David H. Birnie

Cardiac-Resynchronization Therapy for Mild-to-Moderate Heart Failure

BACKGROUND Cardiac-resynchronization therapy (CRT) benefits patients with left ventricular systolic dysfunction and a wide QRS complex. Most of these patients are candidates for an implantable cardioverter-defibrillator (ICD). We evaluated whether adding CRT to an ICD and optimal medical therapy might reduce mortality and morbidity among such patients. METHODS We randomly assigned patients with New York Heart Association (NYHA) class II or III heart failure, a left ventricular ejection fraction of 30% or less, and an intrinsic QRS duration of 120 msec or more or a paced QRS duration of 200 msec or more to receive either an ICD alone or an ICD plus CRT. The primary outcome was death from any cause or hospitalization for heart failure. RESULTS We followed 1798 patients for a mean of 40 months. The primary outcome occurred in 297 of 894 patients (33.2%) in the ICD-CRT group and 364 of 904 patients (40.3%) in the ICD group (hazard ratio in the ICD-CRT group, 0.75; 95% confidence interval [CI], 0.64 to 0.87; P<0.001). In the ICD-CRT group, 186 patients died, as compared with 236 in the ICD group (hazard ratio, 0.75; 95% CI, 0.62 to 0.91; P = 0.003), and 174 patients were hospitalized for heart failure, as compared with 236 in the ICD group (hazard ratio, 0.68; 95% CI, 0.56 to 0.83; P<0.001). However, at 30 days after device implantation, adverse events had occurred in 124 patients in the ICD-CRT group, as compared with 58 in the ICD group (P<0.001). CONCLUSIONS Among patients with NYHA class II or III heart failure, a wide QRS complex, and left ventricular systolic dysfunction, the addition of CRT to an ICD reduced rates of death and hospitalization for heart failure. This improvement was accompanied by more adverse events. (Funded by the Canadian Institutes of Health Research and Medtronic of Canada; ClinicalTrials.gov number, NCT00251251.).

HRS expert consensus statement on the diagnosis and management of arrhythmias associated with cardiac sarcoidosis.

David H. Birnie, MD (Chair), William H. Sauer, MD, FHRS, CCDS (Chair), Frank Bogun, MD, Joshua M. Cooper, MD, FHRS, Daniel A. Culver, DO,* Claire S. Duvernoy, MD, Marc A. Judson, MD, Jordana Kron, MD, Davendra Mehta, MD, PhD, FHRS, Jens Cosedis Nielsen, MD, Amit R. Patel, MD, Tohru Ohe, MD, FHRS, Pekka Raatikainen, MD, Kyoko Soejima, MD From the University of Ottawa Heart Institute, Ottawa, Ontario, Canada, University of Colorado, Aurora, Colorado, University of Michigan, Ann Arbor, Michigan, Temple University Health System, Philadelphia, Pennsylvania, Cleveland Clinic, Cleveland, Ohio, VA Ann Arbor Healthcare System and University of Michigan, Ann Arbor, Michigan, Albany Medical College, Albany, New York, Virginia Commonwealth University, Richmond, Virginia, Mount Sinai School of Medicine, New York, New York, Aarhus University Hospital, Aarhus, Denmark, University of Chicago, Chicago, Illinois, Sakakibara Heart Institute of Okayama, Okayama, Japan, Heart Center, Tampere University Hospital, Tampere, Finland, and Kyorin University School of Medicine, Mitaka City, Japan.

Pacemaker or Defibrillator Surgery without Interruption of Anticoagulation

BACKGROUND Many patients requiring pacemaker or implantable cardioverter-defibrillator (ICD) surgery are taking warfarin. For patients at high risk for thromboembolic events, guidelines recommend bridging therapy with heparin; however, case series suggest that it may be safe to perform surgery without interrupting warfarin treatment. There have been few results from clinical trials to support the safety and efficacy of this approach. METHODS We randomly assigned patients with an annual risk of thromboembolic events of 5% or more to continued warfarin treatment or to bridging therapy with heparin. The primary outcome was clinically significant device-pocket hematoma, which was defined as device-pocket hematoma that necessitated prolonged hospitalization, interruption of anticoagulation therapy, or further surgery (e.g., hematoma evacuation). RESULTS The data and safety monitoring board recommended termination of the trial after the second prespecified interim analysis. Clinically significant device-pocket hematoma occurred in 12 of 343 patients (3.5%) in the continued-warfarin group, as compared with 54 of 338 (16.0%) in the heparin-bridging group (relative risk, 0.19; 95% confidence interval, 0.10 to 0.36; P<0.001). Major surgical and thromboembolic complications were rare and did not differ significantly between the study groups. They included one episode of cardiac tamponade and one myocardial infarction in the heparin-bridging group and one stroke and one transient ischemic attack in the continued-warfarin group. CONCLUSIONS As compared with bridging therapy with heparin, a strategy of continued warfarin treatment at the time of pacemaker or ICD surgery markedly reduced the incidence of clinically significant device-pocket hematoma. (Funded by the Canadian Institutes of Health Research and the Ministry of Health and Long-Term Care of Ontario; BRUISE CONTROL ClinicalTrials.gov number, NCT00800137.).

