Risk Prediction in Male Adolescents With Congenital Long QT Syndrome: Implications for Sex-Specific Risk Stratification in Potassium Channel-Mediated Long QT Syndrome.

BACKGROUND: Sex-specific risk management may improve outcomes in congenital long QT syndrome (LQTS). We recently developed a prediction score for cardiac events (CEs) and life-threatening events (LTEs) in postadolescent women with LQTS. In the present study, we aimed to develop personalized risk estimates for the burden of CEs and LTEs in male adolescents with potassium channel-mediated LQTS. METHODS AND RESULTS: The prognostic model was derived from the LQTS Registry headquartered in Rochester, NY, comprising 611 LQT1 or LQT2 male adolescents from age 10 through 20 years, using the following variables: genotype/mutation location, QTc-specific thresholds, history of syncope, and ß-blocker therapy. Anderson-Gill modeling was performed for the end point of CE burden (total number of syncope, aborted cardiac arrest, and appropriate defibrillator shocks). The applicability of the CE prediction model was tested for the end point of the first LTE (excluding syncope and adding sudden cardiac death) using Cox modeling. A total of 270 CEs occurred during follow-up. The genotype-phenotype risk prediction model identified low-, intermediate-, and high-risk groups, comprising 74%, 14%, and 12% of the study population, respectively. Compared with the low-risk group, high-risk male subjects experienced a pronounced 5.2-fold increased risk of recurrent CEs (P<0.001), whereas intermediate-risk patients had a 2.1-fold (P=0.004) increased risk . At age 20 years, the low-, intermediate-, and high-risk adolescent male patients had on average 0.3, 0.6, and 1.4 CEs per person, respectively. Corresponding 10-year adjusted probabilities for a first LTE were 2%, 6%, and 8%. CONCLUSIONS: Personalized genotype-phenotype risk estimates can be used to guide sex-specific management in male adolescents with potassium channel-mediated LQTS.

QRS Morphology and the Risk of Ventricular Tachyarrhythmia in Cardiac Resynchronization Therapy Recipients.

BACKGROUND: There are conflicting data on the effect of cardiac resynchronization therapy with a defibrillator (CRT-D) on the risk of life-threatening ventricular tachyarrhythmia in heart failure patients. OBJECTIVES: The authors aimed to assess whether QRS morphology is associated with risk of ventricular arrhythmias in CRT recipients. METHODS: The study population comprised 2,862 patients implanted with implantable cardioverter defibrillator (ICD)/CRT-D for primary prevention who were enrolled in 5 landmark primary prevention ICD trials (MADIT-II [Multicenter Automated Defibrillator Implantation Trial], MADIT-CRT [Multicenter Automated Defibrillator Implantation Trial-Cardiac Resynchronization Therapy], MADIT-RIT [Multicenter Automated Defibrillator Implantation Trial-Reduction in Inappropriate Therapy], MADIT-RISK [Multicenter Automated Defibrillator Implantation Trial-RISK], and RAID [Ranolazine in High-Risk Patients With Implanted Cardioverter Defibrillators]). Patients with QRS duration ≥130 ms were divided into 2 groups: those implanted with an ICD only vs CRT-D. The primary endpoint was fast ventricular tachycardia (VT)/ventricular fibrillation (VF) (defined as VT ≥200 beats/min or VF), accounting for the competing risk of death. Secondary endpoints included appropriate shocks, any sustained VT or VF, and the burden of fast VT/VF, assessed in a recurrent event analysis. RESULTS: Among patients with left bundle branch block (n = 1,792), those with CRT-D (n = 1,112) experienced a significant 44% (P < 0.001) reduction in the risk of fast VT/VF compared with ICD-only patients (n = 680), a significantly lower burden of fast VT/VF (HR: 0.55; P = 0.001), with a reduced burden of appropriate shocks (HR: 0.44; P < 0.001). In contrast, among patients with non-left bundle branch block (NLBBB) (N = 1,070), CRT-D was not associated with reduction in fast VT/VF (HR: 1.33; P = 0.195). Furthermore, NLBBB patients with CRT-D experienced a statistically significant increase in the burden of fast VT/VF events compared with ICD-only patients (HR: 1.90; P = 0.013). CONCLUSIONS: Our data suggest a potential proarrhythmic effect of CRT among patients with NLBBB. These data should be considered in patient selection for treatment with CRT.

