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Background: Preventing high heart rates in patients with atrial fibrillation (AF) is a key objective of AF management. Data regarding heart rates in patients with paroxysmal AF (PAF) is lacking. This analysis aimed to provide insight into heart rates during PAF episodes measured with continuous implantable loop monitoring., Methods: In present analysis of the Interaction between hyperCoagulability, Electrical remodeling, and Vascular Destabilization in the Progression of AF study, we included 349 patients with at least one year of continuous rhythm monitoring and an episode of AF. Mean heart rates and duration of AF episodes were used to calculate total AF duration and AF duration above different heart rate cut-offs., Results: The median age was 64.0 (58.4 to 70.5) years, 152 (44%) were women and CHA 2 DS 2 -VASc score ≥2 or higher in 255 (73%) patients. During 28.3 (21.3 to 35.0) months of follow-up, the median number of AF episodes was 62 (12 to 293) with a median total AF duration of 4.6 (0.8 to 26.8) days. At baseline, 172 (49%) patients used beta-blockers, 64 (18%) used diltiazem or verapamil and 5 (1%) used digoxin. A total of 133 patients (38%) experienced a heart rate >110 bpm for more than 50% of the time during AF. Fifty-six (16%) patients had a heart rate >130 bpm for more than 50% of the time while in AF. During follow-up, 39 patients (11%) received an increase of rate-controlling medication., Conclusion: Continuous rhythm monitoring revealed that more than a third of PAF patients had heart rates above 110 bpm for more than half of their time in AF., Trial Registration Number: Clinicaltrials.gov identifier NCT02726698., Competing Interests: Competing interests: RGT reports grants from Medtronic and Abbott, and personal fees from Boehringer Ingelheim, Bayer and Pfizer/Bristol Myers Squibb all outside submitted work. RGT is coinventor of the MyDiagnostick, not receiving royalties for the past 5 years. MDM is a Medtronic employee and WP Coordinator in the H2020 ITN My-Atria (No: 766082). The remaining authors declare no conflicts of interest., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Renal nerve stimulation (RNS) is used to localize sympathetic nerve tissue for selective renal nerve sympathetic denervation (RDN). Examination of heart rate variability (HRV) provides a way to assess the state of the autonomic nervous system. The current study aimed to examine the acute changes in HRV caused by RNS before and after RDN., Methods and Results: 30 patients with hypertension referred for RDN were included. RNS was performed under general anesthesia before and after RDN. Heart rate (HR) and blood pressure (BP) were continuously monitored. HRV characteristics were assessed 1 min before and after RNS and RDN. RNS before RDN elicited a maximum increase in systolic BP of 45 (± 22) mmHg which was attenuated to 13 (± 12) mmHg (p < 0.001) after RDN. RNS before RDN decreased the sinus cycle length from 1210 (± 201) ms to 1170 (± 203) ms (p = 0.03), after RDN this effect was blunted (p = 0.59). The LF/HF ratio in response to RNS changed from ∆ + 0.448 (± 0.550) before RDN to ∆ - 0.656 (± 0.252) after RDN (p = 0.02). Selecting patients off beta-blockade (n = 11), the RNS-induced changes in HRV components before versus after RDN were more pronounced (LF/HF ratio ∆ + 0.900 ± 1.171 versus ∆ - 0.828 ± 0.519, p = 0.01), whereas changes in HRV parameters in patients on beta-blockade (n = 19) were no longer significant. In patients with diabetes mellitus (n = 7), RNS induced no changes in HRV parameters (LF/HF ratio ∆ - 0.039 ± 0.103 versus ∆ - 0.460 ± 0.491, p = 0.92)., Conclusion: RNS induces changes in HRV suggesting increased sympathetic activity. Conversely, after RDN, the RNS-induced changes in HRV suggesting a lower sympathetic autonomic balance. These changes were most pronounced in beta-blocker naïve patients and not present in patients with diabetes mellitus. These findings could support RNS-guided RDN to optimize results.

