Arrhythmia and Survival Outcomes Among Black Patients and White Patients With a Primary Prevention Defibrillator.

BACKGROUND: Black Americans have a higher risk of nonischemic cardiomyopathy (NICM) than White Americans. We aimed to evaluate differences in the risk of tachyarrhythmias among patients with an implantable cardioverter-defibrillator (ICD). METHODS: The study population comprised 3895 ICD recipients in the United States enrolled in primary prevention ICD trials. Outcome measures included ventricular tachyarrhythmia (VTA), atrial tachyarrhythmia (ATA), ICD therapies, VTA burden (using Andersen-Gill recurrent event analysis), death, and the predicted benefit of the ICD. All events were adjudicated blindly. Outcomes were compared between self-reported Black patients versus White patients with cardiomyopathy (ischemic and NICM). RESULTS: Black patients were more likely to be female (35% versus 22%) and younger (57±12 versus 62±12 years) with a higher frequency of comorbidities. In NICM, Black patients had a higher rate of first VTA, fast VTA, ATA, and appropriate and inappropriate ICD therapy (VTA ≥170 bpm, 32% versus 20%; VTA ≥200 bpm, 22% versus 14%; ATA, 25% versus 12%; appropriate therapy, 30% versus 20%; and inappropriate therapy, 25% versus 11%; P<0.001 for all). Multivariable analysis showed that Black patients with NICM experienced a higher risk of all types of arrhythmia or ICD therapy (VTA ≥170 bpm, hazard ratio [HR] 1.71; VTA ≥200 bpm, HR 1.58; ATA, HR 1.87; appropriate therapy, HR 1.62; inappropriate therapy, HR 1.86; P≤0.01 for all), higher burden of tachyarrhythmias or therapies (VTA, HR 1.84; appropriate therapy, HR 1.84; P<0.001 for both), and a higher risk of death (HR 1.92; P=0.014). In contrast, in ischemic cardiomyopathy, the risk of all types of tachyarrhythmia, ICD therapy, or death was similar between Black patients and White patients. Both Black patients and White patients derived a significant and similar benefit from ICD implantation. CONCLUSIONS: Among patients with NICM with an ICD for primary prevention, Black patients compared with White patients had a high risk and burden of VTA, ATA, and ICD therapies with a lower survival rate. Nevertheless, the overall benefit of the ICD was maintained and was similar to that of White patients.

The Influence of Hybrid Comprehensive Telerehabilitation on Anxiety in Heart Failure Patients: The TELEREH-HF Randomized Clinical Trial.

Telerehabilitation for heart failure (HF) patients is beneficial for physical functioning, prognosis, and psychological status. The study aimed at evaluating the influence of hybrid comprehensive telerehabilitation (HCTR) on the level of anxiety in comparison to usual care (UC). The TELEREH-HF study was a multicenter prospective RCT in 850 clinically stable HF participants. Patients underwent clinical examinations, including the assessment of anxiety, at entry and after the 9-week training program (HCTR) or observation (UC). The State-Trait Anxiety Inventory (STAI) was used. 20.3% HCTR and 20.1% UC patients reported high level of anxiety as a state at baseline, with higher STAI results in younger participants (< 63 y.o.) (p = .048 for HCTR; p = .026 for UC). At both stages of the study, patients with lower level of physical capacity (measured by a peak VO2) had shown significantly higher level of anxiety. There were no significant changes in anxiety levels during the 9-week observation for the entire study population, although there were different patterns of change in anxiety (both trait and state) in younger and older groups,with the decrease in younger patients, and the increase-in the older group.Trial registry number NCT02523560 (Clinical Trials.gov), date of registration: August 14, 2015.

Genetic variant annotation scores in congenital long QT syndrome.