Sex-Related Differences in Ventricular Tachyarrhythmia Events in Patients With Implantable Cardioverter-Defibrillator and Prior Ventricular Tachyarrhythmias.

BACKGROUND: Data on the risk of ventricular tachycardia (VT), ventricular fibrillation (VF), and death by sex in patients with prior VT/VF are limited. OBJECTIVES: This study aimed to assess sex-related differences in implantable cardioverter-defibrillator (ICD)-treated VT/VF events and death in patients implanted for secondary prevention or primary prevention ICD indications who experienced VT/VF before enrollment in the RAID (Ranolazine Implantable Cardioverter-Defibrillator) trial. METHODS: Sex-related differences in the first and recurrent VT/VF requiring antitachycardia pacing or ICD shock and death were evaluated in 714 patients. RESULTS: There were 124 women (17%) and 590 men observed during a mean follow-up of 26.81 ± 14.52 months. Compared to men, women were at a significantly lower risk of VT/VF/death (HR: 0.67; P = 0.029), VT/VF (HR: 0.68; P = 0.049), VT/VF treated with antitachycardia pacing (HR: 0.59; P = 0.019), and VT/VF treated with ICD shock (HR: 0.54; P = 0.035). The risk of recurrent VT/VF was also significantly lower in women (HR: 0.35; P < 0.001). HR for death was similar to the other endpoints (HR: 0.61; P = 0.162). In comparison to men, women presented with faster VT rates (196 ± 32 beats/min vs 177 ± 30 beats/min, respectively; P = 0.002), and faster shock-requiring VT/VF rates (258 ± 56 beats/min vs 227 ± 57 beats/min, respectively; P = 0.30). There was a significant interaction for the risk of VT/VF by race (P = 0.013) with White women having significantly lower risk than White men (HR: 0.36; P < 0.001), whereas Black women had a similar risk to Black men (HR: 1.06; P = 0.851). CONCLUSIONS: Women with a history of prior VT/VF experienced a lower risk recurrent VT/VF requiring ICD therapy when compared to men. Black Women had a risk similar to men, whereas the lower risk for VT/VF in women was observed primarily in White women. (Ranolazine Implantable Cardioverter-Defibrillator Trial; NCT01215253).

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.

Utility of Left and Right Ventricular Strain in Arrhythmogenic Right Ventricular Cardiomyopathy: A Prospective Multicenter Registry.

BACKGROUND: Imaging evaluation of arrhythmogenic right ventricular cardiomyopathy (ARVC) remains challenging. Myocardial strain assessment by echocardiography is an increasingly utilized technique for detecting subclinical left ventricular (LV) and right ventricular (RV) dysfunction. We aimed to evaluate the diagnostic and prognostic utility of LV and RV strain in ARVC. METHODS: Patients with suspected ARVC (n = 109) from a multicenter registry were clinically phenotyped using the 2010 ARVC Revised Task Force Criteria and underwent baseline strain echocardiography. Diagnostic performance of LV and RV strain was evaluated using the area under the receiver operating characteristic curve analysis against the 2010 ARVC Revised Task Force Criteria, and the prognostic value was assessed using the Kaplan-Meier analysis. RESULTS: Mean age was 45.3±14.7 years, and 48% of patients were female. Estimation of RV strain was feasible in 99/109 (91%), and LV strain was feasible in 85/109 (78%) patients. ARVC prevalence by 2010 ARVC Revised Task Force Criteria is 91/109 (83%) and 83/99 (84%) in those with RV strain measurements. RV global longitudinal strain and RV free wall strain had diagnostic area under the receiver operating characteristic curve of 0.76 and 0.77, respectively (both P<0.001; difference NS). Abnormal RV global longitudinal strain phenotype (RV global longitudinal strain > -17.9%) and RV free wall strain phenotype (RV free wall strain > -21.2%) were identified in 41/69 (59%) and 56/69 (81%) of subjects, respectively, who were not identified by conventional echocardiographic criteria but still met the overall 2010 ARVC Revised Task Force Criteria for ARVC. LV global longitudinal strain did not add diagnostic value but was prognostic for composite end points of death, heart transplantation, or ventricular arrhythmia (log-rank P=0.04). CONCLUSIONS: In a prospective, multicenter registry of ARVC, RV strain assessment added diagnostic value to current echocardiographic criteria by identifying patients who are missed by current echocardiographic criteria yet still fulfill the diagnosis of ARVC. LV strain, by contrast, did not add incremental diagnostic value but was prognostic for identification of high-risk patients.