Hypertension is a risk factor for both progression of atrial fibrillation (AF) and development of AF-related complications, that is major adverse cardiac and cerebrovascular events (MACCE). It is unknown whether left ventricular hypertrophy (LVH) as a consequence of hypertension is also a risk factor for both these end points. We aimed to assess this in low-risk AF patients, also assessing gender-related differences. We included 799 patients from the Euro Heart Survey with nonvalvular AF and a baseline echocardiogram. Patients with and without hypertension were included. End points after 1 year were occurrence of AF progression, that is paroxysmal AF becoming persistent and/or permanent AF, and MACCE. Echocardiographic LVH was present in 33% of 379 hypertensive patients. AF progression after 1 year occurred in 10.2% of 373 patients with rhythm follow-up. In hypertensive patients with LVH, AF progression occurred more frequently as compared with hypertensive patients without LVH (23.3% vs 8.8%, p = 0.011). In hypertensive AF patients, LVH was the most important multivariably adjusted determinant of AF progression on multivariable logistic regression (odds ratio 4.84, 95% confidence interval 1.70 to 13.78, p = 0.003). This effect was only seen in male patients (27.5% vs 5.8%, p = 0.002), while in female hypertensive patients, no differences were found in AF progression rates regarding the presence or absence of LVH (15.2% vs 15.0%, p = 0.999). No differences were seen in MACCE for hypertensive patients with and without LVH. In conclusion, in men with hypertension, LVH is associated with AF progression. This association seems to be absent in hypertensive women., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Heart rate has been associated with prognosis in patients with heart failure with reduced ejection fraction (HFREF) and sinus rhythm; whether this also holds true in patients with atrial fibrillation (AF) is unknown., Hypothesis: To evaluate cardiac rhythm and baseline heart rate and the influence of outcome in patients with HFREF enrolled in the Cardiac Insufficiency Bisoprolol Study II., Methods: In total, 2539 patients were stratified according to their baseline heart rhythm (AF or sinus rhythm) and into quartiles of heart rate (≤70 bpm, 71-78 bpm, 79-90 bpm, and >90 bpm). The primary outcome was all-cause mortality. Mean follow-up was 1.3 years., Results: Mean age was 61 years, mean left ventricular ejection fraction was 28%, and 80% were male. A total of 521 (21%) patients had AF at baseline. The risk associated with all-cause mortality for each 5 bpm increase in heart rate in patients with sinus rhythm (hazard ratio [HR]: 1.06, 95% confidence interval [CI]: 1.01-1.11, P = 0.012) was significantly different from those with AF (HR: 1.00, 95% CI: 0.94-1.07, P = 0.90, P for interaction = 0.041). The risk associated with higher heart rate in sinus rhythm was primarily attributable to excess risk in the highest quartile (HR: 1.64, 95% CI: 1.18-2.30, P = 0.003). Allocation to bisoprolol did not modify the interaction between heart rate, rhythm and outcome., Conclusions: In HFREF patients with AF, a higher heart rate is not associated with increased event rates in contrast to HFREF patients with sinus rhythm., (© 2017 Wiley Periodicals, Inc.)

Control of the heart rate (rate control) is central to atrial fibrillation management, even for patients who ultimately require control of the rhythm. We review heart rate control in patients with atrial fibrillation, including the rationale for the intervention, patient selection, and the treatments available. The choice of rate control depends on the symptoms and clinical characteristics of the patient, but for all patients with atrial fibrillation, rate control is part of the management. Choice of drugs is patient-dependent. β blockers, alone or in combination with digoxin, or non-dihydropyridine calcium-channel blockers (not in heart failure) effectively lower the heart rate. Digoxin is least effective, but a reasonable choice for physically inactive patients aged 80 years or older, in whom other treatments are ineffective or are contraindicated, and as an additional drug to other rate-controlling drugs, especially in heart failure when instituted cautiously. Atrioventricular node ablation with pacemaker insertion for rate control should be used as an approach of last resort but is also an option early in the management of patients with atrial fibrillation treated with cardiac resynchronisation therapy. However, catheter ablation of atrial fibrillation should be considered before atrioventricular node ablation. Although rate control is a top priority and one of the first management issues for all patients with atrial fibrillation, many issues remain., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: The Atrial Fibrillation Follow-up Investigation of Rhythm Management trial showed that digoxin was associated with increased mortality in patients with atrial fibrillation., Objectives: To assess the association of digoxin with cardiovascular (CV) morbidity and mortality in patients with permanent atrial fibrillation enrolled in the Dutch Rate Control Efficacy in Permanent AF: A Comparison Between Lenient Versus Strict Rate Control II trial as well as to assess the role of digoxin to achieve heart rate targets., Methods: The primary outcome was a composite of CV morbidity and mortality. Secondary outcomes included CV hospitalization and all-cause mortality or heart failure (HF) hospitalization. Of the 614 patients, 608 (99%) completed the dose-adjustment phase. Outcome events were analyzed from the end of the dose-adjustment phase until the end of follow-up. The median follow-up period was 2.9 years (interquartile range 2.7-3.0 years)., Results: In total, 284 patients (46.7%) used digoxin after the dose-adjustment phase (median dosage 0.250 mg; interquartile range 0.0625-0.750 mg). These patients were more often women, previously admitted for HF, had an increased left ventricular end-systolic diameter, and more often randomized to strict rate control. By using Cox proportional hazards regression analysis, the use of digoxin was not associated with an increased risk for the primary and secondary outcomes. For the primary outcome, the 3-year estimated cumulative incidence was 12.9% vs 13.4% in the digoxin group vs the no-digoxin group (unadjusted hazard ratio [HR] 0.97; 95% confidence interval [CI] 0.62-1.52). Incidence was 19.4% vs. 19.5% for CV hospitalization (unadjusted HR 1.00; 95% CI 0.69-1.45) and 6.6% vs. 9.9% for all-cause mortality or HF hospitalization (unadjusted HR 0.62; 95% CI 0.34-1.13) in the digoxin group vs the no-digoxin group., Conclusion: The use of digoxin was not associated with increased morbidity and mortality., (Copyright © 2014 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Aims: It is unknown whether lenient rate control is an acceptable strategy in patients with AF and heart failure. We evaluated differences in outcome in patients with AF and heart failure treated with lenient or strict rate control., Methods and Results: This post-hoc analysis of the RACE II trial included patients with an LVEF ≤ 40% at baseline or a previous hospitalization for heart failure or signs and symptoms of heart failure. Primary outcome was a composite of cardiovascular morbidity and mortality. Secondary endpoints were AF-related symptoms and quality of life. Two hundred and eighty-seven (46.7%) of the 614 patients had heart failure. Patients with heart failure had significantly higher NT-proBNP plasma levels, a lower LVEF, and more often used ACE inhibitors, ARBs, and diuretics. At 3 years follow-up, the primary outcome occurred more frequently in patients with heart failure (16.7% vs. 11.5%, P = 0.04). In heart failure patients, the estimated cumulative incidence of the primary outcome was 15.0% (n = 20) in the lenient and 18.2% (n = 26) in the strict group (P = 0.53). No differences were found in any of the primary outcome components, in either heart failure hospitalizations [8 (6.1%) vs. 9 (6.8%) patients in the lenient vs. strict group, respectively], symptoms, or quality of life., Conclusion: In patients with AF and heart failure with a predominantly preserved EF, the stringency of rate control seems to have no effect on cardiovascular morbidity and mortality, symptoms, and quality of life.