BACKGROUND: Congenital Long QT Syndrome (LQTS) is a hereditary arrhythmic disorder. We aimed to assess the performance of current genetic variant annotation scores among LQTS patients and their predictive impact. METHODS: We evaluated 2025 patients with unique mutations for LQT1-LQT3. A patient-specific score was calculated for each of four established genetic variant annotation algorithms: CADD, SIFT, REVEL, and PolyPhen-2. The scores were tested for the identification of LQTS and their predictive performance for cardiac events (CE) and life-threatening events (LTE) and then compared with the predictive performance of LQTS categorization based on mutation location/function. Score performance was tested using Harrell's C-index. RESULTS: A total of 917 subjects were classified as LQT1, 838 as LQT2, and 270 as LQT3. The identification of a pathogenic variant occurred in 99% with CADD, 92% with SIFT, 100% with REVEL, and 86% with PolyPhen-2. However, none of the genetic scores correlated with the risk of CE (Harrell's C-index: CADD = 0.50, SIFT = 0.51, REVEL = 0.50, and PolyPhen-2 = 0.52) or LTE (Harrell's C-index: CADD = 0.50, SIFT = 0.53, REVEL = 0.54, and PolyPhen-2 = 0.52). In contrast, high-risk mutation categorization based on location/function was a powerful independent predictor of CE (HR = 1.88; p < .001) and LTE (HR = 1.89, p < .001). CONCLUSION: In congenital LQTS patients, well-established algorithms (CADD, SIFT, REVEL, and PolyPhen-2) were able to identify the majority of the causal variants as pathogenic. However, the scores did not predict clinical outcomes. These results indicate that mutation location/functional assays are essential for accurate interpretation of the risk associated with LQTS mutations.

Confirm Rx insertable cardiac monitor for primary atrial fibrillation detection in high-risk heart failure patients (Confirm-AF trial).

BACKGROUND: Patients with heart failure (HF) represent a large population of patients who are at high risk for complications related to undiagnosed atrial fibrillation (AF). However, currently there are limited modalities available for early AF detection in this high-risk population. An implantable cardiac monitor (ICM) is inserted subcutaneously and can provide long-term arrhythmia information via remote monitoring. METHODS AND RESULTS: Confirm-AF is a prospective randomized, nonblinded, two arm, multicenter clinical trial to be performed in the United States, enrolling 477 patients with a history of HF hospitalization and left ventricular ejection fraction >35% from 30 medical sites. Patients will be randomized in a 2:1 fashion to undergo ICM implant with remote monitoring and symptom-triggered mobile app transmissions versus (vs.) Non-ICM management and follow-up. The primary objective of this trial is to compare the time to first detection of AF lasting > 5 min using an Abbott ICM compared to non-ICM monitoring in symptomatic HF patients. This article describes the design and analytic plan for the Confirm-AF trial. CONCLUSIONS: The Confirm-AF trial seeks to accurately define the burden of AF in high-risk HF patients with LVEF > 35% using an Abbott ICM. A finding showing significantly higher incidence of AF along with improved clinical outcomes with ICM monitoring is expected to have substantial clinical implications and may change the method of monitoring high-risk HF patients.

Insertable cardiac monitor-guided early intervention to reduce atrial fibrillation burden following catheter ablation: Study design and clinical protocol (ICM-REDUCE-AF trial).

BACKGROUND: Percutaneous catheter ablation (CA) to achieve pulmonary vein isolation is an effective treatment for drug-refractory paroxysmal and persistent atrial fibrillation (AF). However, recurrence rates after a single AF ablation procedure remain elevated. Conventional management after CA ablation has mostly been based on clinical AF recurrence. However, continuous recordings with insertable cardiac monitors (ICMs) and patient-triggered mobile app transmissions post-CA can now be used to detect early recurrences of subclinical AF (SCAF). We hypothesize that early intervention following CA based on personalized ICM data can prevent the substrate progression that promotes the onset and maintenance of atrial arrhythmias. METHODS: This is a randomized, double-blind (to SCAF data), single-tertiary center clinical trial in which 120 patients with drug-refractory paroxysmal or persistent AF are planned to undergo CA with an ICM. Randomization will be to an intervention arm (n = 60) consisting of ICM-guided early intervention based on SCAF and patient-triggered mobile app transmissions versus a control arm (n = 60) consisting of a standard intervention protocol based on clinical AF recurrence validated by the ICM. Primary endpoint is AF burden, which will be assessed from ICMs at 15 months post-AF ablation. Secondary endpoints include healthcare utilization, functional capacity, and quality of life. CONCLUSION: We believe that ICM-guided early intervention will provide a novel, personalized approach to post-AF ablation management that will result in a significant reduction in AF burden, healthcare utilization, and improvements in functional capacity and quality of life.

Design and characteristics of the prophylactic intra-operative ventricular arrhythmia ablation in high-risk LVAD candidates (PIVATAL) trial.

