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.

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.

Smoking and the Risk of Stroke in Patients with a Left Ventricular Assist device.

There are limited data on the association of smoking with the risk of stroke following left ventricular assist device (LVAD) implantation. We designed this study to analyze the impact of smoking status at the time of LVAD implantation on stroke. We hypothesized that current smokers are at increased risk of stroke when compared with patients who were former or never smokers. The study population comprised of 369 patients in the University of Rochester Medical Center LVAD database, implanted with an LVAD between 2008 and 2018. Patients were stratified as current smoker (smoking within 30 days before LVAD implantation), former smoker, and never smoker. Stroke was defined as a transient ischemic attack or cerebrovascular accident (hemorrhagic or ischemic). There were 45 current smokers, 198 former smokers, and 125 never smokers. Current smokers were younger (mean age 50 ± 11 years), as compared with former (58 ± 12 years) and never smokers (56 ± 13 years) p < 0.001. At 2 years following LVAD implantation, the cumulative incidence of stroke was significantly higher among current smokers (39%) as compared with former and never smokers (16% and 15%, respectively; p = 0.022 for the overall difference during follow-up). In a multivariate model adjusted for significant clinical variables, current smoking was associated with a significant 88% (p = 0.018) higher risk of stroke when compared with all noncurrent smokers. In conclusion, our data suggest that LVAD candidates who are current smokers experience a significantly higher risk of stroke following device implantation.

Effectiveness of high rate and delayed detection ICD programming by race: A MADIT-RIT substudy.

INTRODUCTION: Data on inappropriate and appropriate ICD therapy, and efficacy of ICD programing strategies by race are limited. METHODS: In MADIT-RIT, we evaluated the risk of ICD therapy by race, and the efficacy of high rate cut-off ventricular tachycardia (VT) zone ≥200 beats per minute (bpm) (Arm B), or 60 seconds delay in VT zone 170-199 bpm (Arm C), compared to 2.5 seconds delay at 170 bpm (Arm A) among black and white patients. RESULTS: MADIT-RIT enrolled 272 (20%) black and 1119 (80%) white patients. The risk of inappropriate therapy was similar among blacks and whites, HR 1.25, 95% CI (0.82-1.93), P  =  0.30. High rate cut-off or delayed VT therapy was associated with significant reductions in inappropriate therapy among whites, Arm B versus Arm A, HR 0.15, 95% CI (0.08-0.29), P < 0.0001, Arm C versus Arm A, HR 0.19, 95% CI (0.11-0.33), P < 0.001, and black individuals Arm B versus Arm A, HR 0.24, 95% CI (0.01-0.56), P  =  0.0001, Arm C versus Arm A, HR 0.30, 95% CI (0.13-0.68), P  =  0.004, P interaction > 0.10). However, delayed VT therapy was associated with a trend toward greater reduction in appropriate therapy in black individuals, HR 0.08, 95% CI (0.03-0.27), P < 0.0001 relative to white individuals, HR 0.27, 95% CI (0.16-0.43), P < 0.0001, P interaction  =  0.077. CONCLUSION: In MADIT-RIT, high rate and delayed detection ICD programming provided similar benefit with reductions in both inappropriate therapy and unnecessary appropriate therapy among black and white individuals. CLINICALTRIALS. GOV IDENTIFIER: NCT00947310.

Clinical presentation at first heart failure hospitalization does not predict recurrent heart failure admission.

AIMS: There are limited data on whether clinical presentation at first heart failure (HF) hospitalization predicts recurrent HF events. We aimed to assess predictors of recurrent HF hospitalizations in mild HF patients with an implantable cardioverter defibrillator or cardiac resynchronization therapy with defibrillator. METHODS AND RESULTS: Data on HF hospitalizations were prospectively collected for patients enrolled in MADIT-CRT. Predictors of recurrent HF hospitalization (HF2) after the first HF hospitalization were assessed using Cox proportional hazards regression models including baseline covariates and clinical presentation or management at first HF hospitalization. There were 193 patients with first HF hospitalization, and 156 patients with recurrent HF events. Recurrent HF rate after the first HF hospitalization was 43% at 1 year, 52% at 2 years, and 55% at 2.5 years. Clinical signs and symptoms, medical treatment, or clinical management of HF at first HF admission was not predictive for HF2. Baseline covariates predicting recurrent HF hospitalization included prior HF hospitalization (HR = 1.59, 95% CI: 1.15-2.20, P = 0.005), digitalis therapy (HR = 1.58, 95% CI: 1.13-2.20, P = 0.008), and left ventricular end-diastolic volume >240 mL (HR = 1.62, 95% CI: 1.17-2.25, P = 0.004). CONCLUSIONS: Recurrent HF events are frequent following the first HF hospitalization in patients with implanted implantable cardioverter defibrillator or cardiac resynchronization therapy with defibrillator. Neither clinical presentation nor clinical management during first HF admission was predictive of recurrent HF. Prior HF hospitalization, digitalis therapy, and left ventricular end-diastolic volume at enrolment predicted recurrent HF hospitalization, and these covariates could be used as surrogate markers for identifying a high-risk cohort.