In the last few years, there has been a major shift in the treatment of atrial fibrillation (AF) in the setting of hear failure (HF), from rhythm to ventricular rate control in most patients with both conditions. In this article, the authors focus on ventricular rate control and discuss the indications; the optimal ventricular rate-control target, including detailed results of the Rate Control Efficacy in Permanent Atrial Fibrillation: a Comparison Between Lenient versus Strict Rate Control II (RACE II) study; and the pharmacologic and nonpharmacologic options to control the ventricular rate during AF in the setting of HF., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objectives: This study sought to investigate differences in outcome between patients treated with successful strict, failed strict, and lenient rate control., Background: The RACE II (Rate Control Efficacy in Permanent Atrial Fibrillation) study showed no difference in outcome between lenient and strict rate control in patients with permanent atrial fibrillation (AF). However, in the strict group not all patients achieved the pre-defined heart rate target., Methods: The primary outcome was a composite of cardiovascular morbidity and mortality. For the current analysis outcome events were analyzed from end of the dose-adjustment phase until end of follow-up (median 2.9 years [interquartile range: 2.4 to 3.0 years]). Of 614 patients, 608 completed the dose-adjustment phase-301 in the strict (resting heart rate <80 beats/min, and during moderate exercise <110 beats/min) and 307 in the lenient group (resting heart rate <110 beats/min). In the strict group, 203 of 301 patients achieved the rate control target, and 98 failed., Results: Heart rate was different after the dose-adjustment phase between the successful strict (72 ± 7 beats/min), failed strict (86 ± 14 beats/min), and lenient (93 ± 8 beats/min) group (p < 0.001) and remained significantly different during follow-up. The primary outcome was reached in 27 of 203 (14.2% KM estimate) in the successful strict versus 14 of 98 (15%) in the failed strict versus 35 of 307 (12.1%) in the lenient group (p = 0.5). The components of the primary outcome and quality of life were similar in the groups., Conclusions: In patients with permanent AF, successful strict rate control does not improve outcome. Therefore, lenient rate control might be frontline therapy., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to investigate the influence of rate control on quality of life (QOL)., Background: The RACE II (Rate Control Efficacy in Permanent Atrial Fibrillation II) trial showed that lenient rate control is not inferior to strict rate control in terms of cardiovascular morbidity and mortality. The influence of stringency of rate control on QOL is unknown., Methods: In RACE II, a total of 614 patients with permanent atrial fibrillation (AF) were randomized to lenient (resting heart rate [HR] <110 beats/min) or strict (resting HR <80 beats/min, HR during moderate exercise <110 beats/min) rate control. QOL was assessed in 437 patients using the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) questionnaire, AF severity scale, and Multidimensional Fatigue Inventory-20 (MFI-20) at baseline, 1 year, and end of study. QOL changes were related to patient characteristics., Results: Median follow-up was 3 years. Mean age was 68 ± 8 years, and 66% were males. At the end of follow-up, all SF-36 subscales were comparable between both groups. The AF severity scale was similar at baseline and end of study. At baseline and at end of study there were no differences in the MFI-20 subscales between the 2 groups. Symptoms at baseline, younger age, and less severe underlying disease, rather than assigned therapy or heart rate, were associated with QOL improvements. Female sex and cardiovascular endpoints during the study were associated with worsening of QOL., Conclusions: Stringency of heart rate control does not influence QOL. Instead, symptoms, sex, age, and severity of the underlying disease influence QOL. (Rate Control Efficacy in Permanent Atrial Fibrillation; NCT00392613)., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to evaluate echocardiographic remodeling in permanent atrial fibrillation (AF) patients treated with either lenient or strict rate control., Background: It is unknown whether in permanent AF, lenient rate control is associated with more adverse cardiac remodeling than strict rate control., Methods: Echocardiography was conducted at baseline and at follow-up in 517 patients included in the RACE II (RAte Control Efficacy in permanent atrial fibrillation II) trial. Echocardiographic parameters were compared between patients randomized to lenient rate control (n = 261) or strict rate control (n = 256)., Results: Baseline echocardiographic parameters were comparable between patients randomized to lenient and strict rate control. Between baseline and follow-up, significant adverse atrial or ventricular remodeling was not observed in either group. There were also no significant differences in atrial and ventricular remodeling between patients who continuously had heart rates between 80 and 110 beats/min and patients who continuously had heart rates <80 beats/min during follow-up. Lenient rate control was not independently associated with changes in echocardiographic parameters: mean adjusted effect on left atrial size was 1.6 mm (p = 0.09) and 1.1 mm on left ventricular end-diastolic diameter (p = 0.23). Instead, female sex was independently associated with adverse remodeling: mean adjusted effect on left atrial size was 2.4 mm (p = 0.02) and 6.5 mm on left ventricular end-diastolic diameter (p < 0.0001)., Conclusions: Female sex, not lenient rate control, seemed to be associated with significant adverse cardiac remodeling in patients with permanent AF such as those enrolled in the RACE II study. (RAte Control Efficacy in Permanent Atrial Fibrillation [RACE II]; NCT00392613)., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Rate control is often the therapy of choice for atrial fibrillation. Guidelines recommend strict rate control, but this is not based on clinical evidence. We hypothesized that lenient rate control is not inferior to strict rate control for preventing cardiovascular morbidity and mortality in patients with permanent atrial fibrillation., Methods: We randomly assigned 614 patients with permanent atrial fibrillation to undergo a lenient rate-control strategy (resting heart rate <110 beats per minute) or a strict rate-control strategy (resting heart rate <80 beats per minute and heart rate during moderate exercise <110 beats per minute). The primary outcome was a composite of death from cardiovascular causes, hospitalization for heart failure, and stroke, systemic embolism, bleeding, and life-threatening arrhythmic events. The duration of follow-up was at least 2 years, with a maximum of 3 years., Results: The estimated cumulative incidence of the primary outcome at 3 years was 12.9% in the lenient-control group and 14.9% in the strict-control group, with an absolute difference with respect to the lenient-control group of -2.0 percentage points (90% confidence interval, -7.6 to 3.5; P<0.001 for the prespecified noninferiority margin). The frequencies of the components of the primary outcome were similar in the two groups. More patients in the lenient-control group met the heart-rate target or targets (304 [97.7%], vs. 203 [67.0%] in the strict-control group; P<0.001) with fewer total visits (75 [median, 0], vs. 684 [median, 2]; P<0.001). The frequencies of symptoms and adverse events were similar in the two groups., Conclusions: In patients with permanent atrial fibrillation, lenient rate control is as effective as strict rate control and is easier to achieve. (ClinicalTrials.gov number, NCT00392613.), (2010 Massachusetts Medical Society)