BACKGROUND: The use of a Left Ventricular Assist Device (LVAD) in patients with advanced heart failure refractory to optimal medical management has progressed steadily over the past two decades. Data have demonstrated reduced LVAD efficacy, worse clinical outcome, and higher mortality for patients who experience significant ventricular tachyarrhythmia (VTA). We hypothesize that a novel prophylactic intra-operative VTA ablation protocol at the time of LVAD implantation may reduce the recurrent VTA and adverse events postimplant. METHODS: We designed a prospective, multicenter, open-label, randomized-controlled clinical trial enrolling 100 patients who are LVAD candidates with a history of VTA in the previous 5 years. Enrolled patients will be randomized in a 1:1 fashion to intra-operative VTA ablation (n = 50) versus conventional medical management (n = 50) with LVAD implant. Arrhythmia outcomes data will be captured by an implantable cardioverter defibrillator (ICD) to monitor VTA events, with a uniform ICD programming protocol. Patients will be followed prospectively over a mean of 18 months (with a minimum of 9 months) after LVAD implantation to evaluate recurrent VTA, adverse events, and procedural outcomes. Secondary endpoints include right heart function/hemodynamics, healthcare utilization, and quality of life. CONCLUSION: The primary aim of this first-ever randomized trial is to assess the efficacy of intra-operative ablation during LVAD surgery in reducing VTA recurrence and improving clinical outcomes for patients with a history of VTA.

Evaluation of gene validity for CPVT and short QT syndrome in sudden arrhythmic death.

AIMS: Catecholaminergic polymorphic ventricular tachycardia (CPVT) and short QT syndrome (SQTS) are inherited arrhythmogenic disorders that can cause sudden death. Numerous genes have been reported to cause these conditions, but evidence supporting these gene-disease relationships varies considerably. To ensure appropriate utilization of genetic information for CPVT and SQTS patients, we applied an evidence-based reappraisal of previously reported genes. METHODS AND RESULTS: Three teams independently curated all published evidence for 11 CPVT and 9 SQTS implicated genes using the ClinGen gene curation framework. The results were reviewed by a Channelopathy Expert Panel who provided the final classifications. Seven genes had definitive to moderate evidence for disease causation in CPVT, with either autosomal dominant (RYR2, CALM1, CALM2, CALM3) or autosomal recessive (CASQ2, TRDN, TECRL) inheritance. Three of the four disputed genes for CPVT (KCNJ2, PKP2, SCN5A) were deemed by the Expert Panel to be reported for phenotypes that were not representative of CPVT, while reported variants in a fourth gene (ANK2) were too common in the population to be disease-causing. For SQTS, only one gene (KCNH2) was classified as definitive, with three others (KCNQ1, KCNJ2, SLC4A3) having strong to moderate evidence. The majority of genetic evidence for SQTS genes was derived from very few variants (five in KCNJ2, two in KCNH2, one in KCNQ1/SLC4A3). CONCLUSIONS: Seven CPVT and four SQTS genes have valid evidence for disease causation and should be included in genetic testing panels. Additional genes associated with conditions that may mimic clinical features of CPVT/SQTS have potential utility for differential diagnosis.

Newly developed cardiovascular risk factors in rheumatoid arthritis patients initiating biologic treatment.

Introduction: Rheumatoid arthritis (RA) is a risk factor (RF) for cardiovascular (CV) disease, a leading cause of mortality in RA patients. Material and methods: Consecutive records of RA patients with high disease activity screened upon biologic therapy initiation were reviewed between January 2001 and 2018. Patients with at least 6-month follow-up and baseline disease activity scores were enrolled (n = 353) and stratified into manifest CV disorder ("overt CVD"), any traditional CV risk factor ("atCVrisk") and no CV risk factor ("vlCVrisk") groups. Results: Overall, mean (SD) patient age was 51.4 (±12.2) years, and 291 (82.4%) subjects were female. Median follow-up was 41.9 (IQR 18.6, 80) months. Overall, 89 (25.2%) individuals developed at least one new CV RF, of which 65 (18.4%) acquired one and 24 (6.8%) two or more. Incident lipid disorders (42, 11.9%), followed by hypertension (14, 4%), atrial fibrillation (17, 4.8%) and venous thromboembolism (VTE) (16, 4.5%), were common. Incident major adverse cardiac events (MACE) were not reported in the vlCVrisk group, in contrast to atCVrisk (n = 8, 4.2%) or overt CVD (n = 4, 18.2%). Age was a significant predictor of incident CV risk factor (HR 1.04, 95% CI: 1.02-1.07; p < 0.01). In age-adjusted analyses, only baseline body mass index (BMI) (HR 1.11, 95% CI: 1.04-1.18; p < 0.01), but not ever smoking (p = 0.93), male sex (p = 0.26), positive RF (p = 0.24), positive ACPA (p = 0.90), or baseline disease activity (p = 0.19), were independent predictor of incident CV risk factors. Conclusions: Patients with RA initiating biologics should be screened for cardiometabolic risk factors, especially at an older age. The presence of at least one risk factor may be linked to a worse long-term prognosis.