Effect of cardiac resynchronization therapy on the risk of ventricular tachyarrhythmias in patients with chronic kidney disease.

BACKGROUND: The effect of chronic kidney disease (CKD) on benefit from cardiac resynchronization therapy with defibrillator (CRT-D) in reducing ventricular tachyarrhythmia (VTA) risk among mild heart failure (HF) patients is not well understood. METHODS: We evaluated the impact of baseline renal function on VTAs in 1274 left bundle branch block (LBBB) patients enrolled in MADIT-CRT. Two prespecified subgroups were created based on estimated glomerular filtration rate (GFR): GFR <60 (n = 413) and GFR ≥60 ml/min/1.73 m2 (n = 861). Primary end point was ventricular tachycardia/ventricular fibrillation/death (VT/VF/death). Secondary end points were any VT/VF and ventricular tachycardia ≥ 200 bpm or VF (fast VT/VF). RESULTS: There were 413 (32%) LBBB patients presenting with CKD, primarily of moderate severity (GFR mean 48.1 ± 8.3). For patients with and without CKD, CRT-D was associated with lower risk of the primary end point (GFR<60: HR = 0.61, 95% CI: 0.41-0.89, p = .010; GFR≥60: HR = 0.58, 95% CI: 0.52-0.89, p = .005), relative to ICD-only treatment. For patients in both renal function categories, CRT-D in comparison to ICD alone was associated with lower risk of VT/VF (GFR<60: HR = 0.68, 95% CI: 0.42-1.10, p = .113; GFR≥60: HR = 0.65, 95% CI: 0.48-0.88, p = .005) and fast VT/VF (GFR<60: HR = 0.49, 95% CI: 0.25-0.96, p = .038; GFR≥60: HR = 0.55, 95% CI: 0.39-0.80, p = .001), when accounting for competing mortality risk. This effect was independent of CRT-induced reverse remodeling. CONCLUSION: Among mild HF patients with LBBB, those with and without CKD both derived benefit from CRT-D in risk reduction in VTAs, independent of cardiac reverse remodeling.

Clinical Presentation and Outcomes by Sex in Arrhythmogenic Right Ventricular Cardiomyopathy: Findings from the North American ARVC Registry.

BACKGROUND: Sex differences in clinical presentation and outcomes of hereditary arrhythmias are commonly reported. We aimed to compare clinical presentation and outcomes in men and women with arrhythmogenic right ventricular cardiomyopathy (ARVC) enrolled in the North American ARVC Registry. METHODS: A total of 125 ARVC probands (55 females, mean age 38 ± 12; 70 males, mean age 41 ± 15) diagnosed, as either "affected" or "borderline" were included. Baseline clinical characteristics and time-dependent outcomes including syncope, ventricular tachycardia (VT), fast VT (>240 bpm), ventricular fibrillation (VF), and death were compared between males and females. RESULTS: The percentage of ARVC subjects diagnosed as "affected" (84% vs. 89%; P = 0.424) or "borderline" (16% vs. 11%; P = 0.424) was similar between females and males. Among the baseline characteristics, inverted T-waves in V2 trended to be more common in women (P = 0.09), whereas abnormal signal-averaged ECGs (SAECGs; P < 0.001) and inducible VT/VF (P = 0.026) were more frequent in men. During a mean follow-up of 37 ± 20 months, the probability of ICD-recorded VT/VF or death was not significantly different between men and women (P = 0.456). However, there was a trend toward lower risk of fast VT/VF or death in women compared to men (hazard ratio 0.41, 95% CI 0.151-1.113, P = 0.066). Abnormal SAECG and evidence of intramyocardial fat by cardiac MRI was associated with adverse outcomes in men (P = 0.006 and 0.02 respectively). CONCLUSION: In the North American ARVC Registry, we found similar frequency of "affected" and "borderline" subjects between men and women. Sex-related differences were observed in baseline ECG, SAECG, Holter-recorded ventricular arrhythmias, and VT inducibility. Men showed a trend toward greater risk of fast VT than women.