Genetic QT Score and Sleep Apnea as Predictors of Sudden Cardiac Death in the UK Biobank.

Introduction: The goal of this study was to evaluate the association between a polygenic risk score (PRS) for QT prolongation (QTc-PRS), QTc intervals and mortality in patients enrolled in the UK Biobank with and without sleep apnea. Methods: The QTc-PRS was calculated using allele copy number and previously reported effect estimates for each single nuclear polymorphism SNP. Competing-risk regression models adjusting for age, sex, BMI, QT prolonging medication, race, and comorbid cardiovascular conditions were used for sudden cardiac death (SCD) analyses. Results: 500,584 participants were evaluated (56.5 ±8 years, 54% women, 1.4% diagnosed with sleep apnea). A higher QTc-PRS was independently associated with the increased QTc interval duration (p<0.0001). The mean QTc for the top QTc-PRS quintile was 15 msec longer than the bottom quintile (p<0.001). Sleep apnea was found to be an effect modifier in the relationship between QTc-PRS and SCD. The adjusted HR per 5-unit change in QTc-PRS for SCD was 1.64 (95% CI 1.16 - 2.31, p=0.005) among those with sleep apnea and 1.04 (95% CI 0.95 - 1.14, p=0.44) among those without sleep apnea (p for interaction =0.01). Black participants with sleep apnea had significantly elevated adjusted risk of SCD compared to White participants (HR=9.6, 95% CI 1.24 - 74, p=0.03). Conclusion: In the UK Biobank population, the QTc-PRS was associated with SCD among participants with sleep apnea but not among those without sleep apnea, indicating that sleep apnea is a significant modifier of the genetic risk. Black participants with sleep apnea had a particularly high risk of SCD.

Beyond gene-disease validity: capturing structured data on inheritance, allelic requirement, disease-relevant variant classes, and disease mechanism for inherited cardiac conditions.

BACKGROUND: As the availability of genomic testing grows, variant interpretation will increasingly be performed by genomic generalists, rather than domain-specific experts. Demand is rising for laboratories to accurately classify variants in inherited cardiac condition (ICC) genes, including secondary findings. METHODS: We analyse evidence for inheritance patterns, allelic requirement, disease mechanism and disease-relevant variant classes for 65 ClinGen-curated ICC gene-disease pairs. We present this information for the first time in a structured dataset, CardiacG2P, and assess application in genomic variant filtering. RESULTS: For 36/65 gene-disease pairs, loss of function is not an established disease mechanism, and protein truncating variants are not known to be pathogenic. Using the CardiacG2P dataset as an initial variant filter allows for efficient variant prioritisation whilst maintaining a high sensitivity for retaining pathogenic variants compared with two other variant filtering approaches. CONCLUSIONS: Access to evidence-based structured data representing disease mechanism and allelic requirement aids variant filtering and analysis and is a pre-requisite for scalable genomic testing.

Primary prevention implantable cardioverter defibrillator in cardiac resynchronization therapy recipients with advanced chronic kidney disease.