Independent validation and clinical implications of the risk prediction model for long QT syndrome (1-2-3-LQTS-Risk).

AIMS: Risk stratification of patients with long QT syndrome (LQTS) represents a difficult task. In 2018, we proposed a granular estimate of the baseline 5-year risk of life-threatening arrhythmias (LAE) for patients with LQTS, based on the genotype (long QT syndrome Type 1, long QT syndrome Type 2, and long QT syndrome Type 3) and the duration of the QTc interval. We sought to externally validate a novel risk score model (1-2-3-LQTS-Risk model) in a geographically diverse cohort from the USA and to evaluate its performance and assess potential clinical implication of this novel model. METHODS AND RESULTS: The prognostic model (1-2-3-LQTS-Risk model) was derived using data from a prospective, single-centre longitudinal cohort study published in 2018 (discovery cohort) and was validated using an independent cohort of 1689 patients enrolled in the International LQTS Registry (Rochester NY, USA). The validation study revealed a C-index of 0.69 [95% confidence interval (CI): 0.61-0.77] in the validation cohort, when compared with C-index of 0.79 (95% CI: 0.70-0.88) in the discovery cohort. Adopting a 5-year risk ≥5%, as suggested by the ROC curve analysis as the most balanced threshold for implantable cardioverter-defibrillator (ICD) implantation, would result in a number needed to treat (NNT) of nine (NNT = 9; 95% CI: 6.3-13.6). CONCLUSION: The 1-2-3-LQTS-Risk model, the first validated 5-year risk score model for patients with LQTS, can be used to aid clinicians to identify patients at the highest risk of LAE who could benefit most from an ICD implant and avoid unnecessary implants.

Predictors of proarrhythmic effect in heart failure patients after 9-week hybrid comprehensive telerehabilitation and their influence on cardiovascular mortality in long-term follow-up: Subanalysis of the TELEREH-HF randomized clinical trial.

BACKGROUND: Regular exercise training is beneficial in heart failure (HF) patients. However, its potential proarrhythmic effect is possible but has not been sufficiently investigated. OBJECTIVE: To identify patients at risk for proarrhythmic effect after the 9-week of hybrid comprehensive telerehabilitation (HCTR) program vs the 9-week of usual care (UC) and to investigate its predictors and impact on cardiovascular mortality based on data from the TELEREH-HF RCT. METHODS: Proarrhythmic effect, strictly defined on the basis of available standards was evaluated by comparing 24-h Holter ECG before and after 9-week of HCTR or UC of 773 HF patients (The New York Heart Association class I-III, left ventricular ejection fraction ≤40%). RESULTS: The proarrhytmic effect was found in 78 (20.4%) and in 61 (15.6%) patients in the HCTR and UC group respectively, and the difference between groups was not statistically significant (p = 0.081). However, univariate analysis identified several statistically significant predictors of proarrhythmia in HCTR only vs the UC group. After a multivariate analysis ischaemic aetiology of HF (OR = 2.27, p = 0.008), peak oxygen consumption at baseline <14 ml/kg/min (OR = 2.03, p = 0.012) and level of N-terminal-pro B-type natriuretic peptide (NT-proBNP) in the first and the second tercile (OR = 1.85, p = 0.043) were identified to be independent predictors of proarrhytmic effect of exercise training among the HF patients in HCTR group only. CONSLUSIONS: Patients who underwent a 9-week HCTR were not at a higher risk of proarrhythmic effect after its completion compared to UC. However, predictors of proarrhythmia such as ischemic aetiology of HF, poor physical capacity, lower NT-proBNP level were discovered in the HCTR group only, yet it does not cause a significant risk of cardiovascular mortality including sudden cardiac death in long-term follow-up.

Predicted benefit of an implantable cardioverter-defibrillator: the MADIT-ICD benefit score.

