Risk Of Life-threatening Arrhythmic Events Research Articles

Ablation of the epicardial substrate in patients with long-QT syndrome at risk of sudden death.

Sudden cardiac death remains a critical public health concern globally, affecting millions annually. Recent advances in cardiac arrhythmia mapping have demonstrated that the ventricular epicardial region has a critical arrhythmogenic role in some inherited cardiogenetic diseases. Among these, long-QT syndrome (LQTS) exposes patients to the risk of life-threatening arrhythmic events. Despite advancements, there is a need for more effective therapeutic strategies. A recent study has uncovered a noteworthy connection between LQTS and epicardial structural abnormalities, challenging the traditional view of LQTS as purely an electrical disorder. High-density mapping revealed electroanatomic abnormalities in the right ventricular epicardium, presenting a potential target for catheter ablation, to finally suppress ventricular fibrillation recurrences in high-risk LQTS patients.

Assessment of absolute risk of life-threatening cardiac events in long QT syndrome patients.

BackgroundRisk stratification in long QT syndrome (LQTS) patients is important for optimizing patient care and informing clinical decision making. We developed a risk prediction algorithm with prediction of 5-year absolute risk of the first life-threatening arrhythmic event [defined as aborted cardiac arrest, sudden cardiac death, or appropriate implantable cardioverter defibrillator (ICD) shock] in LQTS patients, accounting for individual risk factors and their changes over time.MethodsRochester-based LQTS Registry included the phenotypic cohort consisting of 1,509 LQTS patients with a QTc ≥ 470 ms, and the genotypic cohort including 1,288 patients with single LQT1, LQT2, or LQT3 mutation. We developed two separate risk prediction models which included pre-specified time-dependent covariates of beta-blocker use, syncope (never, syncope while off beta blockers, and syncope while on beta blockers), and sex by age < and ≥13 years, baseline QTc, and genotype (for the genotypic cohort only). Follow-up started from enrollment in the registry and was censored at patients’ 50s birthday, date of death due to reasons other than sudden cardiac death, or last contact, whichever occurred first. The predictive models were externally validated in an independent cohort of 1,481 LQTS patients from Pavia, Italy.ResultsIn Rochester dataset, there were 77 endpoints in the phenotypic cohort during a median follow-up of 9.0 years, and 47 endpoints in the genotypic cohort during a median follow-up of 9.8 years. The time-dependent extension of Harrell’s generalized C-statistics for the phenotypic model and genotypic model were 0.784 (95% CI: 0.740–0.827) and 0.785 (95% CI: 0.721–0.849), respectively, in the Rochester cohort. The C-statistics obtained from external validation in the Pavia cohort were 0.700 (95% CI: 0.610–0.790) and 0.711 (95% CI: 0.631–0.792) for the two models, respectively. Based on the above models, an online risk calculator estimating a 5-year risk of life-threatening arrhythmic events was developed.ConclusionThis study developed two risk prediction algorithms for phenotype and genotype positive LQTS patients separately. The estimated 5-year absolute risk can be used to quantify a LQTS patient’s risk of developing life-threatening arrhythmic events and thus assisting in clinical decision making regarding prophylactic ICD therapy.

The peri-infarct gray zone of myocardial fibrosis is a better predictor of ventricular arrhythmias than dense core fibrosis in patients with previous myocardial infarction