The problem of non-response to cardiac resynchronization therapy.

Purpose of review Cardiac resynchronization therapy improves quality of life, exercise performance, left ventricular ejection fraction, and reduces heart failure hospitalizations and mortality in patients with New York Heart Association class III or IV congestive heart failure and intraventricular conduction delay. A number of key clinical research questions remain, perhaps most importantly the issue of why apparently suitable patients do not respond to cardiac resynchronization therapy. These issues are also relevant to patients who do respond to cardiac resynchronization therapy as potentially their response might be further increased. This article will review the data regarding the frequency of the problem of non-response to cardiac resynchronization therapy and then discuss the postulated reasons and potential solutions. Recent findings Rates of non-response to cardiac resynchronization therapy are often quoted as 20–30%, but a critical analysis of the data would suggest the true non-responder rate can be estimated as perhaps 40–50%. The data indicate that on a population basis non-response is multi-factorial and the extent of mechanical dyssynchrony, left ventricular pacing site and cause of congestive heart failure are likely to be important. Ongoing research is exploring the utility of various techniques for quantifying mechanical dyssynchrony and the potential benefits of targeted left ventricular lead placement and post-implant optimization. Summary Cardiac resynchronization therapy is a major breakthrough in treatment for advanced congestive heart failure patients. There is substantial rate of non-response to this therapy, however, and research is exploring various ways to increase the response to the technique.

The Use of 18F-FDG PET in the Diagnosis of Cardiac Sarcoidosis: A Systematic Review and Metaanalysis Including the Ontario Experience

Cardiac sarcoidosis is a potentially fatal complication of sarcoidosis. The 1993 guidelines of the Ministry of Health, Labour, and Welfare (MHLW) of Japan have been used as the diagnostic gold standard and for comparison with imaging modalities. 18F-FDG PET is not currently included in the guidelines. However, studies have shown promising data using 18F-FDG PET. We conducted a systematic review of studies that evaluated the accuracy of 18F-FDG PET for the diagnosis of cardiac sarcoidosis compared with MHLW guidelines. Data from a prospective Ontario provincial registry are also reported and included in the metaanalysis. Methods: PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched for studies that satisfied predetermined criteria. Quality evaluation using the Quality Assessment for Diagnostic Accuracy Studies was performed by 2 independent masked observers. Data were extracted and analyzed to measure study-specific and pooled accuracy for 18F-FDG PET compared with the MHLW as the reference. Results: A total of 519 titles was identified; 7 studies, including the Ontario registry, were selected for inclusion. Metaanalysis of these 7 studies was conducted, with a total of 164 patients, most of whom had been diagnosed with systemic sarcoidosis. The prevalence of cardiac sarcoidosis was 50% in the whole population. Pooled estimates for 18F-FDG PET yielded 89% sensitivity (95% confidence interval [CI], 79%–96%), 78% specificity (95% CI, 68%–86%), a 4.1 positive likelihood ratio (95% CI, 1.7–10), and a 0.19 negative likelihood ratio (95% CI, 0.1–0.4). The overall diagnostic odds ratio was 25.6 (95% CI, 7.3–89.5), and the area under the summary receiver operator characteristic curve was 93% ± 3.5. The Ontario study yielded sensitivity and specificity of 79% and 70%, respectively. Conclusion: The high diagnostic accuracy determined for 18F-FDG PET in this metaanalysis suggests potential value for diagnosis of cardiac sarcoidosis compared with the MHLW guidelines. These results may affect patient care by providing supportive evidence for more effective use of 18F-FDG PET in the diagnosis of cardiac sarcoidosis. Large-scale multicenter studies are required to further evaluate this role.