AIMS: The benefit of prophylactic implantable cardioverter-defibrillator (ICD) is not uniform due to differences in the risk of life-threatening ventricular tachycardia (VT)/ventricular fibrillation (VF) and non-arrhythmic mortality. We aimed to develop an ICD benefit prediction score that integrates the competing risks. METHODS AND RESULTS: The study population comprised all 4531 patients enrolled in the MADIT trials. Best-subsets Fine and Gray regression analysis was used to develop prognostic models for VT (≥200 b.p.m.)/VF vs. non-arrhythmic mortality (defined as death without prior sustained VT/VF). Eight predictors of VT/VF (male, age < 75 years, prior non-sustained VT, heart rate > 75 b.p.m., systolic blood pressure < 140 mmHg, ejection fraction ≤ 25%, myocardial infarction, and atrialarrhythmia) and 7 predictors of non-arrhythmic mortality (age ≥ 75 years, diabetes mellitus, body mass index < 23 kg/m2, ejection fraction ≤ 25%, New York Heart Association ≥II, ICD vs. cardiac resynchronization therapy with defibrillator, and atrial arrhythmia) were identified. The two scores were combined to create three MADIT-ICD benefit groups. In the highest benefit group, the 3-year predicted risk of VT/VF was three-fold higher than the risk of non-arrhythmic mortality (20% vs. 7%, P < 0.001). In the intermediate benefit group, the difference in the corresponding predicted risks was attenuated (15% vs. 9%, P < 0.01). In the lowest benefit group, the 3-year predicted risk of VT/VF was similar to the risk of non-arrhythmic mortality (11% vs. 12%, P = 0.41). A personalized ICD benefit score was developed based on the distribution of the two competing risks scores in the study population (https://is.gd/madit). Internal and external validation confirmed model stability. CONCLUSIONS: We propose the novel MADIT-ICD benefit score that predicts the likelihood of prophylactic ICD benefit through personalized assessment of the risk of VT/VF weighed against the risk of non-arrhythmic mortality.

An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome.

BACKGROUND: Long QT syndrome (LQTS) is the first described and most common inherited arrhythmia. Over the last 25 years, multiple genes have been reported to cause this condition and are routinely tested in patients. Because of dramatic changes in our understanding of human genetic variation, reappraisal of reported genetic causes for LQTS is required. METHODS: Utilizing an evidence-based framework, 3 gene curation teams blinded to each other's work scored the level of evidence for 17 genes reported to cause LQTS. A Clinical Domain Channelopathy Working Group provided a final classification of these genes for causation of LQTS after assessment of the evidence scored by the independent curation teams. RESULTS: Of 17 genes reported as being causative for LQTS, 9 (AKAP9, ANK2, CAV3, KCNE1, KCNE2, KCNJ2, KCNJ5, SCN4B, SNTA1) were classified as having limited or disputed evidence as LQTS-causative genes. Only 3 genes (KCNQ1, KCNH2, SCN5A) were curated as definitive genes for typical LQTS. Another 4 genes (CALM1, CALM2, CALM3, TRDN) were found to have strong or definitive evidence for causality in LQTS with atypical features, including neonatal atrioventricular block. The remaining gene (CACNA1C) had moderate level evidence for causing LQTS. CONCLUSIONS: More than half of the genes reported as causing LQTS have limited or disputed evidence to support their disease causation. Genetic variants in these genes should not be used for clinical decision-making, unless accompanied by new and sufficient genetic evidence. The findings of insufficient evidence to support gene-disease associations may extend to other disciplines of medicine and warrants a contemporary evidence-based evaluation for previously reported disease-causing genes to ensure their appropriate use in precision medicine.

Effects of hybrid comprehensive telerehabilitation on cardiopulmonary capacity in heart failure patients depending on diabetes mellitus: subanalysis of the TELEREH-HF randomized clinical trial.

BACKGROUND: Type 2 diabetes mellitus (DM) is one of the most common comorbidities among patients with heart failure (HF) with reduced ejection fraction (HFrEF). There are limited data regarding efficacy of hybrid comprehensive telerehabilitation (HCTR) on cardiopulmonary exercise capacity in patients with HFrEF with versus those without diabetes. AIM: The aim of the present study was to analyze effects of 9-week HCTR in comparison to usual care on parameters of cardiopulmonary exercise capacity in HF patients according to history of DM. METHODS: Clinically stable HF patients with left ventricular ejection fraction [LVEF] < 40% after a hospitalization due to worsening HF within past 6 months were enrolled in the TELEREH-HF (The TELEREHabilitation in Heart Failure Patients) trial and randomized to the HCTR or usual care (UC). Cardiopulmonary exercise tests (CPET) were performed on treadmill with an incremental workload according to the ramp protocol. RESULTS: CPET was performed in 385 patients assigned to HCTR group: 129 (33.5%) had DM (HCTR-DM group) and 256 patients (66.5%) did not have DM (HCTR-nonDM group). Among 397 patients assigned to UC group who had CPET: 137 (34.5%) had DM (UC-DM group) and 260 patients (65.5%) did not have DM (UC-nonDM group). Among DM patients, differences in cardiopulmonary parameters from baseline to 9 weeks remained similar among HCTR and UC patients. In contrast, among patients without DM, HCTR was associated with greater 9-week changes than UC in exercise time, which resulted in a statistically significant interaction between patients with and without DM: difference in changes in exercise time between HCTR versus UC was 12.0 s [95% CI - 15.1, 39.1 s] in DM and 43.1 s [95% CI 24.0, 63.0 s] in non-DM, interaction p-value = 0.016. Furthermore, statistically significant differences in the effect of HCTR versus UC between DM and non-DM were observed in ventilation at rest: - 0.34 l/min [95% CI - 1.60, 0.91 l/min] in DM and 0.83 l/min [95% CI - 0.06, 1.73 l/min] in non-DM, interaction p value = 0.0496 and in VE/VCO2 slope: 1.52 [95% CI - 1.55, 4.59] for DM vs. - 1.44 [95% CI - 3.64, 0.77] for non-DM, interaction p value = 0.044. CONCLUSIONS: The benefits of hybrid comprehensive telerehabilitation versus usual care on the improvement of physical performance, ventilatory profile and gas exchange parameters were more pronounced in patients with HFrEF without DM as compared to patients with DM. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02523560. Registered 3rd August 2015. https://clinicaltrials.gov/ct2/show/NCT02523560?term=NCT02523560&draw=2&rank=1 . Other Study ID Numbers: STRATEGME1/233547/13/NCBR/2015.