Abstract Background Current sudden cardiac death (SCD) risk stratification relies heavily on left ventricular ejection fraction (LVEF), but markers to refine risk assessment are needed. Dense core fibrosis (DCF) and peri-infarct “gray zone” of myocardial fibrosis (GZF) on late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) have been proposed as potential arrhythmogenic substrates. The aim of our study was to determine whether DCF and GZF could predict the occurrence of ventricular arrhythmias in patients with previous myocardial infarction. Methods We performed a single centre retrospective study enrolling consecutive patients with previous myocardial infarction undergoing CMR before implantable cardioverter-defibrillator (ICD) implantation. Areas of LGE were subdivided into “core” DCF and “peri-infarct” GZF zones based on signal intensity (&amp;gt;5 SD, and 2–5 SD above the mean of reference myocardium, respectively). The primary endpoint was a composite of sudden arrhythmic death, appropriate ICD shock, ventricular fibrillation (VF), or sustained ventricular tachycardia (VT) as detected by the device. Results A total of 88 patients (median age 61 years [IQR 54–73], 84% male, median LVEF 30% [IQR 23–36%], 14% secondary prevention) were included. During a median follow-up of 23 months [IQR 9–38], 13 patients reached the primary endpoint (10 appropriate ICD shock, 2 sustained VT or VF, and 1 sudden arrhythmic death). Patients who attained the primary endpoint had similar DCF (30.4±14.7 g vs. 28.0±15.3 g; P=0.601) but a greater amount of GZF (18.1±9.6 g vs. 11.9±6.7 g; P=0.005). On univariate analysis, GZF was associated with the composite endpoint (HR: 1.09 per gram; 95% CI: 1.02–1.15; P=0.006), whereas DCF was not (HR: 1.01 per gram; 95% CI: 0.98–1.05; P=0.571). After adjustment for LVEF, GZF remained independently associated with the primary endpoint (adjusted HR: 1.06 per gram; 95% CI: 1.01–1.12; P=0.035). Decision tree analysis identified 11.9g of GZF as the best cut-off to predict life-threatening arrhythmic events. The primary endpoint occurred in 11 out of the 35 patients (31.4%) with GZF ≥11.9 g, but in only 2 of the 53 patients (3.8%) with GZF &amp;lt;11.9 g – Figure 1. Conclusions The extent of peri-infarct GZF seems to be a better predictor of ventricular arrhythmias than DCF. This parameter may be useful to identify a subgroup of patients with previous myocardial infarction at increased risk of life-threatening arrhythmic events. Funding Acknowledgement Type of funding sources: None.

Predictors of late arrhythmic events after generator replacement in Brugada syndrome treated with prophylactic ICD.

IntroductionPredictors of late life-threatening arrhythmic events in Brugada syndrome (BrS) patients who received a prophylactic ICD implantation remain to be evaluated. The aim of the present long-term multicenter study was to assess the incidence and clinical-electrocardiographic predictors of late life-threatening arrhythmic events in BrS patients with a prophylactic implantable cardioverter defibrillator (ICD) and undergoing generator replacement (GR).MethodsThe study population included 105 patients (75% males; mean age 45 ± 14years) who received a prophylactic ICD and had no arrhythmic event up to first GR.ResultsThe median period from first ICD implantation to last follow-up was 155 (128–181) months and from first ICD Implantation to the GR was 84 (61–102) months. During a median follow-up of 57 (38–102) months after GR, 10 patients (9%) received successful appropriate ICD intervention (1.6%/year). ICD interventions included shock on ventricular fibrillation (n = 8 patients), shock on ventricular tachycardia (n = 1 patient), and antitachycardia pacing on ventricular tachycardia (n = 1 patient). At survival analysis, history of atrial fibrillation (log-rank test; P = 0.02), conduction disturbances (log-rank test; P < 0.01), S wave in lead I (log-rank test; P = 0.01) and first-degree atrioventricular block (log-rank test; P = 0.04) were significantly associated with the occurrence of late appropriate ICD intervention. At Cox-regression multivariate analysis, S-wave in lead I was the only independent predictor of late appropriate ICD intervention (HR: 9.17; 95%CI: 1.15–73.07; P = 0.03).ConclusionsThe present study indicates that BrS patient receiving a prophylactic ICD may experience late appropriate intervention after GR in a clinically relevant proportion of cases. S-wave in lead I at the time of first clinical evaluation was the only independent predictor of persistent risk of life-threatening arrhythmic events. These findings support the need for GR at the end of service regardless of previous appropriate intervention, mostly in BrS patients with conduction abnormalities.

The peri-infarct gray zone of myocardial fibrosis is a better predictor of ventricular arrhythmias than dense core fibrosis in patients with previous myocardial infarction

