Active comparator trials have demonstrated that amiodarone is more efficacious in maintaining sinus rhythm than propafenone and sotalol. Multiple trials have demonstrated the safety of amiodarone, sotalol, dofetilide and azimilide in a post-myocardial infarction population and amiodarone and dofetilide in a congestive heart failure population. Newer antiarrhythmic agents, some with novel mechanisms of action, will add to the pharmacologic armamentarium in treating atrial fibrillation.

Entrainment of ventricular tachycardia with a permanent biventricular pacemaker.

Biventricular pacing has been introduced as a treatment for congestive heart failure. These devices presently pace and sense from two disparate ventricular sites. Antitachycardia pacing (ATP) is used for termination of sustained monomorphic ventricular tachycardia (VT) and has been incorporated with simultaneous dual site ventricular pacing for treatment of VT. We report a case of entrainment of sustained monomorphic VT in a 62-year-old female with an ischemic cardiomyopathy and VT, who received a biventricular pacemaker-implantable cardioverter defibrillator, Contak CD (Guidant, St. Paul, MN). Biventricular pacing sites were at the right ventricular apex and the middle of the anterior cardiac vein on the left ventricle. The entrained VT has a left bundle branch block and left axis deviation morphology with a cycle length of 350 msec. ATP at 270 msec produced concealed entrainment of an induced VT. Only one pacing site demonstrated capture. The inability to capture both pacing sites simultaneously was the result of ventricular refractoriness at one of the sites during ATP of the VT. The entrance and exit points of the loop for VT appeared to rest between the two pacing sites in the intraventricular septum. This case illustrates one of the sensing limitations of today's biventricular pacing defibrillator systems.

Clinical efficacy of dofetilide for the treatment of atrial tachyarrhythmias in adults with congenital heart disease.

BACKGROUND: Atrial tachyarrhythmias (AT) including atrial fibrillation (AF), atrial flutter (AFL), and atrial tachycardia represent a clinical challenge in the adult with congenital heart disease (CHD). Dofetilide (D) is a rapidly activating delayed rectifier potassium channel (IKr) blocker effective in pharmacological conversion and maintenance of normal sinus rhythm in patients with AF and AFL. There is limited knowledge regarding the role of D in adults with CHD. METHODS: Safety and efficacy of D was evaluated in a consecutive group of thirteen adult patients (age 40 ± 11; six women) with CHD and refractory AT. RESULTS: Ten patients had persistent (four AFL, one AF, and five atrial tachycardia) and three paroxysmal (one AF and two atrial tachycardia) AT. All patients were symptomatic during tachycardia, 12 patients had previously failed 2 ± 1 antiarrhythmic drugs. Mean systemic ventricular ejection fraction was 55 ± 9%; baseline QRS complex duration was 129 ± 45 ms (>120 ms in six patients). Patients were followed on D for 33 ± 39 months (median 16). Among 10 patients with persistent AT, seven patients (70%) pharmacologically converted to sinus rhythm on D and three patients (30%) required direct current cardioversion. Two patients (15.4%) experienced complete arrhythmia suppression, and seven (53.8%) experienced significant clinical improvement with sporadic recurrences; average time to recurrence was 5.5 ± 3.5 months. One patient developed torsade de pointes during loading, and the drug was discontinued. D was discontinued in five (38.5%) other patients due to recurrence of AT (n = 4) and renal failure (n = 1). Corrected QT interval (QTc) increased from 452 ± 61 to 480 ± 49 ms (P = .04) and corrected JT interval (JTc) from 323 ± 39 to 341 ± 33 ms (P = .09). CONCLUSIONS: D should be considered a pharmacologic alternative when adult patients with CHD develop AT. D does not depress conduction, sinus node, or ventricular function but needs close monitoring for potential ventricular pro-arrhythmia.

Clinical significance of increased tricuspid valve incompetence following implantation of ventricular leads.