Association of competitive and recreational sport participation with cardiac events in patients with arrhythmogenic right ventricular cardiomyopathy: results from the North American multidisciplinary study of arrhythmogenic right ventricular cardiomyopathy.

AIMS: It has been proposed that competitive sport increases the risk of ventricular tachyarrhythmias (VTA) and death in patients with arrhythmogenic right-ventricular cardiomyopathy (ARVC). However, it is unknown whether this only applies to competitive sport or if recreational sports activity also increases the risk of VTA/death. METHODS AND RESULTS: Probands diagnosed with ARVC according to the 2010 task force criteria for ARVC (n = 108) were included in the current analysis. At the time of enrolment, study participants were questioned about exercise level prior to and after ARVC diagnosis, within three categories of sports participation: competitive (n = 41), recreational (n = 48), and inactive (n = 19). Competitive sport was associated with a significantly higher risk of VTA/death when compared with both recreational sport [HR = 1.99 (1.21-3.28), P = 0.007] and inactive patients [HR = 2.05 (1.07-3.91), P = 0.030]. No increased risk of VTA/death was associated with recreational sport when compared with patients who were inactive [HR = 1.03 (0.54-1.97), P = 0.930]. Symptoms developed at an earlier age in patients who participated in competitive sport (30 ± 12 years), when compared with patients who participated in recreational sport (38 ± 17 years) (P = 0.015) and inactive patients (41 ± 11 years) (P = 0.002). No difference in age at first symptom was seen between patients who participated in recreational sport and inactive patients (P = 0.651). CONCLUSION: Competitive sport was associated with a two-fold increased risk of VTA/death, and earlier presentation of symptoms, when compared with inactive patients, and to patients who participated in recreational sport. When compared with inactive patients, recreational sport was not associated with earlier onset of symptoms or increased risk of VTA/death. ClinicalTrials.gov Identifier: NCT00024505.

Syncope in genotype-negative long QT syndrome family members.

Unaffected long-QT syndrome family members (FMs) frequently experience syncope. The aims of this study were to test the hypothesis that syncope events in FMs are benign events and to compare clinical characteristics, triggers eliciting the syncope events, and long-term outcomes between FMs and those with LQT1 or LQT2 mutations from the international Long QT Syndrome Registry. A total of 679 FMs, 864 LQT1 patients, and 782 LQT2 patients were included. Seventy-eight FMs (11%) experienced cardiovascular events. Almost all cardiovascular events were nonfatal syncope; only 1 FM, with an additional mitral valve prolapse, experienced aborted cardiac arrest during exercise. The mean age at first syncope in FMs was 17 years, and female FMs experienced syncope more frequently than male FMs (14% vs 9%, p = 0.027). Syncope was more frequently triggered by exercise in LQT1 patients (43% in LQT1 patients vs 5% in FMs, p <0.001), while syncope triggered by a variety of other triggers was more frequent in FMs (54% in FMs vs 22% in LQT1 patients and 30% in LQT2 patients, p <0.001 for both). None of the FMs experienced aborted cardiac arrest or sudden cardiac death after the first syncopal episode. In conclusion, syncope is frequently present in FMs, and these syncopal events occurred more frequently in female than in male FMs, with an increased incidence in midadolescence. Triggers eliciting the syncopal events were different between FMs and patients with long-QT syndrome mutations. Hence, the type of trigger is useful in distinguishing between high- and low-risk syncope. These data indicate that FMs from families with LQTS have a benign form of syncope, most likely related to vasovagal syncope and not ventricular tachyarrhythmic syncope.

Ventricular arrhythmias in the North American multidisciplinary study of ARVC: predictors, characteristics, and treatment.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with sudden cardiac death. However, the selection of patients for implanted cardioverter-defibrillators (ICDs), as well as programming of the ICD, is unclear. OBJECTIVES: The objective of this study was to identify predictors, characteristics, and treatment of ventricular arrhythmias in patients with ARVC. METHODS: The Multidisciplinary Study of Right Ventricular Cardiomyopathy established the North American ARVC Registry and enrolled patients with a diagnosis of ARVC. Patients were followed prospectively. RESULTS: Of 137 patients enrolled, 108 received ICDs. Forty-eight patients had 502 sustained episodes of ventricular arrhythmias, including 489 that were monomorphic and 13 that were polymorphic. In the patients with ICDs, independent predictors of ventricular arrhythmias in follow-up included spontaneous sustained ventricular arrhythmias before ICD implantation and T-wave inversions inferiorly. The only independent predictor for life-threatening arrhythmias, defined as sustained ventricular tachycardia (VT) ≥240 beats/min or ventricular fibrillation, was a younger age at enrollment. Anti-tachycardia pacing (ATP), independent of the cycle length of the VT, was successful in terminating 92% of VT episodes. CONCLUSIONS: In the North American ARVC Registry, the majority of ventricular arrhythmias in follow-up are monomorphic. Risk factors for ventricular arrhythmias were spontaneous ventricular arrhythmias before enrollment and a younger age at ICD implantation. ATP is highly successful in terminating VT, and all ICDs should be programmed for ATP, even for rapid VT.