Abstract Funding Acknowledgements Type of funding sources: None. Background Current sudden cardiac death (SCD) risk stratification relies heavily on left ventricular ejection fraction (LVEF), but markers to refine risk assessment are needed. Dense core fibrosis (DCF) and peri-infarct "gray zone" of myocardial fibrosis (GZF) on late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) have been proposed as potential arrhythmogenic substrates. The aim of our study was to determine whether DCF and GZF could predict the occurrence of ventricular arrhythmias in patients with previous myocardial infarction. Methods We performed a single centre retrospective study enrolling consecutive patients with previous myocardial infarction undergoing CMR before implantable cardioverter-defibrillator (ICD) implantation. Areas of LGE were subdivided into "core" DCF and "peri-infarct" GZF zones based on signal intensity (&amp;gt;5 SD, and 2-5 SD above the mean of reference myocardium, respectively). The primary endpoint was a composite of sudden arrhythmic death, appropriate ICD shock, ventricular fibrillation (VF), or sustained ventricular tachycardia (VT) as detected by the device. Results A total of 88 patients (median age 61 years [IQR 54-73], 84% male, median LVEF 30% [IQR 23-36%], 14% secondary prevention) were included. During a median follow-up of 23 months [IQR 9-38], 13 patients reached the primary endpoint (10 appropriate ICD shock, 2 sustained VT or VF, and 1 sudden arrhythmic death). Patients who attained the primary endpoint had similar DCF (30.4g ± 14.7 vs. 28.0g ± 15.3; P = 0.601) but a greater amount of GZF (18.1g ± 9.6 vs. 11.9g ± 6.7; P = 0.005). On univariate analysis, GZF was associated with the composite endpoint (HR: 1.09 per gram; 95%CI: 1.02-1.15; P = 0.006), whereas DCF was not (HR: 1.01 per gram; 95%CI: 0.98-1.05; P = 0.571). After adjustment for LVEF, GZF remained independently associated with the primary endpoint (adjusted HR: 1.06 per gram; 95% CI: 1.01-1.12; P = 0.035). Decision tree analysis identified 11.9g of GZF as the best cut-off to predict life-threatening arrhythmic events. The primary endpoint occurred in 11 out of the 35 patients (31.4%) with GZF ≥11.9g, but in only 2 of the 53 patients (3.8%) with GZF &amp;lt;11.9g – Figure. Conclusions The extent of peri-infarct GZF seems to be a better predictor of ventricular arrhythmias than DCF. This parameter may be useful to identify a subgroup of patients with previous myocardial infarction at increased risk of life-threatening arrhythmic events.

PO-626-04 THE PERI-INFARCT “GRAY ZONE” OF MYOCARDIAL FIBROSIS IS A BETTER PREDICTOR OF VENTRICULAR ARRHYTHMIAS THAN DENSE CORE FIBROSIS IN PATIENTS WITH PREVIOUS MYOCARDIAL INFARCTION

Current sudden cardiac death (SCD) risk stratification relies heavily on left ventricular ejection fraction (LVEF), but markers to refine risk assessment are needed. Dense core fibrosis (DCF) and peri-infarct “gray zone” of myocardial fibrosis (GZF) on late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) have been proposed as arrhythmogenic substrates. We aimed to determine whether DCF and GZF could predict the occurrence of ventricular arrhythmias in patients with previous myocardial infarction. We performed a single centre retrospective study enrolling consecutive patients with previous myocardial infarction undergoing CMR before implantable cardioverter-defibrillator (ICD) implantation. Areas of LGE were subdivided into “core” DCF and “peri-infarct” GZF zones based on signal intensity (>5 SD, and 2-5 SD above the mean of reference myocardium, respectively). The primary endpoint was a composite of sudden arrhythmic death, appropriate ICD shock, ventricular fibrillation (VF), or sustained ventricular tachycardia (VT) as detected by the device. A total of 88 patients (median age 61 years [IQR 54-73], 84% male, median LVEF 30% [IQR 23-36%]) were included. During a median follow-up of 23 months [IQR 9-38], 13 patients reached the primary endpoint. Patients who attained the primary endpoint had similar DCF (30.4g ± 14.7 vs. 28.0g ± 15.3; P = 0.601) but a greater amount of GZF (18.1g ± 9.6 vs. 11.9g ± 6.7; P = 0.005). On univariate analysis, GZF was associated with the composite endpoint (HR: 1.09 per gram; 95%CI: 1.02-1.15; P=0.006), whereas DCF was not (HR: 1.01 per gram; 95%CI: 0.98-1.05; P=0.571). After adjustment for LVEF, GZF remained independently associated with the primary endpoint (adjusted HR: 1.06 per gram; 95% CI: 1.01-1.12; P=0.035). Decision tree analysis identified 11.9g of GZF as the best cut-off to predict arrhythmic events. The primary endpoint occurred in 11 out of the 35 patients (31.4%) with GZF ≥11.9g, but in only 2 of the 53 patients (3.8%) with GZF <11.9g - Figure. The extent of peri-infarct GZF seems to be a better predictor of ventricular arrhythmias than DCF. This parameter may be useful to identify a subgroup of patients with previous myocardial infarction at increased risk of life-threatening arrhythmic events.

