KCNQ1 p.L353L affects splicing and modifies the phenotype in a founder population with long QT syndrome type 1.

BACKGROUND: Variable expressivity and incomplete penetrance between individuals with identical long QT syndrome (LQTS) causative mutations largely remain unexplained. Founder populations provide a unique opportunity to explore modifying genetic effects. We examined the role of a novel synonymous KCNQ1 p.L353L variant on the splicing of exon 8 and on heart rate corrected QT interval (QTc) in a population known to have a pathogenic LQTS type 1 (LQTS1) causative mutation, p.V205M, in KCNQ1-encoded Kv7.1. METHODS: 419 adults were genotyped for p.V205M, p.L353L and a previously described QTc modifier (KCNH2-p.K897T). Adjusted linear regression determined the effect of each variant on QTc, alone and in combination. In addition, peripheral blood RNA was extracted from three controls and three p.L353L-positive individuals. The mutant transcript levels were assessed via qPCR and normalised to overall KCNQ1 transcript levels to assess the effect on splicing. RESULTS: For women and men, respectively, p.L353L alone conferred a 10.0 (p=0.064) ms and 14.0 (p=0.014) ms increase in QTc and in men only a significant interaction effect in combination with the p.V205M (34.6 ms, p=0.003) resulting in a QTc of ∼500 ms. The mechanism of p.L353L's effect was attributed to approximately threefold increase in exon 8 exclusion resulting in ∼25% mutant transcripts of the total KCNQ1 transcript levels. CONCLUSIONS: Our results provide the first evidence that synonymous variants outside the canonical splice sites in KCNQ1 can alter splicing and clinically impact phenotype. Through this mechanism, we identified that p.L353L can precipitate QT prolongation by itself and produce a clinically relevant interactive effect in conjunction with other LQTS variants.

Impact of cardiac resynchronization therapy on hospitalizations in the Resynchronization-Defibrillation for Ambulatory Heart Failure trial.

BACKGROUND: This study reports the impact of cardiac resynchronization therapy (CRT) on hospitalizations in patients randomized to implantable cardioverter-defibrillator (ICD) or ICD-CRT in the Resynchronization-Defibrillation for Ambulatory Heart Failure Trial (RAFT). METHODS AND RESULTS: Hospitalization rates and lengths of hospital stay were compared between the 2 groups. At the 18-month follow-up, the numbers of patients hospitalized for any cause were similar in the ICD (n=351, 38.8%) and ICD-CRT (n=331, 30.0%) groups. The number of patients hospitalized for heart failure was significantly lower in the ICD-CRT (n=101, 11.3%) compared with the ICD (n=141, 15.6%; P=0.003) group. The number of patients hospitalized for a device-related indication was similar in the ICD-CRT group (n=147, 16.4%) and ICD group (n=126, 13.9%; P=0.148). The total number of hospitalizations for any cause (n=1448 versus n=1553; P=0.042), any cardiovascular cause (n=667 versus n=790; P=0.017), and any heart failure cause (n=385 versus n=505; P<0.0001) was significantly lower in ICD-CRT group compared with the ICD group, whereas the number of hospitalizations for device-related causes was significantly higher in the ICD-CRT group compared with the ICD group (246 versus 159; P<0.001). Although the reduction in hospitalizations for heart failure in the CRT-ICD group was offset by an increased number of hospitalizations for device-related indications, the length of hospital stay for any cause was significantly shorter in the ICD-CRT group (8.83±13.30 days) compared with the ICD group (9.59±14.40 days; P=0.005). CONCLUSION: ICD-CRT therapy significantly reduces hospitalizations and total days in hospital in patients with New York Heart Association class II/III heart failure compared with ICD therapy despite increased admissions for device-related indications. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00251251.

Lead Integrity Alert Is Useful for Assessment of Performance of Biotronik Linox Leads.

