Clinical and molecular characterization of a cardiac ryanodine receptor founder mutation causing catecholaminergic polymorphic ventricular tachycardia

Background Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a difficult-to-diagnose cause of sudden cardiac death (SCD). We identified a family of 1400 individuals with multiple cases of CPVT, including 36 SCDs during youth. Objectives We sought to identify the genetic cause of CPVT in this family, to preventively treat and clinically characterize the mutation-positive individuals, and to functionally characterize the pathogenic mechanisms of the mutation. Methods Genetic testing was performed for 1404 relatives. Mutation-positive individuals were preventively treated with β-blockers and clinically characterized with a serial exercise treadmill test (ETT) and Holter monitoring. In vitro functional studies included caffeine sensitivity and store overload–induced calcium release activity of the mutant channel in HEK293 cells. Results We identified the p.G357S_RyR2 mutation, in the cardiac ryanodine receptor, in 179 family members and in 6 SCD cases. No SCD was observed among treated mutation-positive individuals over a median follow-up of 37 months; however, 3 relatives who had refused genetic testing (confirmed mutation-positive individuals) experienced SCD. Holter monitoring did not provide relevant information for CPVT diagnosis. One single ETT was unable to detect complex cardiac arrhythmias in 72% of mutation-positive individuals, though the serial ETT improved the accuracy. Functional studies showed that the G357S mutation increased caffeine sensitivity and store overload–induced calcium release activity under conditions that mimic catecholaminergic stress. Conclusion Our study supports the use of genetic testing to identify individuals at risk of SCD to undertake prophylactic interventions. We also show that the pathogenic mechanisms of p.G357S_RyR2 appear to depend on β-adrenergic stimulation

Prognostic implications of left ventricular global longitudinal strain in heart failure patients with narrow QRS complex treated with cardiac resynchronization therapy: a subanalysis of the randomized EchoCRT trial

Aim: Left ventricular (LV) global longitudinal strain (GLS) reflects LV systolic function and correlates inversely with the extent of LV myocardial scar and fibrosis. The present subanalysis of the Echocardiography Guided CRT trial investigated the prognostic value of LV GLS in patients with narrow QRS complex. Methods and results: Left ventricular (LV) global longitudinal strain (GLS) was measured on the apical 2-, 4- and 3-chamber views using speckle tracking analysis. Measurement of baseline LV GLS was feasible in 755 patients (374 with cardiac resynchronization therapy (CRT)-ON and 381 with CRT-OFF). The median value of LV GLS in the overall population was 7.9%, interquartile range 6.2–10.1%. After a mean follow-up period of 19.4 months, 95 patients in the CRT-OFF group and 111 in the CRT-ON group reached the combined primary endpoint of all-cause mortality and heart failure hospitalization. Each 1% absolute unit decrease in LV GLS was independently associated with 11% increase in the risk to reach the primary endpoint (Hazard ratio 1.11; 95% confidence interval 95% 1.04–1.17, P < 0.001), after adjusting for ischaemic cardiomyopathy and randomization treatment among other clinically relevant variables. When categorizing patients according to quartiles of LV GLS, the primary endpoint occurred more frequently in patients in the lowest quartile (<6.2%) treated with CRT-ON vs. CRT-OFF (45.6% vs. 28.7%, P = 0.009) whereas, no differences were observed in patients with LV GLS ≥6.2% treated with CRT-OFF vs. CRT-ON (23.7% vs. 24.5%, respectively; P  = 0.62). Conclusion: Low LV GLS is associated with poor outcome in heart failure patients with QRS width <130 ms, independent of randomization to CRT or not. Importantly, in the group of patients with the lowest LV GLS quartile, CRT may have a detrimental effect on clinical outcomes

Displasia ventricular direita arritmogênica: diagnóstico, prognóstico e tratamento

Descritas as características anátomo-clinicas da displasia ventricular direita arritmogênica e discutidos os métodos diagnósticos e terapêuticos, é apresentada a Série de Maastricht constituída de 14 pacientes, com os dados clínicos, diagnósticos e terapêuticos num tempo médio de 4.2 anos de acompanhamento

Cryoballoon or Radiofrequency Ablation for Paroxysmal Atrial Fibrillation.