Genetic Variant Score and Arrhythmogenic Right Ventricular Cardiomyopathy Phenotype in Plakophilin-2 Mutation Carriers.

INTRODUCTION: Whether detailed genetic information contributes to risk stratification of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) remains uncertain. Pathogenic genetic variants in some genes seem to carry a higher risk for arrhythmia and earlier disease onset than others, but comparisons between variants in the same gene have not been done. Combined Annotation Dependent Depletion (CADD) score is a bioinformatics tool that measures the pathogenicity of each genetic variant. We hypothesized that a higher CADD score is associated with arrhythmic events and earlier age at ARVC manifestations in individuals carrying pathogenic or likely pathogenic genetic variants in plakophilin-2 (PKP2). METHODS: CADD scores were calculated using the data from pooled Scandinavian and North American ARVC cohorts, and their association with cardiac events defined as ventricular tachycardia/ventricular fibrillation (VT/VF) or syncope and age at definite ARVC diagnosis were assessed. RESULTS: In total, 33 unique genetic variants were reported in 179 patients (90 males, 71 probands, 96 with definite ARVC diagnosis at a median age of 35 years). Cardiac events were reported in 76 individuals (43%), of whom 53 had sustained VT/VF (35%). The CADD score was neither associated with age at cardiac events (HR 1.002, 95% CI: 0.953-1.054, p = 0.933) nor with age at definite ARVC diagnosis (HR 0.992, 95% CI: 0.947-1.039, p = 0.731). CONCLUSION: No correlation was found between CADD scores and clinical manifestations of ARVC, indicating that the score has no additional risk stratification value among carriers of pathogenic or likely pathogenic PKP2 genetic variants.

Risk factors for ventricular tachyarrhythmic events in patients without left bundle branch block who receive cardiac resynchronization therapy.

INTRODUCTION: Cardiac resynchronization therapy (CRT) may be pro-arrhythmic in patients with non-left bundle branch block (non-LBBB). We hypothesized that combined assessment of risk factors (RF) for ventricular tachyarrhythmias (VTAs) can be used to stratify non-LBBB patients for CRT implantation. METHODS: The study comprised 412 non-LBBB patients from MADIT-CRT randomized to CRT-D (n = 215) versus ICD only (n = 197). Best-subset regression analysis was performed to identify RF associated with increased VTA risk in CRT-D patients without LBBB. The primary end point was first occurrence of sustained VTA during follow-up. Secondary end points included VTA/death and appropriate shock. RESULTS: Four RFs were associated with increased VTA risk: blood urea nitrogen >25mg/dl, ejection fraction <20%, prior nonsustained VT, and female gender. Among CRT-D patients, 114 (53%) had no RF, while 101 (47%) had ≥1 RF. The 4-year cumulative probability of VTA was higher among those with ≥1 RF compared with those without RF (40% vs. 14%, p < .001). Multivariate analysis showed that in patients without RF, treatment with CRT-D was associated with a 61% reduction in VTA compared with ICD-only therapy (p = .002), whereas among patients with ≥1 RF, treatment with CRT-D was associated with a corresponding 73% (p = .025) risk increase. Consistent results were observed when the secondary end points of VTA/death and appropriate ICD shocks were assessed. CONCLUSION: Combined assessment of factors associated with increased risk for VTA can be used for improved selection of non-LBBB patients for CRT-D.