INTRODUCTION: Medtronic's Lead Integrity Alert (LIA) software algorithm is useful for detecting abnormal parameters across various ICD-lead families. However, its utility in the assessment of the Biotronik Linox™ family of high-voltage (HV) leads is unknown. METHODS: We conducted a retrospective cohort study to assess the performance of the LIA algorithm to detect abnormalities and lead failure in Linox ICD-leads. All LIA-enabled Medtronic devices connected to an active Linox lead were included. The alerts were adjudicated by 2 blinded electrophysiologists and correlated with clinical data. RESULTS: Between 2008 and 2012, data from 208 patients with 564 patient-years of follow-up were available for analysis. The median follow-up duration was 32 (IQR 21-41 months). Twenty-one LIA triggers were noted in 20 different patients. The median delay until a positive LIA was 32 months (IQR 21-41 months) postimplant with a 5-year lead survival free from LIA of 76%. Ninety-five percent (19/20) LIA alerts were true lead failures. The most common LIA triggers were short V-V intervals (85%) and nonsustained ventricular tachycardia (85%). Abrupt changes of the ICD-lead impedance occurred in 5/20 triggers. Inappropriate ICD-shocks were strongly associated with a positive LIA (30% vs. 7.4%; P = 0.006). Of the explanted Linox leads 53% had visible abnormalities. The sensitivity, specificity, and positive predictive value for lead failure in the presence of a LIA trigger were 87%, 99.5%, and 95.2%, respectively. CONCLUSIONS: A positive LIA trigger in Biotronik Linox ICD-leads is highly predictive of lead failure. LIA is useful in ongoing surveillance of lead performance.

Prevention of atrial fibrillation: report from a national heart, lung, and blood institute workshop.

The National Heart, Lung, and Blood Institute convened an expert panel April 28 to 29, 2008, to identify gaps and recommend research strategies to prevent atrial fibrillation (AF). The panel reviewed the existing basic scientific, epidemiological, and clinical literature about AF and identified opportunities to advance AF prevention research. After discussion, the panel proposed the following recommendations: (1) enhance understanding of the epidemiology of AF in the population by systematically and longitudinally investigating symptomatic and asymptomatic AF in cohort studies; (2) improve detection of AF by evaluating the ability of existing and emerging methods and technologies to detect AF; (3) improve noninvasive modalities for identifying key components of cardiovascular remodeling that promote AF, including genetic, fibrotic, autonomic, structural, and electrical remodeling markers; (4) develop additional animal models reflective of the pathophysiology of human AF; (5) conduct secondary analyses of already-completed clinical trials to enhance knowledge of potentially effective methods to prevent AF and routinely include AF as an outcome in ongoing and future cardiovascular studies; and (6) conduct clinical studies focused on secondary prevention of AF recurrence, which would inform future primary prevention investigations.

Canadian Registry of ICD Implant Testing procedures (CREDIT): current practice, risks, and costs of intraoperative defibrillation testing.

BACKGROUND: There is uncertainty about the proper role of defibrillation testing (DT) at the time of implantable cardioverter defibrillator (ICD) insertion. METHODS: A prospective registry was conducted at 13 sites in Canada between January 2006 and October 2007. OBJECTIVES: To document the details of DT, the reasons for not conducting DT, and the costs and complications associated with DT. RESULTS: DT was conducted at implantation in 230 of 361 patients (64%). DT was more likely to be conducted for new implants compared with impulse generator replacements (71% vs 32%, P = 0.0001), but was similar for primary and secondary prevention indications (64% vs 63%, P = NS). Among patients not having DT, the reason(s) given were: considered unnecessary (44%); considered unsafe, mainly due to persistent atrial fibrillation (37%); lack of an anesthetist (20%); and, patient or physician preference (6%). When performed, DT consisted of a single successful shock > or = 10J below maximum device output in 65% of cases. A 10J safety-margin was met by 97% of patients, requiring system modification in 2.3%. Major perioperative complications occurred in 4.4% of patients having DT versus 6.6% of patients not having DT (P = NS). ICD insertion was $844 more expensive for patients having DT (P = 0.16), largely due to increased costs ($28,017 vs $24,545) among patients having impulse generator replacement (P = 0.02). CONCLUSIONS: DT was not performed in a third of ICD implants, usually due to a perceived lack of need or relative contraindication.

Characteristics of patients and implantable defibrillators associated with failure to sense device alert systems.