PURPOSE: Cardiac rhythm management devices (CRMD) require a ventricular lead to be placed across the tricuspid valve. Tricuspid regurgitation (TR) is an under-recognized clinical complication of lead implantation and its clinical significance is unknown. We studied the incidence of hospitalizations for congestive heart failure (CHF) exacerbation among patients with worsening TR after ventricular lead implantation. METHODS: We reviewed 148 patients (age 68 ± 15) that received a CRMD. TR and pulmonary artery systolic pressure (PASP) measured by Doppler echocardiography before and after CRMD implantation were analyzed. Hospitalizations for CHF exacerbation post-implantation were counted. RESULTS: Follow-up was 32 ± 14 months. Ninety-nine (67%) patients had no change, 24 (16%) slight, and 9 (6%) significant increase in TR after CRMD implantation, while 13 (9%) patients had slight and 3 (2%) significant improvement. Patients with a significant increase in TR had higher incidence of hospitalizations (1.7 ± 0.5) compared to patients with slight (0.8 ± 1; p = 0.006) or no increase (0.5 ± 1; p = 0.0002) in TR. Patients with significant increase in TR had a greater change in PASP (25 mmHg; p = 0.002) after device implantation compared to those with a slight (10 mmHg; p = 0.002) or no increase (0.7 mmHg; p = 0.17). CONCLUSION: Increased TR following CRMD implantation is relatively common (33%) and correlated with subsequent risk of hospitalization for heart failure. A preventive strategy and close monitoring for development or worsening of CHF after CRMD implantation may help prevent hospital admissions.

Individual-level PM2.5 exposure and the time course of impaired heart rate variability: the APACR Study.

In 106 community-dwelling middle-aged non-smokers we examined the time-course and the acute effects of fine particles (PM2.5) on heart rate variability (HRV), which measures cardiac autonomic modulation (CAM). Twenty-four hours beat-to-beat ECG data were visually examined. Artifacts and arrhythmic beats were removed. Normal beat-to-beat RR data were used to calculate HRV indices. Personal PM2.5 nephelometry was used to estimate 24-h individual-level real-time PM2.5 exposures. We use linear mixed-effects models to assess autocorrelation- and other major confounder-adjusted regression coefficients between 1-6 h moving averages of PM2.5 and HRV indices. The increases in preceding 1-6 h moving averages of PM2.5 was significantly associated with lower HF, LF, and SDNN, with the largest effect size at 4-6 h moving averages and smallest effects size at 1 h moving average. For example, a 10 µg/m³ increase in 1 and 6-h moving averages was associated with 0.027 and 0.068 ms² decrease in log-HF, respectively, and with 0.024 and 0.071 ms² decrease in log-LF, respectively, and with 0.81 and 1.75 ms decrease in SDNN, respectively (all P-values <0.05). PM2.5 exposures are associated with immediate impairment of CAM. With a time-course of within 6 h after elevated PM2.5 exposure, with the largest effects around 4-6 h.

Safety and efficacy of dronedarone in the treatment of atrial fibrillation/flutter.

Dronedarone is an amiodarone analog but differs structurally from amiodarone in that the iodine moiety was removed and a methane-sulfonyl group was added. These modifications reduced thyroid and other end-organ adverse effects and makes dronedarone less lipophilic, shortening its half-life. Dronedarone has been shown to prevent atrial fibrillation/flutter (AF/AFl) recurrences in several multi-center trials. In addition to its rhythm control properties, dronedarone has rate control properties and slows the ventricular response during AF. Dronedarone is approved in Europe for rhythm and rate control indications. In patients with decompensated heart failure, dronedarone treatment increased mortality and cardiovascular hospitalizations. However, when dronedarone was used in elderly high risk AF/AFl patients excluding such high risk heart failure, cardiovascular hospitalizations were significantly reduced and the drug was approved in the USA for this indication in 2009 by the Food and Drug Administration. Updated guidelines suggest dronedarone as a front-line antiarrhythmic in many patients with AF/Fl but caution that the drug should not be used in patients with advanced heart failure. In addition, the recent results of the PALLAS trial suggest that dronedarone should not be used in the long-term treatment of patients with permanent AF.

Systemic inflammation and circadian rhythm of cardiac autonomic modulation.