Introduction: The implantable cardioverter defibrillator (ICD) is effective for the prevention of sudden cardiac death (SCD) in patients with heart failure and a reduced ejection fraction (HFrEF). The benefit of the ICD in patients with advanced CKD, remains elusive. Moreover, the benefit of the ICD in patients with advanced chronic kidney disease (CKD) and HFrEF who are cardiac resynchronization therapy (CRT) recipients may be attenuated. Hypothesis: We hypothesized that patients with CKD who are CRT recipients may derive less benefit from the ICD due to the competing risk of dying prior to experiencing an arrhythmia. Methods: The study population included 1,015 patients receiving CRT with defibrillator (CRT-D) device for primary prevention of SCD who were enrolled in either (Multicenter Automated Defibrillator Implantation Trial) MADIT-CRT trial or the Ranolazine in High-Risk Patients with Implanted Cardioverter Defibrillator (RAID) trial. The cohort was divided into two groups based on the stage of CKD: those with Stage 1 to 3a KD, labeled as (S1-S3a)KD. The second group included patients with Stage 3b to stage 5 kidney disease, labeled as (S3b-S5)KD. The primary endpoint was any ventricular tachycardia (VT) or ventricular fibrillation (VF) (Any VT/VF). Results: The cumulative incidence of Any VT/VF was 23.5% in patients with (S1-S3a)KD and 12.6% in those with (S3b-S5)KD (p < 0.001) The incidence of Death without Any VT/VF was 6.6% in patients with (S1-S3a)KD and 21.6% in patients with (S3b-S5)KD (p < 0.001). A Fine and Gray multivariate competing risk regression model showed that Patients with (S3b-S5)KD had a 43% less risk of experiencing Any VT/VF when compared to those with (S1-S3a)KD (HR = 0.56, 95% CI [0.33-0.94] p = 0.03. After two years of follow up, there was almost a 5-fold increased risk of Death without Any VT/VF among patients with (S3b-S5)KD when compared to those with (S1-S3a)KD [HR = 4.63, 95% CI (2.46-8.72), p for interaction with time = 0.012]. Conclusion: Due to their lower incidence of arrhythmias and higher risk of dying prior to experiencing an arrhythmia, the benefit of the ICD may be attenuated in CRT recipients with advanced CKD. Future prospective trials should evaluate whether CRT without a defibrillator may be more appropriate for these patients.

Effect of Carvedilol vs Metoprolol on Atrial and Ventricular Arrhythmias Among Implantable Cardioverter-Defibrillator Recipients.

BACKGROUND: Both selective and nonselective beta-blockers are used to treat patients with heart failure (HF). However, the data on the association of beta-blocker type with risk of atrial arrhythmia and ventricular arrhythmia (VA) in HF patients with a primary prevention implantable cardioverter-defibrillator (ICD) are limited. OBJECTIVES: This study sought to evaluate the effect of metoprolol vs carvedilol on the risk of atrial tachyarrhythmia (ATA) and VA in HF patients with an ICD. METHODS: This study pooled primary prevention ICD recipients from 5 landmark ICD trials (MADIT-II, MADIT-CRT, MADIT-RIT, MADIT-RISK, and RAID). Fine and Gray multivariate regression models, stratified by study, were used to evaluate the risk of ATA, inappropriate ICD shocks, and fast VA (defined as ventricular tachycardia ≥200 beats/min or ventricular fibrillation) by beta-blocker type. RESULTS: Among 4,194 patients, 2,920 (70%) were prescribed carvedilol and 1,274 (30%) metoprolol. The cumulative incidence of ATA at 3.5 years was 11% in patients treated with carvedilol vs 15% in patients taking metoprolol (P = 0.003). Multivariate analysis showed that carvedilol treatment was associated with a 35% reduction in the risk of ATA (HR: 0.65; 95% CI: 0.53-0.81; P < 0.001) when compared to metoprolol, and with a corresponding 35% reduction in the risk of inappropriate ICD shocks (HR: 0.65; 95% CI: 0.47-0.89; P = 0.008). Carvedilol vs metoprolol was also associated with a 16% reduction in the risk of fast VA. However, these findings did not reach statistical significance (HR: 0.84; 95% CI: 0.70-1.02; P = 0.085). CONCLUSIONS: These findings suggests that HF patients with ICDs on carvedilol treatment experience a significantly lower risk of ATA and inappropriate ICD shocks when compared to treatment with metoprolol.

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.

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.

Association Between Syncope Trigger Type and Risk of Subsequent Life-Threatening Events in Patients With Long QT Syndrome.