Assessment of ECG during hybrid comprehensive telerehabilitation in heart failure patients-Subanalysis of the Telerehabilitation in Heart Failure Patients (TELEREH-HF) randomized clinical trial.

BACKGROUND: Exercise training in heart failure (HF) patients should be monitored to ensure patients' safety. Electrocardiographic (ECG) telemonitoring was used to assess the safety of hybrid comprehensive telerehabilitation (HCTR). OBJECTIVE: Analysis of ECG recorded during HCTR in HF patients. METHODS: The TELEREH-HF multicenter, randomized, controlled trial enrolled 850 HF patients with New York Heart Association class I-III and left ventricular ejection fraction of ≤40%. This subanalysis focuses on 386 patients (aged 62 ± 11 years, LVEF 31 ± 7%) randomized to HCTR. HCTR was telemonitored with a device allowing to record 16-s fragments of ECG and to transmit the data via mobile phone network to the monitoring center. ResultsIn 386 patients, 16,622 HCTR sessions were recorded and 66,488 ECGs fragments were evaluated. Sinus rhythm was present in 320 (83%) and permanent atrial fibrillation (AF) in 66 (17%) patients, respectively. The most common arrhythmias were ventricular and atrial premature beats, recorded in 76.4% and 27.7% of the patients, respectively. Non-sustained ventricular tachycardia (21 episodes in 8 patients) and paroxysmal AF episodes (6 in 4 patients) were rare. None of the analyzed demographic and clinical characteristics was predictive for onset of the new arrhythmias on exercise. CONCLUSION: Telerehabilitation in HF patients was safe without the evidence for symptomatic arrhythmias requiring discontinuation of telerehabilitation. Only one mildly symptomatic paroxysmal AF episode led to the short-term suspension of the training program. The most common arrhythmias were atrial and ventricular premature beats. These arrhythmias did not result in any changes in rehabilitation and therapy regimens.

The role and outcomes of new supraventricular tachycardia among patients with mild heart failure.

INTRODUCTION: We aimed to assess the predictors of new supraventricular tachycardia (SVT) and the association of new SVT with subsequent clinical outcomes among mild heart failure (HF) patients. METHODS AND RESULTS: The study population comprised patients enrolled in MADIT-CRT, after exclusion of patients with atrial arrhythmias before enrollment (N = 325). Multivariate analysis was used to identify predictors of new-onset SVT and the association of time-dependent development of SVT with subsequent ventricular tachyarrhythmic events (VTEs), HF-hospitalizations, and death. SVT burden was categorized into three groups based on the number of episodes per patient; (a) Low <10, (b) Intermediate ≥10 but <20, and (c) High ≥20. During mean follow up of 3.4 ± 1.1 years, 41(3%) subjects developed new SVT. African American race, diastolic blood pressure (DBP) >80 mmHg and prior non sustained ventricular arrhythmia were independent predictors for SVT. Multivariate analysis showed that the development of time-dependent SVT was associated with a >4-fold increased risk for VTEs (HR = 4.3; 95% CI: 1.6-11.7; P = .004) and with a >6-fold increased risk for all-cause mortality (HR = 6.5; 95% CI: 2.3-18.7; P < .001), but not with HF hospitalizations (HR = 2.2; 95% CI: 0.7-7.2; P = .17). Intermediate, and high SVT-burden were each independent risk factors for death when compared with Low burden (HR = 9.1; P = .03, and HR = 19.4; P < .001; respectively). CONCLUSIONS: In patients with mild HF, the development of new-onset SVT after device implantation is related to distinct baseline clinical and epidemiologic characteristics and is associated with a significant increase in subsequent adverse outcomes, including VTEs and death.

Competing risk analysis of ventricular arrhythmia events in heart failure patients with moderately compromised renal dysfunction.