AIMS: In the era of increasing implantable cardioverter defibrillator (ICD) complexity, the ICD patient alert is deemed to be an important feature in the early detection of ICD system malfunction and is either an audible or a vibratory alert. We sought to evaluate the patient's ability to detect these ICD alerts in the device clinic setting as a surrogate endpoint of clinical utility. METHODS AND RESULTS: From 1 November 2006 to 31 March 2008, 563 patients with an ICD equipped with either an audible patient alert (APA, Medtronic and Guidant; n = 485) or a vibratory monitoring alert ([VMA, St Jude Medical; n = 78) had their alarm demonstrated in the quiet clinic setting. The ability to recognize the alert was analysed and then stratified by gender, age, manufacturer, type of alert, and pocket location. The average patient age was 63.3 (± 13.6) years and 82.8% of patients were male. Implantable cardioverter defibrillator manufacturers were Medtronic (n = 464), Boston Scientific (n = 21), and SJM (n = 78). The APA was heard in 86.0% of patients. This was less likely in patients who were older, male, and where the device was placed in the submuscular position. Every patient with a VMA sensed their alert. CONCLUSION: In the current ICD alert technology, the ability to sense the ICD alert in the device clinic appears to be higher for the VMA than for the APA. In particular, older patients and male patients are less likely to sense the APA.

Cost comparison of ablation versus antiarrhythmic drugs as first-line therapy for atrial fibrillation: an economic evaluation of the RAAFT pilot study.

INTRODUCTION: Radiofrequency ablation (RFA) has become an accepted therapy for atrial fibrillation (AF). The objective of this study was to perform an economic evaluation of RFA versus antiarrhythmic drug therapy (AAD) as first-line treatment of symptomatic paroxysmal AF. METHODS: To estimate and compare the costs of RFA versus AAD, a decision analytic model was developed using data on AF recurrence, hospitalization rates, AAD use, and treatment crossover rates derived directly from the Randomized Trial of RFA versus AAD as First-Line Treatment of Symptomatic Atrial Fibrillation (RAAFT). Resource utilization was modeled to reflect Canadian clinical practice in AF management. Unit costs of healthcare interactions were based on available Canadian government resources and published literature. Costs were assessed based on intention-to-treat. Total expected costs were computed to include initial treatment, hospital stay, physician fees, diagnostic tests, and outpatient visits. Sensitivity analyses were performed to account for the uncertainties. The study was conducted from the third party payer's perspective and costs are reported in 2005 Canadian dollars with 3% discount rate used in the analysis. RESULTS: During the 2-month blanking period following therapy selection, total average costs for RFA and AAD were $10,465 and $2,556, respectively; at 1-year follow-up, these were $12,823 and $6,053; and total 2-year cumulative total average costs were $15,303 and $14,392. Sensitivity analyses did not alter the results, suggesting the model is robust. CONCLUSIONS: RFA as first-line treatment strategy in patients with symptomatic paroxysmal AF was cost neutral 2 years after the initial procedure compared to AAD.

Association Between Patient and Physician Sex and Physician-Estimated Stroke and Bleeding Risks in Atrial Fibrillation.

BACKGROUND: Physicians treating nonvalvular atrial fibrillation (AF) assess stroke and bleeding risks when deciding on anticoagulation. The agreement between empirical and physician-estimated risks is unclear. Furthermore, the association between patient and physician sex and anticoagulation decision-making is uncertain. METHODS: We pooled data from 2 national primary care physician chart audit databases of patients with AF (Facilitating Review and Education to Optimize Stroke Prevention in Atrial Fibrillation and Coordinated National Network to Engage Physicians in the Care and Treatment of Patients with Atrial Fibrillation Chart Audit) with a combined 1035 physicians (133 female, 902 male) and 10,927 patients (4567 female and 6360 male). RESULTS: Male physicians underestimated stroke risk in female patients and overestimated risk in male patients. Female physicians estimated stroke risk well in female patients but underestimated the risk in male patients. Risk of bleeding was underestimated in all. Despite differences in risk assessment by physician and patient sex, > 90% of patients received anticoagulation across all subgroups. There was modest agreement between physician estimated and calculated (ie, CHADS2 score) stroke risk: Kappa scores were 0.41 (0.35-0.47) for female physicians and 0.34 (0.32-0.36) for male physicians. CONCLUSIONS: Our study is the first to examine the association between patient and physician sex influences and stroke and bleeding risk estimation in AF. Although there were differences in agreement between physician estimated stroke risk and calculated CHADS2 scores, these differences were small and unlikely to affect clinical practice; further, despite any perceived differences in the accuracy of risk assessment by sex, most patients received anticoagulation.

Statin use and recurrence of atrial fibrillation after successful cardioversion.