Importance: Syncope is the most powerful predictor for subsequent life-threatening events (LTEs) in patients with congenital long QT syndrome (LQTS). Whether distinct syncope triggers are associated with differential subsequent risk of LTEs is unknown. Objective: To evaluate the association between adrenergic (AD)- and nonadrenergic (non-AD)-triggered syncopal events and the risk of subsequent LTEs in patients with LQT types 1 to 3 (LQT1-3). Design, Setting, and Participants: This retrospective cohort study included data from 5 international LQTS registries (Rochester, New York; the Mayo Clinic, Rochester, Minnesota; Israel, the Netherlands, and Japan). The study population comprised 2938 patients with genetically confirmed LQT1, LQT2, or LQT3 stemming from a single LQTS-causative variant. Patients were enrolled from July 1979 to July 2021. Exposures: Syncope by AD and non-AD triggers. Main Outcomes and Measures: The primary end point was the first occurrence of an LTE. Multivariate Cox regression was used to determine the association of AD- or non-AD-triggered syncope on the risk of subsequent LTE by genotype. Separate analysis was performed in patients with ß-blockers. Results: A total of 2938 patients were included (mean [SD] age at enrollment, 29 [7] years; 1645 [56%] female). In 1331 patients with LQT1, a first syncope occurred in 365 (27%) and was induced mostly with AD triggers (243 [67%]). Syncope preceded 43 subsequent LTEs (68%). Syncopal episodes associated with AD triggers were associated with the highest risk of subsequent LTE (hazard ratio [HR], 7.61; 95% CI, 4.18-14.20; P < .001), whereas the risk associated with syncopal events due to non-AD triggers was statistically nonsignificant (HR, 1.50; 95% CI, 0.21-4.77; P = .97). In 1106 patients with LQT2, a first syncope occurred in 283 (26%) and was associated with AD and non-AD triggers in 106 (37%) and 177 (63%), respectively. Syncope preceded 55 LTEs (56%). Both AD- and non-AD-triggered syncope were associated with a greater than 3-fold increased risk of subsequent LTE (HR, 3.07; 95% CI, 1.66-5.67; P ≤ .001 and HR, 3.45, 95% CI, 1.96-6.06; P ≤ .001, respectively). In contrast, in 501 patients with LQT3, LTE was preceded by a syncopal episode in 7 (12%). In patients with LQT1 and LQT2, treatment with ß-blockers following a syncopal event was associated with a significant reduction in the risk of subsequent LTEs. The rate of breakthrough events during treatment with ß-blockers was significantly higher among those treated with selective agents vs nonselective agents. Conclusion and Relevance: In this study, trigger-specific syncope in LQTS patients was associated with differential risk of subsequent LTE and response to ß-blocker therapy.

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.

Predictors of long-term prognosis based on clinical status and measurements obtained in heart failure patients after 9-week hybrid comprehensive telerehabilitation: A subanalysis of the TELEREH-HF randomized clinical trial.

BACKGROUND: Assessing prognosis in heart failure (HF) is of major importance. AIMS: The study aimed to define predictors influencing long-term cardiovascular mortality or HF hospitalization ("composite outcome") based on clinical status and measurements obtained after a 9-week hybrid comprehensive telerehabilitation (HCTR) program. METHODS: This analysis is based on the TELEREH-HF (TELEREHabilitation in Heart Failure) multicenter randomized trial that enrolled 850 HF patients (left ventricular ejection fraction [LVEF] ≤40%). Patients were randomized 1:1 to 9-week HCTR plus usual care (experimental arm) or usual care only (control arm) and followed for median (interquartile range [IQR]) 24 (20-24) months for development of the composite outcome. RESULTS: Over 12-24 months of follow-up, 108 (28.1%) patients experienced the composite outcome. The predictors of our composite outcome were: nonischemic etiology of HF, diabetes, higher serum level of N-terminal prohormone of brain natriuretic peptide, creatinine, and high-sensitivity C-reactive protein; low carbon dioxide output at peak exercise; high minute ventilation and breathing frequency at maximum effort in cardiopulmonary exercise tests; increase in delta of average heart rate in 24-hour Holter ECG monitoring, lower LVEF, and patients' non-adherence to HCTR. The model discrimination C-index was 0.795 and decreased to 0.755 on validation conducted in the control sample which was not used in derivation. The 2-year risk of the composite outcome was 48% in the top tertile versus 5% in the bottom tertile of the developed risk score. CONCLUSION: Risk factors collected at the end of the 9-week telerehabilitation period performed well in stratifying patients based on their 2-year risk of the composite outcome. Patients in the top tertile had an almost ten-fold higher risk compared to patients in the bottom tertile. Treatment adherence, but not peak VO2 or quality of life, was significantly associated with the outcome.

