Abstract
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.
Graphical Abstract
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.
Objectives The present study was designed to explore the 8-year survival benefit of a nonresynchronization implantable cardioverter-defibrillator (ICD) according to a simple risk stratification ...score. Background There is limited information regarding factors that predict the benefit of primary prevention with an ICD during long-term follow-up. Methods This study used a previously developed risk score including 5 clinical factors (New York Heart Association functional class >II, age >70 years, blood urea nitrogen >26 mg/dl, QRS duration >0.12 s, and atrial fibrillation) to evaluate 8-year ICD survival benefit within risk score categories among 1,191 MADIT-II (Multicenter Automatic Defibrillator Implantation Trial II) patients. Results Patients with low (0 risk factors, n = 345) and intermediate risk (1 to 2 risk factors, n = 646) demonstrated a significantly higher probability of survival at 8-year follow-up when treated by ICD as compared with non-ICD therapy (75% vs. 58%, p = 0.004; and 47% vs. 31%, p < 0.001, respectively). By contrast, among high-risk patients (3 or more risk factors, n = 200), there was no significant difference in 8-year survival between the ICD and non-ICD subgroups (19% vs. 17%, p = 0.50). Consistently, multivariate analysis showed that ICD therapy was associated with a significant long-term survival benefit among low- and intermediate-risk patients (hazard ratio HR: 0.52, p < 0.001, and HR: 0.66, p < 0.001, respectively), whereas treatment with an ICD was not associated with a significant benefit among high-risk patients (HR: 0.84, p = 0.25). Conclusions These findings suggest that a simple risk score can identify patients who derive significant long-term benefit from primary ICD therapy. High-risk patients with multiple comorbidities composed 17% of the MADIT-II population and did not derive long-term benefit from nonresynchronization device therapy.
In this trial, two new programs for delivering implantable cardioverter–defibrillator therapy resulted in fewer inappropriate interventions (shocks or antitachycardia pacing) and an unexpected ...reduction in mortality. Improved programming could benefit patients with ICDs.
The implantable cardioverter–defibrillator (ICD), either alone or in conjunction with cardiac-resynchronization therapy (CRT), is highly effective in reducing the rate of death due to ventricular tachyarrhythmia among high-risk cardiac patients.
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However, inappropriate ICD activations, which are typically caused by supraventricular tachyarrhythmias, are frequent, despite sophisticated device-related detection algorithms that are designed to differentiate supraventricular from ventricular tachyarrhythmias; such activations have potentially life-threatening side effects.
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Inappropriate device-delivered therapy, defined as therapy delivered for nonventricular tachyarrhythmias, affects 8 to 40% of patients with ICDs.
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The best method for programming ICD devices to reduce inappropriate therapy is unknown.
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We conducted a . . .
Abstract
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.
Graphical Abstract
Graphical Abstract
This study aimed to determine whether QRS morphology identifies patients who benefit from cardiac resynchronization therapy with a defibrillator (CRT-D) and whether it influences the risk of primary ...and secondary end points in patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT) trial.
Baseline 12-lead ECGs were evaluated with regard to QRS morphology. Heart failure event or death was the primary end point of the trial. Death, heart failure event, ventricular tachycardia, and ventricular fibrillation were secondary end points. Among 1817 patients with available sinus rhythm ECGs at baseline, there were 1281 (70%) with left bundle-branch block (LBBB), 228 (13%) with right bundle-branch block, and 308 (17%) with nonspecific intraventricular conduction disturbances. The latter 2 groups were defined as non-LBBB groups. Hazard ratios for the primary end point for comparisons of CRT-D patients versus patients who only received an implantable cardioverter defibrillator (ICD) were significantly (P < 0.001) lower in LBBB patients (0.47; P < 0.001) than in non-LBBB patients (1.24; P = 0.257). The risk of ventricular tachycardia, ventricular fibrillation, or death was decreased significantly in CRT-D patients with LBBB but not in non-LBBB patients. Echocardiographic parameters showed significantly (P < 0.001) greater reduction in left ventricular volumes and increase in ejection fraction with CRT-D in LBBB than in non-LBBB patients.
Heart failure patients with New York Heart Association class I or II and ejection fraction ≤ 30% and LBBB derive substantial clinical benefit from CRT-D: a reduction in heart failure progression and a reduction in the risk of ventricular tachyarrhythmias. No clinical benefit was observed in patients with a non-LBBB QRS pattern (right bundle-branch block or intraventricular conduction disturbances).
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00180271.
Abstract Brugada syndrome is an inherited heart disease without structural abnormalities that is thought to arise as a result of accelerated inactivation of Na channels and predominance of transient ...outward K current ( Ito ) to generate a voltage gradient in the right ventricular layers. This gradient triggers ventricular tachycardia/ventricular fibrillation possibly through a phase 2 reentrant mechanism. The Brugada electrocardiographic (ECG) pattern, which can be dynamic and is sometimes concealed, being only recorded in upper precordial leads, is the hallmark of Brugada syndrome. Because of limitations of previous consensus documents describing the Brugada ECG pattern, especially in relation to the differences between types 2 and 3, a new consensus report to establish a set of new ECG criteria with higher accuracy has been considered necessary. In the new ECG criteria, only 2 ECG patterns are considered: pattern 1 identical to classic type 1 of other consensus (coved pattern) and pattern 2 that joins patterns 2 and 3 of previous consensus (saddle-back pattern). This consensus document describes the most important characteristics of 2 patterns and also the key points of differential diagnosis with different conditions that lead to Brugada-like pattern in the right precordial leads, especially right bundle-branch block, athletes, pectus excavatum, and arrhythmogenic right ventricular dysplasia/cardiomyopathy. Also discussed is the concept of Brugada phenocopies that are ECG patterns characteristic of Brugada pattern that may appear and disappear in relation with multiple causes but are not related with Brugada syndrome.
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