BACKGROUND: Statins have important pleiotropic effects and have been shown to reduce vascular inflammation and the incidence of atrial fibrillation (AF) after cardiac surgery. The role of statins in patients with existing AF is poorly understood. We examined the effect of statins on recurrence of AF in patients after successful cardioversion. METHODS: Statin use and documented recurrence of AF after successful cardioversion were evaluated in 625 patients with new onset AF who were followed prospectively in the Canadian Registry of Atrial Fibrillation. Logistic regression was used to model the effect of statin use on the recurrence of AF at 1 year while adjusting for potential confounders including concurrent medications. RESULTS: In a predominantly male population (62%) with median age 63 years, 12.3% were on statins at baseline. Overall, 32.5% had documented recurrence of AF at 1 year; 23.4% in patients on statins compared to 33.8% in those not on statins (P = .07). After adjustment for baseline differences and concomitant beta-blocker use, statin use was associated with a 74% reduction in AF recurrence, but only in statin users on beta-blockers (OR 0.26, 95% CI 0.10-0.66); statin users not on beta-blockers (OR 1.07, 95% CI 0.44-2.58). CONCLUSIONS: In an observational study of patients with new onset AF, statin use was associated with a significant 74% reduction in the odds of recurrent AF, but only in patients also taking beta-blockers. Importantly, statin without concomitant beta-blocker use was not associated with any changes in AF recurrence.

Cost comparison of catheter ablation and medical therapy in atrial fibrillation.

INTRODUCTION: There is emerging evidence for clinical superiority of catheter ablation over rate and rhythm control strategies in paroxysmal atrial fibrillation (PAF). The objective of this study was to compare costs related to medical therapy versus catheter ablation for PAF in Ontario (Canada). METHODS: Costs related to medical therapy in the analysis included the cost of anticoagulation, rate and rhythm control medications, noninvasive testing, physician follow-up visits, and hospital admissions, as well as the cost of complications related to this management strategy. Costs related to catheter ablation were assumed to include the cost of the ablation tools (electroanatomic mapping or intracardiac echocardiography-guided pulmonary vein ablation), hospital and physician billings, and costs related to periprocedural medical care and complications. Costs related to these various elements were obtained from the Canadian Registry of Atrial Fibrillation (CARAF), government fee schedules, and published data. Sensitivity analyses looking at a range of initial success rates (50-75%) and late attrition rates (1-5%), prevalence of congestive heart failure (CHF) (20-60%), as well as discounting varying from 3% to 5% per year were performed. RESULTS: The cost of catheter ablation ranged from $16,278 to $21,294, with an annual cost of $1,597 to $2,132. The annual cost of medical therapy ranged from $4,176 to $5,060. Costs of ongoing medical therapy and catheter ablation for PAF equalized at 3.2-8.4 years of follow-up. CONCLUSION: Catheter ablation is a fiscally sensible alternative to medical therapy in PAF with cost equivalence after 4 years.

The effect of atrial-based pacing on exercise capacity as measured by the 6-minute walk test: a substudy of the Canadian Trial of Physiological Pacing (CTOPP).

BACKGROUND: Although several randomized trials have detected no reduction in major cardiovascular events with the routine use of dual-chamber as opposed to ventricular pacemakers, many individuals continue to advocate their use as a means of improving exercise capacity. METHODS: The Canadian Trial of Physiological Pacing (CTOPP) trial is the largest trial comparing ventricular pacing to atrial-based pacing (atrial or dual-chamber) in patients with bradycardia. All patients in this trial were asked to complete a 6-minute hall walk test (6MWT) at the time of their first study follow-up. The distance walked in 6 minutes and the patient's heart rate before and immediately after the walk were recorded. RESULTS: Of the 2568 patients in the CTOPP, 76% completed the 6MWT. The mean distance walked was 350 +/- 127 m in the ventricular pacing group and 356 +/- 127 m in the atrial-based group (P = NS). Similarly, there was no difference in the change in heart rate between the two groups (17 +/- 13 vs. 18 +/- 12 bpm: P = NS). However, among patients with an unpaced heart rate of

Progression of paroxysmal to persistent atrial fibrillation: 10-year follow-up in the Canadian Registry of Atrial Fibrillation.