Arrhythmia and Survival Outcomes among Black and White Patients with a Primary Prevention Defibrillator.

Background: Black Americans have a higher risk of non-ischemic cardiomyopathy (NICM) than White Americans. We aimed to evaluate racial disparities in the risk of tachyarrhythmias among patients with an implantable cardioverter defibrillator (ICD). Methods: The study population comprised 3,895 ICD recipients enrolled in the U.S. in primary prevention ICD trials. Outcome measures included first and recurrent ventricular tachy-arrhythmia (VTA) and atrial tachyarrhythmia (ATA), derived from adjudicated device data, and death. Outcomes were compared between self-reported Black vs. White patients with a cardiomyopathy (ischemic [ICM] and NICM). Results: Black patients were more likely to be female (35% vs 22%) and younger (57±12 vs 62±12) with a higher frequency of comorbidities. Blacks patients with NICM compared with Whites patients had a higher rate of first VTA, fast VTA, ATA, appropriate-, and inappropriate-ICD-therapy (VTA≥170bpm: 32% vs. 20%; VTA≥200bpm: 22% vs. 14%; ATA: 25% vs. 12%; appropriate 30% vs 20%; and inappropriate: 25% vs. 11%; p<0.001 for all). Multivariable analysis showed that Black patients with NICM experienced a higher risk of all types of arrhythmia/ICD-therapy (VTA≥170bpm: HR=1.69; VTA≥200bpm: HR=1.58; ATA: HR=1.87; appropriate: HR=1.62; and inappropriate: HR=1.86; p≤0.01 for all), higher burden of VTA, ATA, ICD therapies, and a higher risk of death (HR=1.86; p=0.014). In contrast, in ICM, the risk of all types of tachyarrhythmia, ICD therapy, or death was similar between Black and White patients. Conclusions: Among NICM patients with an ICD for primary prevention, Black compared with White patients had a high risk and burden of VTA, ATA, and ICD therapies. Clinical Perspective: What Is New?: Black patients have a higher risk of developing non-ischemic cardiomyopathy (NICM) but are under-represented in clinical trials of implantable cardioverter defibrillators (ICD). Therefore, data on disparities in the presentation and outcomes in this population are limited.This analysis represents the largest group of self-identified Black patients implanted in the U.S. with an ICD for primary prevention with adjudication of all arrhythmic events.What Are the Clinical Implications?: In patients with a NICM, self-identified Black compared to White patients experienced an increased incidence and burden of ventricular tachyarrhythmia, atrial tachyarrhythmia, and ICD therapies. These differenced were not observed in Black vs White patients with ischemic cardiomyopathy (ICM).Although Black patients with NICM were implanted at a significantly younger age (57±12 vs 62±12 years), they experienced a 2-fold higher rate of all-cause mortality during a mean follow up of 3 years compared with White patients.These findings highlight the need for early intervention with an ICD, careful monitoring, and intensification of heart failure and antiarrhythmic therapies among Black patients with NICM.

Beyond gene-disease validity: capturing structured data on inheritance, allelic-requirement, disease-relevant variant classes, and disease mechanism for inherited cardiac conditions.