Evaluation of Early Complications Related to De Novo Cardioverter Defibrillator Implantation : Insights From the Ontario ICD Database

OBJECTIVES This study examined the predictors of early complications after defibrillator implantation. BACKGROUND Although implantable cardioverter-defibrillators are widely used, predictors of procedural complications and the consequences of these events have not been determined. METHODS In a prospective, multicenter, population-based clinical outcomes registry of all newly implanted defibrillator patients at 18 centers in Ontario, Canada, we examined 45-day complications and all-cause mortality from February 2007 to May 2009. Complications were determined longitudinally and were categorized as direct implant-related or indirect events. RESULTS Among 3,340 patients (mean age 63.8 +/- 12.5 years, 78.5% men), major complications occurred in 4.1% of de novo procedures. Compared with those undergoing a single-chamber device, implantation of a cardiac resynchronization defibrillator (adjusted hazard ratio [HR]: 2.17, 95% confidence interval [CI]: 1.38 to 3.43, p < 0.001) or dual-chamber device (adjusted HR: 1.82, 95% CI: 1.19 to 2.79, p = 0.006) was associated with increased risk of major complications. Major complications were increased in women (adjusted HR: 1.49, 95% CI: 1.02 to 2.16, p = 0.037) and when left ventricular end-systolic dimension exceeded 45 mm (adjusted HR: 1.54, 95% CI: 1.08 to 2.20, p = 0.018). Major complications (excluding death) occurring early after defibrillator implantation were associated with increased adjusted risk of subsequent death up to 180 days after defibrillator implant (adjusted HR: 3.70, 95% CI: 1.64 to 8.33, p = 0.002). Direct implant-related complications were associated with increased risk of early death (adjusted HR: 24.89, p = 0.01), whereas indirect clinical complications conferred increased risk of near-term death (adjusted HR: 12.35, p < 0.001) after defibrillator implantation. CONCLUSIONS Complications after de novo defibrillator implantation were strongly associated with device type. Major complications were associated with increased risk of mortality.

Systematic Assessment of Patients With Unexplained Cardiac Arrest Cardiac Arrest Survivors With Preserved Ejection Fraction Registry (CASPER)

Background— Cardiac arrest without evident cardiac disease may be caused by subclinical genetic conditions. Provocative testing to unmask a phenotype is often necessary to detect primary electrical disease, direct genetic testing, and perform family screening. Methods and Results— Patients with apparently unexplained cardiac arrest and no evident cardiac disease (normal cardiac function on echocardiogram, no evidence of coronary artery disease, and a normal ECG) underwent systematic evaluation that included cardiac magnetic resonance imaging, signal-averaged ECG, exercise testing, drug challenge, and selective electrophysiological testing. Diagnostic criteria were based on accepted criteria or provocation of the characteristic clinical features for long-QT syndrome, catecholaminergic polymorphic ventricular tachycardia, Brugada syndrome, early repolarization, arrhythmogenic right ventricular cardiomyopathy, coronary spasm, and myocarditis. Sixty-three patients in 9 centers were enrolled (age 43.0±13.4 years, 29 women). A diagnosis was obtained in 35 patients (56%): Long-QT syndrome in 8, catecholaminergic polymorphic ventricular tachycardia in 8, arrhythmogenic right ventricular cardiomyopathy in 6, early repolarization in 5, coronary spasm in 4, Brugada syndrome in 3, and myocarditis in 1. Targeted genetic testing demonstrated evidence of causative mutations in 9 (47%) of 19 patients. Screening of 64 family members of these patients identified 15 affected individuals who were treated (24%). The remaining 28 patients (44%) were considered to have idiopathic ventricular fibrillation. Conclusions— Systematic clinical testing, including drug provocation and advanced imaging, results in unmasking of the cause of apparently unexplained cardiac arrest in >50% of patients. This approach assists in directing genetic testing to diagnose genetically mediated arrhythmia syndromes, which results in successful family screening.

Complications associated with defibrillation threshold testing: The Canadian experience

BACKGROUND Defibrillation threshold (DFT) testing has traditionally been a routine part of implantable cardioverter-defibrillator (ICD) implantation, despite a lack of compelling evidence that it predicts or improves outcomes. In the past, when devices were much less reliable, DFT testing seemed prudent; however, modern ICD systems have such a high rate of successful defibrillation that many electrophysiologists now question whether DFT testing is still worthwhile, particularly since DFT testing may now be the highest acute risk component of ICD implantation. OBJECTIVE The purpose of this study was to systematically document complications directly attributable to intraoperative DFT testing. METHODS We obtained data on DFT-related complications from all 21 adult ICD implant centers in Canada, covering the period from January 1, 2000, to September 30, 2006. RESULTS There were a total of 19,067 ICD implants in Canada during the study period. There were three DFT testing-related deaths, five DFT testing-related strokes, and 27 episodes that required prolonged resuscitation. Two patients had significant clinical sequelae after prolonged resuscitation. CONCLUSIONS The risk of severe complications from intraoperative DFT testing appears small, even allowing for the underestimation of its true rate with the current study methodology. These slight but measurable risks must be considered when assessing the risk-benefit ratio of the procedure. Additional data from ongoing prospective ICD registries and/or clinical trials are required.