BACKGROUND: Progression from paroxysmal to persistent atrial fibrillation (AF) has important clinical implications and is relevant to the management of patients with AF. OBJECTIVE: The purpose of this study was to define the long-term rate of progression from paroxysmal to persistent AF and the relevant clinical variables. METHODS: The Canadian Registry of Atrial Fibrillation enrolled patients after a first electrocardiographic diagnosis of paroxysmal AF. Associations between baseline characteristics and clinical outcomes were evaluated using a multivariable Cox proportional hazard model and a competing risk model accounting for death as a competing risk, where appropriate. RESULTS: We enrolled 755 patients (61.7% men) aged between 14 and 91 years (mean age 61.2 ± 14.2 years). The median follow-up was 6.35 years (interquartile range 2.93-10.04 years), with a rate of progression to persistent AF at 1, 5, and 10 years was 8.6%, 24.3%, and 36.3%, respectively. All-cause mortality was 30.3% at 10 years. Factors associated with AF progression were increasing age (hazard ratio [HR] 1.40; 95% confidence interval [CI] 1.23-1.60, for each 10-year increment), mitral regurgitation (HR 1.87; 95% CI 1.28-2.73), left atrial dilatation (HR 3.01; 95% CI 2.03-4.47), aortic stenosis (HR 2.40; 95% CI 1.05-5.48), and left ventricular hypertrophy (HR .47; 95% CI 1.04-2.08). Factors associated with a lower rate of progression were a faster heart rate during AF (HR 0.94; 95% CI 0.92-0.96 per 5-beat/min increment) and angina (HR 0.54; 95% CI 0.38-0.77). After accounting for death as a competing risk, left ventricular hypertrophy and aortic stenosis were no longer significant. CONCLUSION: Within 10 years of presenting with paroxysmal AF, >50% of patients will progress to persistent AF or be dead. Increasing age, mitral regurgitation, aortic stenosis, left ventricular hypertrophy, and left atrial dilatation were associated with progression to persistent AF.

Use of Evidence-Based Therapy for Cardiovascular Risk Factors in Canadian Outpatients With Atrial Fibrillation: From the Facilitating Review and Education to Optimize Stroke Prevention in Atrial Fibrillation (FREEDOM AF) and Co-ordinated National Network to Engage Physicians in the Care and Treatment of Patients With Atrial Fibrillation (CONNECT AF).

Using data collected from 2 national atrial fibrillation (AF) primary care physician chart audits (Facilitating Review and Education to Optimize Stroke Prevention in Atrial Fibrillation [FREEDOM AF] and Co-ordinated National Network to Engage Physicians in the Care and Treatment of Patients With Atrial Fibrillation [CONNECT AF]), we evaluated the frequency of, and factors associated with, the use of cardiovascular (CV) evidence-based therapies in Canadian AF outpatients with at least 1 CV risk factor or co-morbidity. Of the 11,264 patients enrolled, 9,495 (84.3%) were eligible for one or more CV evidence-based therapies. The proportions of patients with AF receiving all eligible guideline-recommended therapies were 40.8% of patients with coronary artery disease, 48.9% of patients with diabetes mellitus, 40.2% of patients with heart failure, 96.7% of patients with hypertension, and 55.1% of patients with peripheral arterial disease. Factors that were independently associated with nonreceipt of all indicated evidence-based therapies included sinus rhythm rather than AF at baseline and liver disease. In conclusion, although most Canadian outpatients with AF have CV risk factors or co-morbidities, a substantial portion of these patients did not receive all guideline-recommended therapies. These findings suggest that there is an opportunity to improve the quality of care for patients with AF in Canada.

Efficacy of azimilide for the maintenance of sinus rhythm in patients with paroxysmal atrial fibrillation in the presence and absence of structural heart disease.

Azimilide hydrochloride (azimilide), an investigational antiarrhythmic drug, has shown variable efficacy in preventing atrial fibrillation (AF). This study was designed to assess its efficacy in maintaining sinus rhythm in patients with paroxysmal AF and heart disease. Patients with symptomatic paroxysmal AF were screened for 1 month by transtelephonic monitoring. After recording 1 episode of AF in the screening period, they were randomized to receive azimilide 125 mg or placebo once daily. Patients were stratified by the presence or absence of congestive heart failure or coronary heart disease (CHF/CHD). A maximum of 220 patients without CHF/CHD were randomized, with the remainder having CHF/CHD. Patients with CHF/CHD were monitored for 3 days during loading. The primary efficacy analysis was the time to the first symptomatic recurrence of AF in the CHF/CHD group. Secondary analyses were the time to the first recurrence in the entire population and the time to the first recurrence in those with significant structural heart disease. The median time to recurrence of AF in the CHF/CHD group was 10 days in the 2 treatment arms. Nonsignificant trends were seen toward efficacy of azimilide in the CHF/CHD group (hazard ratio 1.28, 95% confidence interval 0.97 to 1.70, p=0.087), structural heart disease group (hazard ratio 1.22, 95% confidence interval 0.96 to 1.56, p=0.11), and overall group (hazard ratio 1.22, 95% confidence interval 1.00 to 1.49, p=0.053). No patient died. In conclusion, azimilide showed a nonsignificant trend toward efficacy in maintaining sinus rhythm in patients with AF.