Machine learning-based risk model using 123I-metaiodobenzylguanidine to differentially predict modes of cardiac death in heart failure

BackgroundCardiac sympathetic dysfunction is closely associated with cardiac mortality in patients with chronic heart failure (CHF). We analyzed the ability of machine learning incorporating 123I-metaiodobenzylguanidine (MIBG) to differentially predict risk of life-threatening arrhythmic events (ArE) and heart failure death (HFD). Methods and ResultsA model was created based on patients with documented 2-year outcomes of CHF (n = 526; age, 66 ± 14 years). Classifiers were trained using 13 variables including age, gender, NYHA functional class, left ventricular ejection fraction and planar 123I-MIBG heart-to-mediastinum ratio (HMR). ArE comprised arrhythmic death and appropriate therapy with an implantable cardioverter defibrillator. The probability of ArE and HFD at 2 years was separately calculated based on appropriate classifiers. The probability of HFD significantly increased as HMR decreased when any variables were combined. However, the probability of arrhythmic events was maximal when HMR was intermediate (1.5-2.0 for patients with NYHA class III). Actual rates of ArE were 3% (10/379) and 18% (27/147) in patients at low- (≤ 11%) and high- (> 11%) risk of developing ArE (P < .0001), respectively, whereas those of HFD were 2% (6/328) and 49% (98/198) in patients at low-(≤ 15%) and high-(> 15%) risk of HFD (P < .0001). ConclusionA risk model based on machine learning using clinical variables and 123I-MIBG differentially predicted ArE and HFD as causes of cardiac death.

The gray zone of myocardial fibrosis is a better predictor of ventricular arrhythmias than total myocardial fibrosis in patients with previous myocardial infarction

Abstract Background Current sudden cardiac death (SCD) risk stratification relies heavily on the assessment of left ventricular ejection fraction (LVEF), but markers that could refine risk assessment are needed. Total fibrosis mass (TFM) and “gray zone” of myocardial fibrosis (GZF) on late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) have been proposed as potential arrhythmogenic substrates. The aim of our study was to determine whether TFM and GZF can predict the occurrence of ventricular arrhythmias in patients with previous myocardial infarction. Methods We performed a single centre retrospective study enrolling all consecutive patients with previous myocardial infarction undergoing LGE-CMR before implantable cardioverter-defibrillator (ICD) implantation for primary or secondary prevention. TFM and GZF were defined as myocardial tissue with signal-intensities &amp;gt;6 SD and 2–6 SD above the mean of reference myocardium, respectively. The primary endpoint was a composite of sudden arrhythmic death, appropriate ICD shock, ventricular fibrillation (VF), or sustained ventricular tachycardia (VT) as detected by the device. Results A total of 55 patients (mean age 62±12 years, 87% male, mean LVEF 30% ± 8%) were included. During a mean follow-up period of 34±15 months, 10 patients reached the primary endpoint (8 appropriate ICD shock, 2 sustained VT or VF). Patients who attained the primary endpoint had similar TFM (28.6g ± 14.5 vs. 23.1g ± 14.5; P=0.283) but larger GZF (25.3g ± 11.0 vs 15.6g ± 7.3; P=0.001). After adjustment for LVEF, GZF remained independently associated with the composite arrhythmic endpoint (adjusted hazard ratio [aHR]: 1.10; 95% CI: 1.03–1.17; P=0.005), whereas TFM did not (aHR: 1.02; 95% CI: 0.98–1.06; P=0.394). Decision tree analysis identified 16.4g of GZF as the best cut-off to predict life-threatening arrhythmic events. The primary endpoint occurred in 9 out of the 22 patients (41%) with GZF &amp;gt;16.4g, but in only 1 of the 33 patients (3%) with GZF ≤16.4g – Figure. Conclusions The extent of GZF seems to be a better predictor of ventricular arrhythmias than TFM. This LGE-CMR parameter may be useful to identify a subgroup of patients with previous myocardial infarction at an increased risk of life-threatening arrhythmic events. Funding Acknowledgement Type of funding sources: None.

Clinical Implications and Gender Differences of KCNQ1 p.Gly168Arg Pathogenic Variant in Long QT Syndrome.