Background: As availability of genomic testing grows, variant interpretation will increasingly be performed by genomic generalists, rather than domain-specific experts. Demand is rising for laboratories to accurately classify variants in inherited cardiac condition (ICC) genes, including as secondary findings. Methods: We analyse evidence for inheritance patterns, allelic requirement, disease mechanism and disease-relevant variant classes for 65 ClinGen-curated ICC gene-disease pairs. We present this information for the first time in a structured dataset, CardiacG2P, and assess application in genomic variant filtering. Results: For 36/65 gene-disease pairs, loss-of-function is not an established disease mechanism, and protein truncating variants are not known to be pathogenic. Using CardiacG2P as an initial variant filter allows for efficient variant prioritisation whilst maintaining a high sensitivity for retaining pathogenic variants compared with two other variant filtering approaches. Conclusions: Access to evidence-based structured data representing disease mechanism and allelic requirement aids variant filtering and analysis and is pre-requisite for scalable genomic testing.

Age and the Risk of Ventricular Tachyarrhythmia in Patients With an Implantable Cardioverter-Defibrillator.

BACKGROUND: The benefit of implantable cardioverter-defibrillators (ICDs) in elderly patients is controversial. OBJECTIVES: The aims of this study were to evaluate the risk for ventricular tachyarrhythmia (VTA) and ICD shocks by age groups and to assess the competing risk for VTA and death without prior VTA. METHODS: The study included 5,170 primary prevention ICD recipients enrolled in 5 landmark ICD trials (MADIT [Multicenter Automatic Defibrillator Implantation Trial] II, MADIT-Risk, MADIT-CRT [MADIT Cardiac Resynchronization Therapy], MADIT-RIT [MADIT Reduce Inappropriate Therapy], and RAID [Ranolazine in High-Risk Patients With Implanted Cardioverter-Defibrillator]). Fine and Gray regression analysis was used to evaluate the risk for fast VTA (ventricular tachycardia ≥200 beats/min or ventricular fibrillation) vs death without prior fast VTA in 3 prespecified age groups: <65, 65 to <75, and ≥75 years. RESULTS: The cumulative incidence of fast VTA at 3 years was similar for patients <65 years of age and those 65 to <75 years of age (17% vs 15%) and was lowest among patients ≥75 years of age (10%) (P < 0.001). Multivariate Fine and Gray analysis showed a 40% lower risk for fast VTA in patients ≥75 years of age (HR: 0.60; 95% CI: 0.46-0.78; P < 0.001) compared with patients <65 years of age. In patients ≥75 years of age, a risk reversal was observed whereby the risk for death without prior fast VTA exceeded the risk for developing fast VTA. A history of nonsustained ventricular tachycardia, male sex, and the presence of nonischemic cardiomyopathy were identified as predictors of fast VTA in patients ≥75 years of age. CONCLUSIONS: Patients ≥75 years of age have a significantly lower risk for VTA and ICD shocks compared with younger patients. Aging is associated with a higher risk for death compared with the risk for fast VTA, the reverse of what is seen in younger patients.

A QTc risk score in patients with obstructive sleep apnea.

INTRODUCTION: Patients with obstructive sleep apnea (OSA) are at risk for QTc prolongation, a known risk factor for increased mortality. The pro-QTc score can help identify individuals at increased risk for mortality associated with increased QTc however, it has not been evaluated in patients with OSA. The goal of this study was to evaluate the pro-QTc score in patients with OSA. METHODS: Medical records of patients undergoing a sleep study at our sleep center from February 2012 to August 2020 were analyzed. Presence or absence of OSA was determined by polysomnography. The pro-QTc score was calculated with 1 point assigned for each of the following: female sex, QT-prolonging diagnoses and conditions, QT-prolonging electrolyte abnormalities, and medications with known risk for QT-prolongation. Mortality was determined from the electronic medical record of an integrated healthcare system. RESULTS: There were 2246 patients (age 58 ± 15 years, 54% male, 82 dead) with OSA and 421 patients (age 54 ± 18 years, 43% male, 18 dead) without OSA. Of those with OSA, 1628 (72.5%) had at least one risk factor for QTc prolongation. A higher pro-QTc score was associated with greater mortality in patients with OSA (HR 1.48 per pro-QTc score, p < 0.001, 95% CI 1.3-1.7) but not in patients without OSA (HR 1.25 per pro-QTc score, p = 0.30, 95% CI 0.82-1.9), after adjusting for age, body mass index (BMI), and smoking status. CONCLUSION: In patients with OSA, a higher pro-QTc score was associated with greater mortality.

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.

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.