A novel, simple scale for assessing the symptom severity of atrial fibrillation at the bedside: the CCS-SAF scale.

BACKGROUND: The severity of symptoms caused by atrial fibrillation (AF) is extremely variable. Quantifying the effect of AF on patient well-being is important but there is no simple, commonly accepted measure of the effect of AF on quality of life (QoL). Current QoL measures are cumbersome and impractical for clinical use. OBJECTIVE: To create a simple, concise and readily usable AF severity score to facilitate treatment decisions and physician communication. METHODS: The Canadian Cardiovascular Society (CCS) Severity of Atrial Fibrillation (SAF) Scale is analogous to the CCS Angina Functional Class. The CCS-SAF score is determined using three steps: documentation of possible AF-related symptoms (palpitations, dyspnea, dizziness/syncope, chest pain, weakness/fatigue); determination of symptom-rhythm correlation; and assessment of the effect of these symptoms on patient daily function and QoL. CCS-SAF scores range from 0 (asymptomatic) to 4 (severe impact of symptoms on QoL and activities of daily living). Patients are also categorized by type of AF (paroxysmal versus persistent/permanent). The CCS-SAF Scale will be validated using accepted measures of patient-perceived severity of symptoms and impairment of QoL and will require 'field testing' to ensure its applicability and reproducibility in the clinical setting. CONCLUSIONS: This type of symptom severity scale, like the New York Heart Association Functional Class for heart failure symptoms and the CCS Functional Class for angina symptoms, trades precision and comprehensiveness for simplicity and ease of use at the bedside. A common language to quantify AF severity may help to improve patient care.

The Risk Stratification and Stroke Prevention Therapy Care Gap in Canadian Atrial Fibrillation Patients.

BACKGROUND: Canadian atrial fibrillation (AF) guidelines recommend that all AF patients be risk stratified with respect to stroke and bleeding, and that most should receive antithrombotic therapy. METHODS: As part of the Canadian Facilitating Review and Education to Optimize Stroke Prevention in Atrial Fibrillation (FREEDOM AF) chart audit, data were collected on 4670 patients ≥ 18 years old without significant valvular heart disease from the primary care practices of 474 physicians (February to September, 2011). RESULTS: Physicians did not provide an estimate of stroke and bleeding risk in 15% and 25% of patients, respectively. When risks were provided, they were on the basis of a predictive stroke and bleeding risk index in only 50% and 26% of patients, respectively. There were over- and underestimation of stroke and bleeding risk in a large proportion of patients. Antithrombotic therapy included warfarin (90%); 24% of patients had a time in the therapeutic range (TTR) < 50%, 9% between 50% and 60%, 11% between 60% and 70%, and 56% had a TTR ≥ 70%. CONCLUSIONS: In a large Canadian AF population, primary care physicians did not provide a stroke or bleeding risk in a substantial proportion of their AF patients. When estimates were provided, they were on the basis of a predictive stroke and bleeding risk index in less than half of the patients. Furthermore, there was under- and overestimation of stroke and bleeding risk in a substantial proportion of patients. As many as 1 in 3 patients receiving warfarin have their TTR < 60%. These findings suggest an opportunity to enhance knowledge translation to primary care physicians.

Experience with bisoprolol in long-QT1 and long-QT2 syndrome.