Background: Long QT syndrome (LQTS) is an inheritable arrhythmogenic disorder associated with life-threatening arrhythmic events (LAEs). In general, patients with LQTS2 (KCNH2) and LQTS3 (SCN5A) are considered to be a greater risk of LAEs than LQTS1 (KCNQ1) patients. Gender differences are also important. Series analyzing families with the same pathogenic variants may help in the progress of elaborating strong specific genotype-phenotype management strategies. In this manuscript, we describe the phenotype of seven unrelated families, carriers of the KCNQ1 G168R pathogenic variant. Methods: we identified all consecutive index cases referred for genetic testing with LQTS diagnosis carriers of KCNQ1 G168R variant. Genetic and clinical screening for all available relatives was performed. Results: we evaluated seven unrelated families, with a total 34 KCNQ1 G168R carriers (two obligated carriers died without available EKGs to evaluate the phenotype). All index cases but one were women and three of them presented with aborted sudden cardiac death (SCD) or syncope. The presence of sudden death in these families is notable, with a total of nine unexplained sudden deaths and four aborted SCD. Phenotype penetrance was 100% in women and 37.5% in men. Conclusions: KCNQ1 G168R is a pathogenic variant, with a high penetrance among women and mild penetrance among men. Risk for LAEs in this variant seems not negligible, especially among woman, and risk stratification should always be carefully evaluated.

Arrhythmic phenotypes in patients with left ventricular non-compaction cardiomyopathy

Abstract Background Identification of pts with left ventricular non-compaction cardiomyopathy (NCCM) at high risk of life-threatening arrhythmic events is focused on clinical and instrumental criteria. The genetic component is not taken into account when deciding on a strategy for preventive measures. Purpose To analyze life-threatening arrhythmic events in pts with the arrhythmic variant of NCCM and to identify genetic factors that may increase the risk of life-threatening arrhythmic events. Methods The study included 159 pts, among whom 58 had malignant ventricular arrhythmias (mean age 43.54±11.95 years, 34/24/58.6% male). The NCCM criteria were confirmed using Echocardiography and CMR. Mutation search was carried out by the next generation sequencing (NGS) in 21 pts with nonsustained ventricular tachycardia (NVT). Results During the follow-up period (median follow-up of 36 months), life-threatening arrhythmic events (documented sustained VT, SCD with successful resuscitation and CD implantation, SCD) were registered in 29 pts (50%), and 10 pts had CD implanted. As a result of sequencing, 23.8% (5 out of 21) of pts with NVT revealed rare genetic variants with uncertain clinical significance (VUS) in 3 genes encoding ion channel proteins: KCNQ1, KCNH2 (9.5%), RYR2 (9.5%). In 9 (42.9%) pts, 10 identified mutations were localized in the genes responsible for the synthesis of sarcomeric proteins: MYBPC3 (23.8%), MYH7 (23.8%). 12 genetic variants were found in overlapping phenotypes between NCCM, ARVC and DCM: PKP2, DSP, PLN, TRPM4 (14.3%), RBM20, LDB3 (9.5%), DPP6, DTNA, NEXN in 11 (52.4%) pts. In this group of pts, the most common (81.8% of cases) were life-threatening arrhythmic events that required surgical intervention: 6 pts were implanted with CD for primary prevention of SCD, two pts - CRT-D, two pts with systolic dysfunction were performed with OHT and one patient was implanted with the Accucinch transcatheter direct mitral valve annuloplasty system. In pts with mutations in sarcomeric protein genes, CD was implanted in 4.7% of cases, and in 14.3% of pts with mutations in ion channel genes (p&amp;lt;0.01). Conclusion The presence of mutations in genes that control the functioning of ion channels in complex overlapping genotypes is an additional risk factor for ventricular arrhythmias in patients with NCCM. Determining the genetic component opens up new opportunities for personalizing the risk stratification of pts with NCCM. Funding Acknowledgement Type of funding source: None

Novel insights on Andersen-Tawil syndrome type 1

Abstract Background Andersen-Tawil Syndrome type 1 (ATS1) in a rare arrhythmogenic disease caused by loss-of-function mutations in the KCNJ2 gene and characterized by ventricular arrhythmias, dysmorphic features and episodes of periodic paralysis. Although the prognosis of ATS1 patients is typically considered benign, definitive outcome data are lacking. Purpose We aimed to: 1) define the risk of life-threatening arrhythmic events (LAEs); 2) identify risk factors for such events; 3) assess the efficacy of anti-arrhythmic drugs in preventing LAEs. Methods We included 118 ATS1 patients from 57 families with confirmed pathogenic or likely pathogenic KCNJ2 mutations. Clinical and genetical data were acquired by investigators from 23 centers in 9 countries. Results Baseline characteristics of the population are presented in the Table. Over a follow-up of 6.2 years, 17/118 (14%) patients experienced a first LAE, with a 5-year cumulative probability of 7.9% (Figure). Cox multivariable analysis demonstrated that a previous history of syncope (HR 4.5, p=0.02), the documentation of sustained VT (HR 9.3, p=0.001) and the administration of amiodarone (HR 268, p&amp;lt;0.001) were associated with an increased risk of LAE. The baseline rate of LAE was not reduced by beta-blockers alone (1.37 per 100 py; p=1), or in combination with class Ic antiarrhythmic drugs (1.46 per 100 py, p=1). Conclusions Our data demonstrate that the clinical course of patients with ATS1 is characterized by a high rate of LAE. A history of unexplained syncope, and documentation of sustained ventricular tachycardia are independently associated with a higher risk of LAE. Amiodarone is proarrhythmic and should be avoided in ATS1 patients. ATS1: Diagnosis, Outcome, Risk Factors Funding Acknowledgement Type of funding source: Public grant(s) – EU funding. Main funding source(s): ERN Guard-Heart European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart

Natural History and Risk Stratification in Andersen-Tawil Syndrome Type 1

BackgroundAndersen-Tawil Syndrome type 1 (ATS1) is a rare arrhythmogenic disorder, caused by loss-of-function mutations in the KCNJ2 gene. We present here the largest cohort of patients with ATS1 with outcome data reported. ObjectivesThis study sought to define the risk of life-threatening arrhythmic events (LAE), identify predictors of such events, and define the efficacy of antiarrhythmic therapy in patients with ATS1. MethodsClinical and genetic data from consecutive patients with ATS1 from 23 centers were entered in a database implemented at ICS Maugeri in Pavia, Italy, and pooled for analysis. ResultsWe enrolled 118 patients with ATS1 from 57 families (age 23 ± 17 years at enrollment). Over a median follow-up of 6.2 years (interquartile range: 2.7 to 16.5 years), 17 patients experienced a first LAE, with a cumulative probability of 7.9% at 5 years. An increased risk of LAE was associated with a history of syncope (hazard ratio [HR]: 4.54; p = 0.02), with the documentation of sustained ventricular tachycardia (HR 9.34; p = 0.001) and with the administration of amiodarone (HR: 268; p < 0.001). The rate of LAE without therapy (1.24 per 100 person-years [py]) was not reduced by beta-blockers alone (1.37 per 100 py; p = 1.00), or in combination with Class Ic antiarrhythmic drugs (1.46 per 100 py, p = 1.00). ConclusionsOur data demonstrate that the clinical course of patients with ATS1 is characterized by a high rate of LAE. A history of unexplained syncope or of documented sustained ventricular tachycardia is associated with a higher risk of LAE. Amiodarone is proarrhythmic and should be avoided in patients with ATS1.

Relation between resting heart rate and the risk of ventricular tachyarrhythmias in MADIT-RIT.

To explore the association between resting heart rate (RHR) and ventricular tachyarrhythmias (VTA) events among patients who were enrolled in MADIT-RIT. Multivariate Cox proportional hazards regression modelling was employed to evaluate the association between baseline RHR [dichotomized at the lower quartile (≤63 b.p.m.) and further assessed as a continuous measure] and the risk for any VTA, fast VTA (>200 b.p.m.), and appropriate implantable cardioverter-defibrillator (ICD) therapy, among 1500 patients who were enrolled in MADIT-RIT. Kaplan-Meier survival analysis showed that at 2 years of follow-up the rate of any VTA was significantly lower among patients with low baseline RHR (≤63 b.p.m.) as compared with faster RHR (11% vs. 19%, respectively; P = 0.001 for the overall difference during follow-up). Similar results were shown for the association with the rate of fast VTA (8% vs. 14%, respectively; P = 0.016), and appropriate ICD therapy (10% vs. 18%, respectively; P = 0.004). Multivariate analysis, after adjustment for medical therapy, showed that low baseline RHR was associated with a significant 45% (P = 0.002) reduction in the VTA risk as compared with faster baseline RHRs. When assessed as a continuous measure, each 10 b.p.m. decrement in RHR was associated with a corresponding 13% (P = 0.014) reduction in the VTA risk. In MADIT-RIT, low RHR was independently associated with a lower risk for life-threatening arrhythmic events. These findings suggest a possible role for RHR for improved selection of candidates for ICD therapy.