Background: Large trials have demonstrated that rate control is an acceptable alternative for rhythm control. However, optimal heart rate during atrial fibrillation (AF) remains unknown. Aim of this analysis was to compare outcome between rate control > or =80 and <80 beat/min in patients with persistent atrial fibrillation., Methods: In the RAte Control versus Electrical cardioversion for persistent atrial fibrillation study, 522 patients were included, and 256 were randomized to rate control. This post hoc analysis included patients randomized to rate control. Patients were divided according to their mean resting heart rate during follow-up, <80 beat/min (n = 75) or > or =80 beat/min (n = 139). The end point, a composite of cardiovascular mortality, heart failure, thromboembolic complications, bleeding, pacemaker implantation, and severe drug side effects, was compared between both groups., Results: During follow-up (2.3 +/- 0.6 years), a significant difference between both groups in heart rate was observed (72 +/- 5 vs 90 +/- 8 beat/min; P < .001). Rate control drugs were not significantly different between both groups. New York Heart Association class and fractional shortening remained unchanged in both groups. There were 17 (23%) end points in the low heart rate group and 24 (17%) in the higher heart rate group (absolute difference, 5.4 [-7.3 to 8.2]; P = ns). Independent predictors for the primary end point were coronary artery disease, digoxin use, and interrupted anticoagulation, not high heart rate. Quality of life was comparable in both groups during follow-up., Conclusions: In patients treated with a rate control strategy, no differences were observed in terms of cardiovascular morbidity, mortality, and quality of life between the observed differences in level of rate control throughout follow-up.