AIMS: Patients with impaired renal function were shown to have an attenuated benefit from implantable cardioverter-defibrillator. However, there are limited data on the competing risk of ventricular arrhythmia events and death by renal function in patients without severe disease. Therefore, we aimed to assess the competing risk of ventricular arrhythmia events and death by renal function. METHODS AND RESULTS: We analysed 1782 patients (99%) enrolled in Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT) with glomerular filtration rate (GFR) data available. Cumulative incidence function curves were used to display the rate of ventricular tachycardia (VT), ventricular fibrillation (VF), and the competing risk of death without experiencing VT/VF. Multivariable Fine and Gray regression models and recurrent event analysis were performed. There were 355 (20%) patients with GFR < 52 and 1427 with GFR ≥ 52 (lowest quintile). The incidence of non-fatal VT/VF at 4 years was higher in patients with high GFR (26%) as compared to low GFR (16%), whereas rates of death without non-fatal VT/VF were 5% and 20% (P < 0.001). In Fine and Gray models, the low GFR group was 35% less likely to experience VT/VF compared to the high GFR [95% confidence interval (CI) 0.48-0.88, P = 0.005]. In contrast,death without experiencing VT/VF was 3.5-fold higher in the low GFR group (95% CI 2.38-5.12, P-value < 0.001). Recurrent event analysis consistently showed a lower risk of recurrent VT/VF, recurrent anti-tachycardia pacing only, and shock in the low GFR group. CONCLUSIONS: We show, in a competing risk model, a lower risk of VT/VF events and a higher risk of mortality without an arrhythmic event in patients with moderate renal dysfunction in MADIT-CRT. These findings can be used for improved selection of patients for defibrillator therapy among CRT candidates. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT00180271.

Circadian variation and seasonal distribution of implantable defibrillator detected new onset atrial fibrillation.

BACKGROUND: We aimed to characterize the hourly, daily, and seasonally variations in the detection of new atrial fibrillation (AF) in heart failure patients implanted with a defibrillator. METHODS: In 1309 patients enrolled in MADIT-RIT without AF at baseline, atrial arrhythmia data were analyzed from device interrogations. The circadian, weekly, and seasonal distribution of device detected AF was evaluated. The morning period was defined as 06:00-11:59, afternoon as 12:00-16:59, evening as 17:00-22:59, and the nighttime as 23:00-05:59. RESULTS: During 17 months of follow-up, 66 (5%) patients developed new device-detected AF. AF patients were less likely to have ischemic cardiomyopathy and were more likely to have received an implantable cardioverter defibrillator rather than a cardiac resynchronization therapy with defibrillator. The highest number of AF occurred during the evening hours (25 patients [38%]) followed by a second peak in AF detection during the afternoon hours (21 patients [32%]). Importantly during the nighttime, new AF occurred only in three patients (4%). In comparison with the nighttime period, the odds ratio (OR) of developing AF during the evening time period was 8.5-fold higher (95% CI 7.3-9.7, P < .01). Detection of AF during the spring and winter seasons accounted for 67% of all new device-detected AF. CONCLUSIONS: There is diurnal and seasonal variation in new onset AF. A double peak in the incidence of AF is observed during the afternoon and evening hours, and during the spring and winter seasons. This information may be useful when deciding when to screen at-risk patients for new AF.

Need for pacing in patients who qualify for an implantable cardioverter-defibrillator: Clinical implications for the subcutaneous ICD.

BACKGROUND: Implantation of the subcutaneous implantable cardioverter-defibrillator (S-ICD) is spreading and has been shown to be safe and effective; however, it does not provide brady-pacing. Currently, data on the need for brady-pacing and cardiac resynchronization therapy (CRT) implantation in patients with ICD indication are limited. METHODS: The Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II enrolled post-MI patients with reduced ejection fraction (EF ≤ 35%), randomized to either an implantable cardioverter-defibrillator (ICD) or conventional medical therapy. Kaplan-Meier analyses and multivariate Cox models were performed to assess the incidence and predictors of pacemaker (PM), or CRT implantation in the conventional arm of MADIT-II, after excluding 32 patients (6.5%) with a previously implanted PM. RESULTS: During the median follow-up of 20 months, 24 of 458 patients (5.2%) were implanted with a PM or a CRT (19 PM, 5 CRT). Symptomatic sinus bradycardia was the primary indication for PM implantation (n = 9, 37%), followed by AV block (n = 5, 21%), tachy-brady syndrome (n = 4, 17%), and carotid sinus hypersensitivity (n = 1, 4%). Baseline PR interval >200 ms (HR = 3.07, 95% CI: 1.24-7.57, p = .02), and CABG before enrollment (HR = 6.88, 95% CI: 1.58-29.84, p = .01) predicted subsequent PM/CRT implantation. Patients with PM/CRT implantation had a significantly higher risk for heart failure (HR = 2.67, 95% CI = 1.38-5.14, p = .003), but no increased mortality risk (HR = 1.06, 95% CI = 0.46-2.46, p = .89). CONCLUSION: The short-term need for ventricular pacing or CRT implantation in patients with MADIT-II ICD indication was low, especially in those with a normal baseline PR interval, and such patients are appropriate candidates for the subcutaneous ICD.