P5482Reverse remodeling by itself does not guarantee a low risk of life-threatening arrhythmic events and sudden cardiac death in cardiac resynchronization therapy patients. The GAUDI-CRT-Remod study

P5482Reverse remodeling by itself does not guarantee a low risk of life-threatening arrhythmic events and sudden cardiac death in cardiac resynchronization therapy patients. The GAUDI-CRT-Remod study

Prolonged right ventricular ejection delay identifies high risk patients and gender differences in Brugada syndrome

Background and objectivesRight ventricular (RV) conduction delay has been suggested as an underlying pathophysiological mechanism in Brugada syndrome (BS). In this cross-sectional study we non-invasively assessed the value of echocardiographic markers reflecting ventricular ejection delay to further assess electromechanical abnormalities in BS and to identify patients at risk for life-threatening arrhythmic events. Furthermore, we sought to assess differences in ejection delays between genders because male BS patients demonstrate a more malignant clinical phenotype. Methods124 BS patients (57.3% males) and 62 controls (CTR) (48.4% males) were included. Using Tissue Velocity Imaging, the ejection delay, determined as the time from QRS onset to the onset of the sustained systolic contraction, was measured for both RV free wall (RVED) and lateral LV wall (LVED). From these parameters, the interventricular ejection delay between both walls (IVED) was calculated. ResultsBS patients had longer RVEDs and IVEDs compared to the CTR. BS patients with a previous history of syncope or spontaneous ventricular arrhythmia showed the longest RVEDs and IVEDs. Male BS patients demonstrated longer RVEDs and IVEDs than females. Male BS patients with malignant events had the longest delays. No significant differences regarding LVED were observed between BS patients and CTR. ConclusionsWe demonstrated that a previous history of malignant events was associated with longer RVEDs. Our findings supported the RV conduction delay mechanism behind BS and demonstrated for the first time that the predominant malignant male Brugada phenotype might also be the result of a more delayed RV conduction in males.

Risk for ventricular fibrillation in peripartum cardiomyopathy with severely reduced left ventricular function-value of the wearable cardioverter/defibrillator.

The true incidence of life-threatening ventricular tachyarrhythmic events and the risk of sudden cardiac death in the early stage of peripartum cardiomyopathy (PPCM) are still unknown. We aimed to assess the usefulness of the wearable cardioverter/defibrillator (WCD) to bridge a potential risk for life-threatening arrhythmic events in patients with early PPCM, severely reduced left ventricular ejection fraction (LVEF) and symptoms of heart failure. Twelve consecutively admitted women with PPCM were included in this single-centre, prospective observational study between September 2012 and September 2013. Patients with LVEF ≤35% were considered to use the WCD for 3 months or even 6 months when considered necessary for LVEF recovery. Nine of the 12 women had a severely reduced LVEF (mean 18.3%) at the time of study enrollment; seven women received a WCD, while two patients refused to wear a WCD. During a median WCD follow-up of 81 days (range 25-345 days), we observed a total of four events of ventricular fibrillation with appropriate and successful WCD shocks in three of the seven women receiving a WCD. No syncope or sudden arrhythmic deaths occurred in women not using the WCD during a median follow-up of 12 months (range 5-15 months). All women showed impressive improvement of LVEF during follow-up. PPCM patients with severely reduced LVEF have an elevated risk for ventricular tachyarrhythmias early after diagnosis. Therefore, use of the WCD should be considered in all women with early-stage PPCM and severely reduced LVEF during the first 6 months after initiation of heart failure therapy.

High frequency of long qt syndrome-associated genetic variants in patients with early-onset lone atrial fibrillation

Background: Atrial fibrillation (AF) is an increasingly common cardiac arrhythmia. Evidence supports that AF has a significant genetic component, and some reports point toward a shared pathophysiology underlying AF and congenital long QT syndrome (LQTS). Purpose: To investigate the frequency of previously published LQTS-associated genetic variants in patients with early-onset lone AF (i.e., AF in the absence of traditional risk factors such as hypertension and ischemic or structural heart disease). Methods and results: We included 210 patients with onset of lone AF before the age of 40 years. Sequencing of all 13 genes so far associated with LQTS revealed 12 patients (6%) carrying a genetic variant previously associated with LQTS. Two LQTS-associated variants were identified in KCNQ1, one in KCNH2, six in SCN5A, one in KCNE2, and two in CAV3. The LQTS-associated variant frequency in the lone AF population was compared to the frequency of LQTS-associated variants in an ethnically matched population represented by recent exome data from the NHLBI GO Exome Sequencing Project (ESP). This comparison revealed that the lone AF patients had a marked overrepresentation of LQTS-associated variants (12 out of 420 alleles, 3.10%) compared with the ESP population (91 out of 6,999 alleles, 1.30%, P = 0.008). Conclusion: We found that patients with early-onset lone AF carry a high frequency of genetic variants previously associated with LQTS. Because such variants may increase the risk of life-threatening arrhythmic events, our finding could have clinical implications for future treatment and risk stratification of lone AF patients.