Background: Cardiac resynchronization therapy (CRT) is an established therapy for patients with severe heart failure and mechanical dyssynchrony. Response is only achieved in 60-70% of patients., Objectives: To study exercise-related factors predicting response to CRT., Methods: We retrospectively examined consecutive patients in whom a CRT device was implanted. All underwent cardiopulmonary exercise testing prior to implantation and after 6 months. The occurrence of chronotropic incompetence and heart rates exceeding the upper rate of the device, thereby compromising biventricular stimulation, was studied. Response was defined as a decrease in LVESV of 10% or more after 6 months., Results: We included 144 patients. After 6 months 86 (60%) patients were responders. Peak VO2 significantly increased in responders. Chronotropic incompetence was more frequently seen in nonresponders (21 [36%] vs 9 [10%], P = 0.03), mostly in patients in SR. At moderate exercise, defined as 25% of the maximal exercise tolerance, that is, comparable to daily life exercise, nonresponders more frequently went above the upper rate of the device (13 [22%] vs 2 [3%], P < 0.0001), most of whom were patients in permanent AF. Multivariate analysis revealed heart rates not exceeding the upper rate of the device during moderate exercise (OR 15.8 [3.3-76.5], P = 0.001) and nonischemic cardiomyopathy (OR 2.4 [1.0-5.7], P = 0.04) as predictive for response., Conclusions: Heart rate exceeding the upper rate during moderate exercise is an independent predictor for nonresponse to CRT in patients with AF, whereas chronotropic incompetence is a predictor for patients in SR.

Background: Acute drug conversion of persistent atrial fibrillation usually fails., Objectives: The purpose of this study was to test the proarrhythmic potential, safety, and efficacy of the novel antiarrhythmic agent AZD7009 in patients with persistent atrial fibrillation (AF) or atrial flutter (mean duration 43 days) scheduled for direct current (DC) cardioversion., Methods: Patients were randomized to AZD7009 (3-hour intravenous infusion; n = 86) or placebo (n = 36). AZD7009 was given in doses intended to produce target pseudo-steady-state plasma levels of 0.25, 0.50, 0.75, 1.0, 1.5, 2.0, or 2.5 micromol/L after 30 minutes of infusion. DC cardioversion was performed if conversion to sinus rhythm (SR) did not occur within 2 hours of infusion., Results: AZD7009 in a concentration-dependent manner increased the rate of conversion of AF to SR and shortened the time to conversion. At the three highest target concentrations of AZD7009, 45%, 64%, and 70% of AF patients converted after a mean time of 62, 55, and 26 minutes, respectively, whereas no placebo-treated patients converted. SR was maintained for 24 hours in 21 of 22 patients with drug-associated conversion. AZD7009 treatment was associated with QT-interval prolongation; the increase in QT corrected according to Fridericia typically ranged from 40 to 80 ms at targeted pseudo-steady-state plasma concentrations >or=0.75 micromol/L, but a number of outliers with QT corrected according to Fridericia >550 ms were seen in the higher concentration groups, particularly after conversion to SR and prolonged infusion. None of the patients exhibited torsades de pointes according to predefined criteria; however, one patient exhibited a nonsustained, polymorphic ventricular tachycardia of eight beats with torsades de pointes-like features after AZD7009 infusion (asymptomatic and discovered only upon retrospective Holter tape analysis). Clinical adverse events (primarily dizziness, bradycardia, hypotension, and nausea) were significantly more common in the highest target concentration AZD7009 group vs placebo (P <.001)., Conclusion: AZD7009 exhibited dose-dependent effects in converting AF to SR in AF patients and appeared to be associated with a low risk of proarrhythmia despite continued administration during a period of heightened vulnerability.

Aims: The AFFIRM and RACE studies showed that rate control is an acceptable treatment strategy for atrial fibrillation (AF). We examined whether strict rate control offers benefit over more lenient rate control., Methods and Results: We compared the outcome of patients enrolled in the rate-control arms of AFFIRM and RACE, using data from patients who met a composite of overlapping inclusion and exclusion criteria. We evaluated 1091 patients, 874 from AFFIRM and 217 from RACE. In AFFIRM, the rate-control strategy aimed for a resting heart rate < or =80 bpm and heart rate during daily activity of < or =110 bpm. In RACE, a more lenient approach was taken: resting heart rate <100 bpm. Primary endpoint was a composite of mortality, cardiovascular hospitalization, and myocardial infarction. Mean heart rate across all follow-up visits for patients in AF was lower in AFFIRM (76.1 vs. 83.4 bpm). Event-free survival for the occurrence of the primary endpoint did not differ (64% in AFFIRM vs. 66% in RACE). Patients with mean heart rates during AF within the AFFIRM (< or =80) or RACE (<100) criteria had a better outcome than patients with heart rates > or =100 (hazard ratios 0.69 and 0.58, respectively, for < or =80 and <100 compared with > or =100 bpm)., Conclusion: Stringency of the approach to rate control, based on the comparison of the AFFIRM and RACE studies, was not associated with an important difference in clinical events.