BACKGROUND: Current guidelines recommend pulmonary-vein isolation by means of catheter ablation as treatment for drug-refractory paroxysmal atrial fibrillation. Radiofrequency ablation is the most common method, and cryoballoon ablation is the second most frequently used technology. METHODS: We conducted a multicenter, randomized trial to determine whether cryoballoon ablation was noninferior to radiofrequency ablation in symptomatic patients with drug-refractory paroxysmal atrial fibrillation. The primary efficacy end point in a time-to-event analysis was the first documented clinical failure (recurrence of atrial fibrillation, occurrence of atrial flutter or atrial tachycardia, use of antiarrhythmic drugs, or repeat ablation) following a 90-day period after the index ablation. The noninferiority margin was prespecified as a hazard ratio of 1.43. The primary safety end point was a composite of death, cerebrovascular events, or serious treatment-related adverse events. RESULTS: A total of 762 patients underwent randomization (378 assigned to cryoballoon ablation and 384 assigned to radiofrequency ablation). The mean duration of follow-up was 1.5 years. The primary efficacy end point occurred in 138 patients in the cryoballoon group and in 143 in the radiofrequency group (1-year Kaplan-Meier event rate estimates, 34.6% and 35.9%, respectively; hazard ratio, 0.96; 95% confidence interval [CI], 0.76 to 1.22; P<0.001 for noninferiority). The primary safety end point occurred in 40 patients in the cryoballoon group and in 51 patients in the radiofrequency group (1-year Kaplan-Meier event rate estimates, 10.2% and 12.8%, respectively; hazard ratio, 0.78; 95% CI, 0.52 to 1.18; P=0.24). CONCLUSIONS: In this randomized trial, cryoballoon ablation was noninferior to radiofrequency ablation with respect to efficacy for the treatment of patients with drug-refractory paroxysmal atrial fibrillation, and there was no significant difference between the two methods with regard to overall safety. (Funded by Medtronic; FIRE AND ICE ClinicalTrials.gov number, NCT01490814.)

The effect of QRS duration on cardiac resynchronization therapy in patients with a narrow QRS complex: a subgroup analysis of the EchoCRT trial

Aims In EchoCRT, a randomized trial evaluating the effect of cardiac resynchronization therapy (CRT) in patients with a QRS duration of <130 ms and echocardiographic evidence of left ventricular dyssynchrony, the primary outcome occurred more frequently in the CRT when compared with the control group. According to current heart failure guidelines, CRT is recommended in patients with a QRS duration of ≥120 ms. However, there is some ambiguity from clinical trial data regarding the benefit of patients with a QRS duration of 120-130 ms. Methods and results The main EchoCRT trial was prematurely terminated due to futility. For the current subgroup analysis we compared data for CRT-ON vs. -OFF in patients with QRS < 120 (n = 661) and QRS 120-130 ms (n = 139). On uni- and multivariable analyses, no significant interaction was observed between the two groups and randomized treatment for the primary or any of the secondary endpoints. On multivariable analysis, a higher risk for the primary endpoint was observed in patients with a QRS duration of 120-130 ms randomized to CRT-ON vs. CRT-OFF (hazard ratio 2.18, 95% CI 1.02-4.65; P = 0.044). However, no statistically significant interaction, compared with patients with QRS < 120 ms randomized to CRT-ON vs. CRT-OFF, was noted (P-interaction = 0.160). Conclusions In this pre-specified subgroup analysis of EchoCRT, no benefit of CRT was evident in patients with a QRS duration of 120-130 ms. These data further question the usefulness of CRT in this patient populatio

Cardiac resynchronization therapy in patients with heart failure and narrow QRS complexes