Smoking is associated with an increased risk of first and recurrent ventricular tachyarrhythmias in ischemic and nonischemic patients with mild heart failure: a MADIT-CRT substudy.

BACKGROUND: Limited data exist regarding the proarrhythmic effects of smoking. OBJECTIVE: To evaluate the relationship between smoking and the risk of first and recurrent ventricular tachyarrhythmias (VTAs) in patients with mild heart failure. METHODS: The risk of a first and recurrent appropriate implantable cardioverter-defibrillator therapy for VTAs or death was compared between nonsmokers (n = 465), past smokers (n = 780), and current smokers (n = 197) in patients with ischemic and nonischemic cardiomyopathy who were enrolled in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy study. RESULTS: The cumulative probability of a first VTA or death was significantly higher in current smokers than in past and nonsmokers (P < .001). Multivariate analysis showed that current smokers had a significantly higher risk of first ventricular tachycardia/ventricular fibrillation or death (hazard ratio [HR] 1.51; 95% confidence interval [CI] 1.14-2.01; P = .005) and a higher risk for first ventricular tachycardia/ventricular fibrillation episode (HR 1.54, 95% CI 1.12-2.13, P = .008) than did nonsmokers. Past smokers had a risk of first VTAs or death similar to that of nonsmokers (HR 1.01; 95% CI 0.80-1.27; P = .953). In comparison to nonsmokers, the risk of recurrent VTAs was significantly higher in the total cohort of patients (HR 1.54; 95% CI 1.21-1.95; P < .001) and in the subgroups of patients with ischemic and nonischemic cardiomyopathy (HR 1.48; 95% CI 1.03-2.13; P = .035). CONCLUSIONS: Current smokers with left ventricular dysfunction and mild heart failure are at a significantly higher risk of VTAs or death than are past smokers and nonsmokers. Smoking is associated with a significant increase in the risk of recurrent VTAs in both patients with ischemic and nonischemic cardiomyopathy.

Efficacy of antiarrhythmic drugs in arrhythmogenic right ventricular cardiomyopathy: a report from the North American ARVC Registry.

OBJECTIVES: This study sought to examine the efficacy of empiric antiarrhythmic drugs in a rigorously characterized cohort of arrhythmogenic right ventricular cardiomyopathy (ARVC) patients. BACKGROUND: Antiarrhythmic drugs are important in protecting against ventricular arrhythmias in ARVC, but no studies have provided data in a group rigorously screened for the disease. METHODS: Antiarrhythmic medicines were examined in all subjects with implantable cardioverter-defibrillators (ICDs) enrolled in the North American ARVC Registry. A Cox proportional hazards model was used to account for time on each drug, and a hierarchical analysis was performed for repeated measures within individuals. RESULTS: Ninety-five patients were studied, with a mean follow-up of 480 +/- 389 days. Fifty-eight (61%) received beta-blockers, and these medicines were not associated with an increased or decreased risk of ventricular arrhythmias. Sotalol was associated with a greater risk of any clinically relevant ventricular arrhythmia as defined by sustained ventricular tachycardia or ICD therapy (hazard ratio [HR]: 2.55, 95% confidence interval [CI]: 1.02 to 6.39, p = 0.045), but this was not statistically significant after adjusting for potential confounders. An increased risk of any ICD shock and first clinically relevant ventricular arrhythmia while on sotalol remained significant after multivariable adjustment. Those on amiodarone (n = 10) had a significantly lower risk of any clinically relevant ventricular arrhythmia (HR: 0.25, 95% CI: 0.07 to 0.95, p = 0.041), a finding that remained significant after multivariable adjustment. CONCLUSIONS: In a cohort of well-characterized ARVC subjects, neither beta-blockers nor sotalol seemed to be protective. Evidence from a small number of patients suggests that amiodarone has superior efficacy in preventing ventricular arrhythmias.