Background: Atrial fibrillation is common in chronic heart failure. Long-term restoration of sinus rhythm is generally unsuccessful. It may be speculated that higher heart rates are unfavorable, since this may lead to tachycardiomyopathy, but there are no data which have examined this., Methods and Results: Seventy-seven patients with atrial fibrillation and advanced chronic heart failure, age 70 +/- 7 years, left-ventricular ejection fraction 0.23 +/- 0.08, 61% with ischemic etiology were included. Patients were dichotomized according to the median heart rate (80 bpm) at inclusion (39 patients with "low" heart rate and 38 patients with "high" heart rate). At baseline, both patient groups were remarkably comparable. After a mean follow-up of 3.3 +/- 0.9 years, mortality was comparable (62% versus 55%, p = non-significant). An independent relation was found between lower heart rate and survival, in addition to absence of hypertension, digoxin use, and higher N-ANP, dopamine, and renin levels., Conclusion: In the present analysis, patients with atrial fibrillation and advanced chronic heart failure with higher heart rates are comparable to those with lower heart rates. Not higher heart rates at baseline but, on the contrary, lower heart rates seem associated with a worse outcome.

Recently, several randomized trials were published on the issue of rate or rhythm control for patients with atrial fibrillation (AF). Patients were typically minor symptomatic, relatively old, with age above 70, presenting with a recurrence of AF and suffering from only mild to moderate underlying heart disease. The main outcome of these trials is that rate control is not inferior to rhythm control for the management of patients with AF concerning morbidity and mortality. Also patients' quality of life did not differ significantly in follow-up in these trials. However, rhythm control is not redundant in the treatment of AF. Focus is now on subgroups of patients who could still have benefit being in sinus rhythm. For severely symptomatic patients, patients presenting with the first episode of AF and probably those with severe congestive heart failure, to restore and maintain sinus rhythm should still be the goal. With the failure of antiarrhythmic therapy, nonpharmacological approaches such as pulmonary vein isolation can be performed. Another finding of the randomized trials is that being in sinus rhythm does not prevent from the occurrence of thromboembolic complications. This means that for patients with AF, with risk factors for thromboembolic events, adequate anticoagulant therapy is indicated irrespective of the current heart rhythm. As with antiarrhythmic therapy, the search for new and safer anticoagulant therapy is underway. This review will focus on the key aspects we have learned from the randomized trials on rate and rhythm controls for patients with AF.

Objectives: This study sought to compare whether gender affects the outcome of rate versus rhythm control treatment in patients with persistent atrial fibrillation (AF)., Background: Large trials have shown that rate control is an acceptable alternative to rhythm control. However, the effects of treatment may differ between male and female patients., Methods: In the Rate Control versus Electrical Cardioversion (RACE) study, 522 patients (192 female) were included and randomized to rate or rhythm control. The occurrence of cardiovascular end points and quality of life (QoL) were compared between female and male patients., Results: At baseline, female patients differed from male patients with regard to age, underlying heart disease, diabetes mellitus, and left ventricular function. Female patients had more AF-related complaints, and QoL was significantly lower. After a mean follow-up of 2.3 +/- 0.6 years, cardiovascular morbidity and mortality was equally distributed between female (21%) and male patients (19%). However, in contrast to male patients, female patients randomized to rhythm control developed more end points (adjusted hazard ratio was 3.1 [95% confidence interval 1.5 to 6.3], p = 0.002), mainly heart failure, thromboembolic complications, and adverse effects of antiarrhythmic drugs, compared with rate control randomized female patients. During follow-up, QoL in female patients remained worse compared with that for male patients. Randomized strategy did not influence QoL in female patients., Conclusions: In female patients with persistent AF, a rhythm control approach leads to more cardiovascular morbidity and mortality. Because treatment strategy did not influence QoL in female patients, a rate control approach may be considered in these patients.

Background: This study was conducted to compare rate- and rhythm-control therapy in patients with persistent atrial fibrillation (AF) and mild to moderate chronic heart failure (CHF). Rate control is not inferior to rhythm control in preventing mortality and morbidity in patients with AF. In CHF, this issue is still unsettled., Methods: In this predefined analysis of the RACE study, a total of 261 patients were in New York Heart Association (NYHA) classes II and III at baseline. These patients were analyzed. The primary end point was a composite of cardiovascular mortality, hospitalization for CHF, thromboembolic complications, bleeding, pacemaker implantation, and life-threatening drug side effects. Furthermore, quality of life was compared., Results: After 2.3 +/- 0.6 years, the primary end point occurred in 29 (22.3%) of the 130 rate-control patients and in 32 (24.4%) of the 131 rhythm-control patients. More cardiovascular deaths, hospitalization for CHF, and bleeding occurred under rate control. Thromboembolic complications, drug side effects, and pacemaker implantation were more frequent under rhythm control. Quality of life did not differ between strategies. In patients successfully treated with rhythm control, the prevalence of end points was not different from those who were in AF at study end. However, the type of end point was different: mortality, bleeding, hospitalization for heart failure, and pacemaker implantation occurred less frequently., Conclusions: In patients with mild to moderate CHF, rate control is not inferior to rhythm control. However, if sinus rhythm can be maintained, outcome may be improved. A prospective randomized trial is necessary to confirm these results.