Background: Cross correlation analysis (CCA) using tissue Doppler imaging has been shown to be associated with outcome after cardiac resynchronization therapy (CRT) in patients with heart failure (HF) with wide QRS. However, its significance in patients with narrow QRS treated with CRT is unknown. Objectives: The aim of the current study was to investigate the association of mechanical activation delay by CCA with study outcome in patients with HF enrolled in the EchoCRT trial. Methods: Baseline CCA could be performed from tissue Doppler imaging in the apical views in 807 of 809 (99.7%) enrolled patients, and 6-month follow-up could be performed in 610 of 635 (96%) patients with available echocardiograms. Patients with a pre-specified maximal activation delay ≥35 ms were considered to have significant delay. The study outcome was HF hospitalization or death. Results: Of 807 patients, 375 (46%) did not have delayed mechanical activation at baseline by CCA. Patients without delayed mechanical activation who were randomized to CRT-On compared with CRT-Off had an increased risk of poor outcome (hazard ratio: 1.70; 95% confidence interval: 1.13 to 2.55; p = 0.01) with a significant interaction term (p = 0.04) between delayed mechanical activation and device randomization for the endpoint. Among patients with paired baseline and follow-up data with no events before 6-month follow-up (n = 541), new-onset delayed mechanical activation in the CRT-On group showed a significant increase in unfavorable events (hazard ratio: 3.73; 95% confidence interval: 1.15 to 12.14; p = 0.03). Conclusions: In the EchoCRT population, absence of delayed mechanical activation by CCA was significantly associated with poor outcomes, possibly due to the onset of new delayed mechanical activation with CRT pacing. (Echocardiography Guided Cardiac Resynchronization Therapy [EchoCRT] Trial; NCT00683696)

Executive Summary: HRS/EHRA/APHRS Expert Consensus Statement on the Diagnosis and Management of Patients with Inherited Primary Arrhythmia Syndromes

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Cryoballoon or radiofrequency ablation for symptomatic paroxysmal atrial fibrillation: reintervention, rehospitalization, and quality-of-life outcomes in the FIRE AND ICE trial.

AIMS: The primary safety and efficacy endpoints of the randomized FIRE AND ICE trial have recently demonstrated non-inferiority of cryoballoon vs. radiofrequency current (RFC) catheter ablation in patients with drug-refractory symptomatic paroxysmal atrial fibrillation (AF). The aim of the current study was to assess outcome parameters that are important for the daily clinical management of patients using key secondary analyses. Specifically, reinterventions, rehospitalizations, and quality-of-life were examined in this randomized trial of cryoballoon vs. RFC catheter ablation. METHODS AND RESULTS: Patients (374 subjects in the cryoballoon group and 376 subjects in the RFC group) were evaluated in the modified intention-to-treat cohort. After the index ablation, log-rank testing over 1000 days of follow-up demonstrated that there were statistically significant differences in favour of cryoballoon ablation with respect to repeat ablations (11.8% cryoballoon vs. 17.6% RFC; P = 0.03), direct-current cardioversions (3.2% cryoballoon vs. 6.4% RFC; P = 0.04), all-cause rehospitalizations (32.6% cryoballoon vs. 41.5% RFC; P = 0.01), and cardiovascular rehospitalizations (23.8% cryoballoon vs. 35.9% RFC; P < 0.01). There were no statistical differences between groups in the quality-of-life surveys (both mental and physical) as measured by the Short Form-12 health survey and the EuroQol five-dimension questionnaire. There was an improvement in both mental and physical quality-of-life in all patients that began at 6 months after the index ablation and was maintained throughout the 30 months of follow-up. CONCLUSION: Patients treated with cryoballoon as opposed to RFC ablation had significantly fewer repeat ablations, direct-current cardioversions, all-cause rehospitalizations, and cardiovascular rehospitalizations during follow-up. Both patient groups improved in quality-of-life scores after AF ablatio

HRS/EHRA/APHRS Expert Consensus Statement on the Diagnosis and Management of Patients with Inherited Primary Arrhythmia Syndromes

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HRS/EHRA/APHRS Expert Consensus Statement on the Diagnosis and Management of Patients with Inherited Primary Arrhythmia Syndromes

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