Discerning the incidence of symptomatic and asymptomatic episodes of atrial fibrillation before and after catheter ablation (DISCERN AF): a prospective, multicenter study.

BACKGROUND The DISCERN AF study (Discerning Symptomatic and Asymptomatic Episodes Pre and Post Radiofrequency Ablation of Atrial Fibrillation) monitored atrial fibrillation (AF) using an implantable cardiac monitor (ICM) to assess the incidence and predictors of asymptomatic AF before and after catheter ablation. METHODS Patients with symptomatic AF underwent implantation of an ICM with an automated AF detection algorithm 3 months before and 18 months after ablation. Patients kept a standardized diary to record symptoms of arrhythmia, and ICM data were downloaded every 3 months. All episodes were blindly adjudicated and correlated with the diary. Asymptomatic recurrences were ICM episodes of 2 minutes or longer with no associated diary symptoms. RESULTS Fifty patients had 2355 ICM episodes. Of these, 69.0% were true AF/atrial flutter (AFL)/atrial tachycardia (AT); 16.0%, sinus with extrasystoles; 11.0%, artifact; and 4.0%, sinus arrhythmia. Total AF/AFL/AT burden was reduced by 86% from a mean (SD) of 2.0 (0.5) h/d per patient before to 0.3 (0.2) h/d per patient after ablation (P < .001), and 56.0% of all episodes were asymptomatic. The ratio of asymptomatic to symptomatic AF episodes increased after ablation from 1.1 to 3.7 (P = .002). By symptoms alone, 29 of 50 patients (58%) were free of AF/AFL/AT after ablation compared with 23 of 50 (46%) using ICM-detected AF/AFL/AT recurrence. Asymptomatic episodes were more likely AFL/AT and were significantly shorter and slower, with lower heart rate variability. However, the postablation state was the strongest independent predictor of asymptomatic AF. CONCLUSIONS The ratio of asymptomatic to symptomatic AF episodes increased from 1.1 before to 3.7 after ablation. Postablation state is the strongest predictor of asymptomatic AF. Symptoms alone underestimate postablation AF burden, with 12% of patients having asymptomatic recurrences only. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00745706.

Arrhythmia characterization and long-term outcomes in catecholaminergic polymorphic ventricular tachycardia.

BACKGROUND Catecholaminergic polymorphic ventricular tachycardia (CPVT) is characterized by adrenergically induced ventricular tachycardia (VT) associated with syncope and sudden death. OBJECTIVE This study sought to characterize arrhythmias associated with CPVT with respect to provocation by exercise and drugs, electrocardiographic characteristics, and association with long-term outcomes; and to explore the relation between age and clinical presentation. METHODS Seventy patients from 16 families were evaluated with exercise and selective adrenaline challenge, and screened for RyR2 mutations. CPVT was diagnosed in probands with symptoms and stress- or adrenaline-provoked VT, or in asymptomatic relatives with provoked VT or RyR2 mutations. Patients were followed up for recurrent syncope, VT, and sudden death. RESULTS Twenty-seven patients including 16 probands were identified (median age 35 years, 67% female). Presentation was cardiac arrest in 33% and syncope in 56%, and 11% were asymptomatic. Polymorphic or bidirectional VT was provoked with exercise in 63% and adrenaline in 82%. The initiating beat of VT was late-coupled and wide (coupling interval 418 ± 42 ms; QRSd 131 ± 17 ms), and QRS morphology suggested an outflow tract origin in 59%. During follow-up of 6.2 ± 5.7 years, 2 patients died despite an implantable cardioverter-defibrillator (ICD), 4 patients received ICD therapy for VT, and 5 patients had inappropriate therapy for supraventricular tachycardia. Patients presenting with late-onset CPVT (age > 21; n = 10) were often female (80%) and less likely to have RyR2 (Ryanodine receptor type 2) mutations (33%), and fatal events were not observed during follow-up (4.1 ± 3.6 years). CONCLUSION Ventricular arrhythmia in CPVT is often initiated from the outflow tract region. Despite β-blocker therapy and selective ICD implantation, breakthrough arrhythmias occur and may be associated with adverse outcomes.