Objectives: The purpose of this study was to evaluate left ventricular function and atrial and ventricular diameters in patients with persistent atrial fibrillation (AF) treated with rate or rhythm control., Background: Restoration of sinus rhythm in patients with persistent AF may improve left ventricular function and reduce atrial dimensions. Adequate rate control in AF may preserve ventricular function., Methods: In 335 patients included in the RAte Control versus Electrical Cardioversion for Persistent Atrial Fibrillation (RACE) study, echocardiography was performed at baseline and 1- and 2-year follow-up. Echocardiography was compared between patients randomized to rate control (n = 160) and rhythm control (n = 175). In the rhythm control group, echocardiography was compared between patients with AF versus sinus rhythm at study end. Multivariate analysis was performed to determine parameters related to improvement of left ventricular function and increase of atrial diameters., Results: Fractional shortening improved significantly under rate and rhythm control (31 +/- 10% at baseline to 33 +/- 9% at 2 years, and from 30 +/- 10% to 34 +/- 9%; both P < .05, respectively). Under rate control, left and right atrial size increased significantly compared to baseline. Under rhythm control, only left atrial size increased. Multivariate analysis revealed that only sinus rhythm at study end was associated with an increase of fractional shortening. AF at study end, hypertension, and no use of angiotensin-converting enzyme inhibitors were independently associated with increase in atrial size., Conclusions: Routine rate control prevents deterioration of left ventricular function. Maintenance of sinus rhythm is associated with improvement of left ventricular function and reduction of atrial sizes.

Introduction: Atrial fibrillation (AF) is characterized by an irregularly irregular ("random") heart beat. However, controversy exists whether the ventricular rhythm in AF is truly random. We investigated randomness by constructing three-dimensional RR interval plots (3D plots), allowing identification of "clustering" of RR intervals. It was hypothesized that electrical cardioversion (ECV) would be more effective in AF patients with clustering, because clustering might reflect a higher degree of organization of atrial fibrillatory activity., Methods and Results: The study group consisted of 66 patients (44 men and 22 women; mean age 68 +/- 11 years), who were referred for ECV because of persistent AF. Twenty-four-hour Holter recordings were used to construct 3D plots by plotting each RR interval (x axis) against the previous RR interval (y axis) and the number of occurrences of each of these x,y combinations (z axis). A clustering index was calculated as the percentage of beats within the peaks in the 3D plot. Based on the 3D plots, clustering of RR intervals was present in 31 (47%) of the 66 patients. ECV was effective in restoring sinus rhythm in 29 (94%) of these 31 patients, whereas sinus rhythm was restored in only 25 (71%) of the remaining 35 patients without clustering (P = 0.020). The clustering index ranged from <2% in the 12 patients with failed ECV to >8% in the 32 patients with sinus rhythm at the end of the study (4 weeks after the ECV); the clustering index in the 22 patients with a relapse of AF after effective ECV was intermediate (P = 0.034 and P = 0.042, respectively)., Conclusion: This study indicates that ECV is more effective in restoring sinus rhythm in AF patients with clustering compared to patients in whom no clustering is apparent on 3D plots. In addition, the degree of clustering appears to be predictive of the overall outcome of ECV; the higher the degree of clustering, the higher the likelihood of sinus rhythm at follow-up.

Objectives: We studied the influence of rate control or rhythm control in patients with persistent atrial fibrillation (AF) on quality of life (QoL)., Background: Atrial fibrillation may cause symptoms like fatigue and dyspnea. This can impair QoL. Treatment of AF with either rate or rhythm control may influence QoL., Method: Quality of life was assessed in patients included in the Rate Control Versus Electrical Cardioversion for Persistent Atrial Fibrillation (RACE) study (rate vs. rhythm control in persistent AF). Rate control patients (n = 175) were given negative chronotropic drugs and oral anticoagulation. Rhythm control patients (n = 177) received serial electrocardioversion, antiarrhythmic drugs, and oral anticoagulation, as needed. Quality of life was studied using the Short Form (SF)-36 health survey questionnaire at baseline, one year, and the end of the study (after 2 to 3 years of follow-up). At baseline, QoL was compared with that of healthy control subjects. Patient characteristics related to QoL changes were determined., Results: Mean follow-up was 2.3 years. At baseline, QoL was lower in patients than in age-matched healthy controls. At study end, under rate control, three subscales of the SF-36 improved. Under rhythm control, no significant changes occurred compared with baseline. At study end, QoL was comparable between both groups. The presence of complaints of AF at baseline, a short duration of AF, and the presence of sinus rhythm (SR) at the end of follow-up, rather than the assigned strategy, were associated with QoL improvement., Conclusions: Quality of life is impaired in patients with AF compared with healthy controls. Treatment strategy does not affect QoL. Patients with complaints related to AF, however, may benefit from rhythm control if SR can be maintained.