BACKGROUND: The protective effect of beta-blockers in patients with inherited Long-QT syndrome is well established. Recent reports have suggested that beta-blockers are not equally effective in Long-QT (LQT). Bisoprolol is an attractive candidate for use in LQT because of its cardioselective properties and favorable side-effect profile. METHODS: We performed a retrospective cohort study of 114 consecutive patients with gene-positive Long-QT syndrome type 1 (LQT1) or Long-QT syndrome type 2 (LQT2) treated with bisoprolol, nadolol or atenolol with a total of 580 person-years of follow-up. Electrocardiogram (ECG) parameters and cardiac events during follow-up were compared. In addition, exercise treadmill testing was performed in bisoprolol-treated patients. RESULTS: Fifty-nine patients were treated with bisoprolol, 39 with atenolol and 16 with nadolol. Overall, 59 % were females and 62 % had LQT1. Baseline heart rate and corrected QT (QTc) interval were similar between the groups. QTc shortening was observed in individuals on bisoprolol (ΔQTc -5 ± 31 ms; p = 0.049) and nadolol (ΔQTc -13 ± 16 ms; p = 0.02) but not on atenolol (ΔQTc +9 ± 24 ms; p = 0.16). Median follow-up was similar for bisoprolol and nadolol (3 years), but longer for atenolol (6 years; p = 0.03); one cardiac event occurred in the bisoprolol group (1.7 %) and two events occurred in the atenolol group (5.1 %; p = 0.45), whereas none occurred in nadolol-treated patients. Beta-blocker efficacy was not affected by the underlying genotype. The antiadrenergic effect of bisoprolol correlated with the reduction of peak heart rates at exercise testing. CONCLUSIONS: Bisoprolol treatment results in QTc shortening in gene-positive LQT1 and LQT2 patients and is well tolerated during long-term administration. The equivalence of bisoprolol for protection from ventricular arrhythmia in LQT patients compared to established beta-blockers remains unknown. Further large-scale studies are required.

Canadian Trial of Physiological Pacing: Effects of physiological pacing during long-term follow-up.

BACKGROUND: The Canadian Trial of Physiological Pacing (CTOPP) reported that the risk of stroke or cardiovascular death was similar between patients receiving ventricular versus physiological pacemakers at the end of the original follow-up period of 3 years. However, the occurrence of atrial fibrillation was significantly less frequent with physiological pacemakers. To assess a potential delayed benefit of physiological pacing, follow-up of patients in this study was extended to 6 years. METHODS AND RESULTS: A total of 1474 patients requiring a pacemaker for symptomatic bradycardia were randomized to receive ventricular and 1094 to physiological pacemakers. The primary outcome was stroke or cardiovascular death. The study was completed in July 1998, and follow-up was extended to July 2001. At a mean follow-up of 6.4 years, there was no difference between treatment groups in the primary outcome of cardiovascular death or stroke. There was no significant difference in total mortality or stroke between groups. There was a significantly lower rate of development of atrial fibrillation in the physiological group, with a relative risk reduction of 20.1% (CI, 5.4 to 32.5; P=0.009). CONCLUSIONS: The CTOPP extended study does not show a difference in cardiovascular death or stroke, or in total mortality, or in stroke between patients implanted with ventricular or physiological pacemakers over a mean follow-up of >6 years. However, there is a persistent significant reduction in the development of atrial fibrillation with physiological pacing.

Progression to chronic atrial fibrillation after the initial diagnosis of paroxysmal atrial fibrillation: results from the Canadian Registry of Atrial Fibrillation.

BACKGROUND: After its initial diagnosis, atrial fibrillation (AF) may progress from paroxysmal to chronic AF (CAF). The rate of progression and risk factors for progression are not clearly defined. METHODS: The Canadian Registry of Atrial Fibrillation (CARAF) enrolled patients from 6 Canadian cities at the time of their first electrocardiographic diagnosis of AF. Comprehensive clinical and echocardiographic data were collected and patients were followed annually, carefully documenting clinical outcomes, recurrence of paroxysmal AF, and progression to CAF. Baseline clinical, electrocardiographic, and echocardiographic variables were evaluated by univariate Cox proportionate hazards analysis. A stepwise approach was used to model the association between echocardiographic and clinical variables with progression to CAF. RESULTS: A total of 757 patients with a baseline diagnosis of paroxysmal AF were evaluated. Median follow-up was 8.0 years (range 2 days to 11.1 years). The probability of progression to CAF by 1 year was 8.6% and thereafter there was a slow but steady progression to 24.7% by 5 years. By 5 years, the probability of documented recurrence of any AF (chronic or paroxysmal) was 63.2%. Increasing age, significant aortic stenosis or mitral regurgitation, left atrial enlargement, and diagnosis of cardiomyopathy were independently associated with progression to CAF. A more rapid heart rate during AF was associated with decreased risk of progression. CONCLUSIONS: After the initial diagnosis of paroxysmal AF, there is a slow but steady progression to CAF. Baseline echocardiographic variables, age, cardiomyopathy, and heart rate were independently associated with progression to CAF.