Systemic inflammation (SI) is associated with impairment of cardiac autonomic modulation (CAM), which is associated with cardiac disease. However, there is limited data about SI on CAM circadian pattern, which this study aimed to investigate in a middle-aged sample. C-reactive protein (CRP) was used as a SI marker. We performed HRV analysis on each 5-min segment RRs from a 24-h 12-lead ECG to obtain time and frequency domain HRV indices as measures of CAM. The circadian pattern of CAM was analyzed by a two-stage modeling. Stage one, for each individual we fit a cosine periodic model based on the 288 segments of 5-min HRV data to produce three individual-level cosine parameters that quantity the circadian pattern: mean (M), amplitude (Â), and acrophase time (θ), measure the overall average, the amplitude of the oscillation, and the timing of the highest oscillation, respectively. Stage two, we used random-effects-meta-analysis to summarize the effects of CRP on the three circadian parameters obtained in stage one. CRP was adversely associated with lower M of log-HF, log-LF, SDNN, and RMSSD [ß (SE): -0.22 (0.07) ms(2), -0.20 (0.06) ms(2), -3.62 (0.99) ms, and -2.32 (0.73) ms, respectively, with all p-values <0.01]. More importantly, CRP was also adversely associated with lower  of SDNN and RMSSD [ß (SE): -0.84 (0.44) ms and -0.86 (0.38) ms, respectively, both p-values <0.05]. SI is adversely associated with circadian pattern of CAM, suggesting that the cardiac risk associated with SI may be partially mediated via inflammation-related changes in CAM.

A review of the appropriate and inappropriate use of dronedarone: lessons learned from controlled studies and regulatory submission.

Dronedarone is a multichannel blocker with electrophysiologic effects similar to amiodarone. Dronedarone has been documented to prevent atrial fibrillation recurrences and also has efficacy in slowing the ventricular response during episodes of atrial fibrillation. However, in the ANDROMEDA trial, dronedarone was associated with increased mortality when tested in New York Heart Association (NYHA) III/IV patients with left ventricular ejection fractions of less than 35%, who also had a recent hospitalization for decompensated heart failure. When such high-risk patients with heart failure were excluded in the ATHENA trial, dronedarone treatment resulted in a statistical reduction in the composite primary end point of all-cause mortality or cardiovascular hospitalization. In ATHENA, dronedarone reduced cardiovascular hospitalizations even though in the DIONY-SOS trial dronedarone had less effect than amiodarone on suppressing atrial fibrillation recurrences. The most appropriate patients for treatment with dronedarone would be patients with a recent history of paroxysmal or persistent atrial fibrillation/atrial flutter (AF/AFL) that have associated risk factors per the inclusion criteria of ATHENA. Inappropriate patients would be those with class IV heart failure or recently hospitalized for heart failure within the last month from an acute decompensation, the main inclusion criteria in ANDROMEDA. Dronedarone is a novel, multichannel blocking antiarrhythmic agent that may have some pleiotropic effects in addition to its ability to suppress and maintain sinus rhythm and control the rate during AF/AFL recurrences.

Acute adverse effects of fine particulate air pollution on ventricular repolarization.

BACKGROUND: The mechanisms for the relationship between particulate pollution and cardiac disease are not fully understood. OBJECTIVE: We examined the effects and time course of exposure to fine particulate matter < or = 2.5 microm in aerodynamic diameter (PM(2.5)) on ventricular repolarization of 106 nonsmoking adults who were living in communities in central Pennsylvania. METHODS: The 24-hr beat-to-beat electrocardiogram (ECG) data were obtained using a high-resolution 12-lead Holter system. After visually identifying and removing artifacts and arrhythmic beats, we summarized normal beat-to-beat QTs from each 30-min segment as heart rate (HR)-corrected QT measures: QT prolongation index (QTI), Bazett's HR-corrected QT (QTcB), and Fridericia's HR-corrected QT (QTcF). A personal PM(2.5) monitor was used to measure individual-level real-time PM(2.5) exposures for 24 hr. We averaged these data and used 30-min time-specific average PM(2.5) exposures. RESULTS: The mean age of the participants was 56 +/- 8 years, with 41% male and 74% white. The means +/- SDs for QTI, QTcB, and QTcF were 111 +/- 6.6, 438 +/- 23 msec, and 422 +/- 22 msec, respectively; and for PM(2.5), the mean +/- SD was 14 +/- 22 microg/m3. We used distributed lag models under a framework of linear mixed-effects models to assess the autocorrelation-corrected regression coefficients (beta) between 30-min PM(2.5) and the HR-corrected QT measures. Most of the adverse ventricular repolarization effects from PM(2.5) exposure occurred within 3-4 hr. The multivariable adjusted beta (SE, p-value) due to a 10-microg/m3 increase in lag 7 PM(2.5) on QTI, QTcB, and QTcF were 0.08 (0.04, p < 0.05), 0.22 (0.08, p < 0.01), and 0.09 (0.05, p < 0.05), respectively. CONCLUSIONS: Our results suggest a significant adverse effect of PM(2.5) on ventricular repolarization. The time course of the effect is within 3-4 hr of elevated PM(2.5).