Introduction: Atrial fibrillation (AF) and congestive heart failure (CHF) are two clinical entities that often coincide. Our aim was to establish the influence of concomitant high ventricular rate and consequent development of CHF on electrical remodeling and dilation during atrial tachycardia., Methods and Results: A total of 14 goats was studied. Five goats were subjected to 3:1 AV pacing (A-paced group, atrial rate 240 beats/min, ventricular rate 80 beats/min). Nine goats were subjected to rapid 1:1 AV pacing (AV-paced group, atrial and ventricular rates 240 beats/min). During 4 weeks, right atrial (RA) and left ventricular (LV) diameters were measured during sinus rhythm. Atrial effective refractory periods (AERP) and inducibility of AF were assessed at three basic cycle lengths (BCL). After 4 weeks of rapid AV pacing, RA and LV diameters had increased to 151% and 113% of baseline, whereas after rapid atrial pacing alone, these parameters were unchanged. Right AERP (157+/-10 msec vs 144+/-16 msec at baseline with BCL of 400 msec in the A-paced and AV-paced group, respectively) initially decreased in both groups, reaching minimum values within 1 week. Subsequently, AERP partially recovered in AV-paced goats, whereas AERP remained short in A-paced goats (79+/-7 msec vs 102+/-12 msec after 4 weeks; P < 0.05). Left AERP demonstrated a similar time course. Inducibility of AF increased in both groups and reached a maximum during the first week in both groups, being 20% and 48% in the A-paced and AV-paced group, respectively., Conclusion: Nature and time course of atrial electrical remodeling and dilation during atrial tachycardia are influenced by concurrent high ventricular rate and consequent development of CHF.

Introduction: Many relapses of atrial fibrillation (AF) occur, especially during the first week(s) after electrical cardioversion (ECV). The aim of the present study was to compare in a randomized design the efficacy of verapamil (intracellular calcium lowering) versus digoxin (calcium increasing) for maintenance of sinus rhythm after ECV., Methods and Results: Ninety-seven patients with persistent AF were randomized to verapamil (n = 49) or digoxin (n = 48) for 1 month before and 1 month after ECV. The first month after ECV, patients recorded heart rhythm using daily transtelephonic monitoring. No additional antiarrhythmic drugs were given. Of the 97 patients, 43 patients (20 verapamil) underwent ECV per protocol. Median previous AF duration was 18 and 26 days for verapamil and digoxin, respectively. There were no differences in atrial dimensions and underlying heart disease between the two groups. The success rate of ECV was 75% versus 83% (P = NS). After 1 month, 47% versus 53% (P = NS) had recurrence of AF. Median time to recurrence was 5 days (range 0 to 26) versus 8 days (range 2 to 28) (P = NS), respectively., Conclusion: Stand-alone intracellular calcium lowering by verapamil around ECV does not enhance cardioversion outcome.

Objective: To study efficacy and safety of low-dose amiodarone for maintenance of sinus rhythm after electrical cardioversion of atrial fibrillation or flutter., Design: Nonrandomized trial; mean duration of follow-up, 20.7 months., Setting: Referral center; institutional practice; both hospitalized and ambulatory care., Patients: Eighty-nine consecutive patients having chronic atrial fibrillation or flutter and eligible for cardioversion. Patients had failed previous treatment aimed at maintaining sinus rhythm. During follow-up one patient was withdrawn because of side effects; all patients were available for follow-up., Intervention: Before cardioversion, patients received 600 mg of amiodarone daily during a 4-week loading period. After conversion, the daily maintenance dose was 204 +/- 66 mg (mean +/- SD)., Main Outcome Measures: Arrhythmia recurrence and adverse effects causing drug discontinuation., Results: During loading, 15 patients (16%) converted, and after electrical cardioconversion, 90% of all patients had sinus rhythm. Actuarially, 53% of these patients were still in sinus rhythm after 3 years. In patients with compromised left ventricular function, 93% maintained sinus rhythm after 6 months. One patient died due to congestive heart failure. Intolerable side effects occurred in one patient. No proarrhythmia was observed. Logistic regression analysis revealed that amiodarone was ineffective in patients with mitral stenosis or chronic arrhythmia., Conclusions: Low-dose amiodarone is effective for maintaining sinus rhythm in patients with difficult to treat chronic atrial fibrillation or flutter and is associated with a low incidence of serious side effects.