Advances in Imaging of the Cardiac Neuronal System

Left ventricular ejection fraction (LVEF) is a useful tool for stratifying risk for heart failure progression and life-threatening arrhythmic events. Yet, the clinical course of heart failure patients with severely reduced LVEF is variable, and the majority of patients who die suddenly do not have an LVEF ≤35%. A recently completed large multicenter trial, ADMIRE-HF, confirms that cardiac neuronal imaging with I-123 metaiodobenzylguanidine is an important independent predictor of heart failure progression and sudden cardiac death. Data from that study indicate that heart failure patients with severe impairment of cardiac sympathetic innervation are at highest risk for heart failure progression, heart failure patients with moderate impairment of sympathetic innervation are at highest risk for life-threatening arrhythmic events, and heart failure patients with preserved sympathetic innervation are at low risk for either death due to heart failure progression or sudden cardiac death.

Effectiveness of Implantable Cardioverter-Defibrillators in Patients With Ischemic Heart Disease and Left Ventricular Dysfunction

Implantable cardioverter-defibrillators (ICDs) have been shown in primary prevention efficacy trials to reduce mortality in patients with ischemic heart disease and left ventricular dysfunction. To investigate the generalizabilty of this mortality reduction, we examined the effectiveness of ICDs in clinical practice. We developed a prospective multicenter cohort of 770 patients with ischemic left ventricular dysfunction (ejection fraction < or =35%) and without a history of ventricular arrhythmia, of whom 395 (52%) received ICDs. Mean +/- SD follow-up was 27 +/- 12 months. We assessed the degree to which ICDs decreased mortality risk using Cox proportional hazards analyses that controlled for clinical predictors of death, receipt of ICD (a propensity score analysis), and predictors of arrhythmic death (including electrophysiologic variables). Multivariate Cox analyses showed that those with ICDs had significantly lower all-cause mortality (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.33-0.86). This mortality reduction was mediated through dramatically lower arrhythmia-related mortality (HR, 0.35; 95% CI, 0.17-0.73), with no significant effect on cardiovascular nonarrhythmic (HR, 0.81; 95% CI, 0.34-1.96) and noncardiovascular (HR, 0.76; 95% CI, 0.29-2.05) mortality. No differences were found between the ICD and non-ICD groups for a composite outcome of all-cause mortality, appropriate ICD shocks, or documented symptomatic ventricular arrhythmia, which suggests that the 2 groups had similar baseline risk for life-threatening arrhythmic events (HR, 0.96; 95% CI, 0.63-1.45). In clinical practice, ICDs appear to reduce all-cause and arrhythmic rates of mortality at levels similar to those found in primary prevention trials.

Assessment of noninvasive markers in identifying patients at risk in the brugada syndrome: insight into risk stratification

OBJECTIVESThe aim of this study was to compare the use of various noninvasive markers for detecting risk of life-threatening arrhythmic events in patients with Brugada syndrome.BACKGROUNDThe role of conduction disturbance in arrhythmogenesis of the syndrome is controversial, whereas it is well established that repolarization abnormalities are responsible for arrhythmias. The value of noninvasive markers reflecting conduction or repolarization abnormalities in identifying patients at risk for significant arrhythmias has not been shown.METHODSWe assessed late potentials (LP) using signal-averaged electrocardiography (ECG), microvolt T-wave alternans (TWA), and corrected QT-interval dispersion (QTD) in 44 consecutive patients who had ECGs showing a pattern of right bundle branch block and ST-segment elevation in leads V1to V3but structurally normal hearts. The patients were compared with 30 normal individuals.RESULTSEleven patients were excluded from data analysis because of an absence of ECG manifestations of Brugada syndrome at the time of the tests. A history of life-threatening events defined as syncope and aborted sudden death was present in 19 of 33 patients (58%); in 15 of the 19 patients, stimulation induced ventricular fibrillation or polymorphic ventricular tachycardia. The LP were present in 24 of 33 patients (73%); TWA were present in 5 of 31 patients (16%); and a QTD >50 ms was present in 9 of 33 patients (27%). The incidence of LP in Brugada patients was significantly (p < 0.0001) higher than in the controls, whereas incidences of TWA and QTD were not significantly different. Multivariate logistic regression analysis revealed that the presence of LP had the most significant correlation to the occurrence of life-threatening events (p = 0.006).CONCLUSIONSLate potentials are a noninvasive risk stratifier in patients with Brugada syndrome. These results may support the idea that conduction disturbance per se is arrhythmogenic.