Elevated B-Type Natriuretic Peptide Level as a Residual Risk Factor for Ventricular Arrhythmias Among Patients Undergoing Cardiac Resynchronization Therapy With Improved Left Ventricular Ejection Fraction.

Background: Patients who achieve improved left ventricular ejection fraction (LVEF >35%) with cardiac resynchronization therapy (CRT) are at a lower risk of ventricular arrhythmia (VA). Little is known about the significance of the B-type natriuretic peptide (BNP) level for the risk of VA. This study investigated the risk factors for VA in CRT and the risk stratification of VA with BNP in CRT with improved LVEF. Methods and Results: This study evaluated 352 CRT patients from 2012 to 2020. Patients were categorized into 2 groups: improved LVEF (impEF; LVEF >35%), and low LVEF (lowEF; LVEF ≤35%). The serum BNP levels 6 months after CRT device implantation were measured. The primary endpoint was defined as VA requiring treatment with anti-tachycardia pacing or shock or persisting for ≥30 s. Overall, 102 patients had improved LVEF. The impEF group had a significantly lower VA risk than the lowEF group. Patients with low BNP had a lower VA risk than those with high BNP; however, no significant difference was observed between patients with high BNP and those in the lowEF group. Univariate analysis revealed that high BNP was a predictor of VA in the impEF group. Conclusions: The VA risk is reduced with improved LVEF after CRT but not with high BNP levels. The post-BNP level after CRT implantation is a useful marker for predicting VA in patients with improved LVEF.

Clinical Features, Long-Term Prognosis, and Clinical Management of Genotype-Negative Long QT Syndrome Patients.

BACKGROUND: Approximately 15% to 20% of patients clinically diagnosed with long QT syndrome (LQTS) are genotype-negative (GEN-). Whether they have a different arrhythmic risk or should be managed differently remains unclear, often leading to incomplete treatment. OBJECTIVES: The purpose of this study was to compare clinical aspects of GEN- and genotype-positive (GEN+) LQTS patients. METHODS: We retrospectively evaluated 832 LQTS patients genetically screened in Japan (n = 347) and Italy (n = 485), including 698 with a disease-causing variant in the KCNQ1, KCNH2, and SCN5A genes (GEN+), and 134 without variants in these LQTS-related genes (GEN-). RESULTS: At diagnosis, the Japanese patients were more often probands (86% vs 60%), symptomatic (39% vs 18%), and of younger age than the Italian patients; conversely, they used less ß-blockers (65% vs 95%), more rarely had a family history (FH) of LQTS (42% vs 73%), and had more cardiac events during follow-up (13% vs 4%) (P < 0.001 for all comparisons). Within the Japanese cohort, the GEN- had more cardiac arrests, used less ß-blockers, and had much less FH for LQTS compared their GEN+ counterpart. The Italian cohort was more homogeneous, with just more LQTS FH among the GEN+. QTc shortening (close to 30 ms in all groups) during follow-up was similar between Japanese and Italian patients, irrespective of their being GEN+ or GEN-. In both cohorts, during an average follow-up of 6 and 7 years, respectively, GEN+ and GEN- patients showed a comparable clinical outcome. CONCLUSIONS: Arrhythmic risk is similar between GEN+ and GEN- LQTS patients; they should be managed and treated in the same way.

SMART Pass automatic deactivation of subcutaneous implantable cardioverter-defibrillators.

BACKGROUND: The SMART Pass algorithm for subcutaneous implantable cardioverter-defibrillator prevents inappropriate shocks due to oversensing. The mechanisms and significance of SMART Pass deactivation remain unclear. OBJECTIVE: The objective of this study was to assess whether SMART Pass deactivation is associated with inappropriate shocks and to elucidate the underlying mechanism. METHODS: We retrospectively investigated 115 patients who underwent subcutaneous implantable cardioverter-defibrillator implantation between 2016 and 2021. SMART Pass deactivation and inappropriate shocks during follow-up were assessed. The QRS amplitudes of the subcutaneous (S-ECG) and 12-lead electrocardiogram (ECG) at the time of implantation (pre) and SMART Pass deactivation (post) were measured. The patients were divided into the SP-ON group with SMART Pass consistently on and the SP-OFF group with the experience of SMART Pass deactivation. RESULTS: Three of 12 patients in the SP-OFF group experienced inappropriate shocks during a median follow-up of 1094 (interquartile range, 887-1502) days compared with 4 of 87 patients in the SP-ON group. Pre- and post-S-ECG QRS amplitudes were significantly lower in the SP-OFF group than in the SP-ON group (both P < .05), despite similar 12-lead ECG QRS amplitude in both groups. A significant temporary drop in the QRS amplitude of the S-ECG led to SMART Pass deactivation (pre-QRS amplitude vs amplitude at deactivation, P = .015; 95% CI, 0.3-1.9). CONCLUSION: The rate of inappropriate shocks was numerically higher after SMART Pass deactivation. A low QRS amplitude in S-ECG was a potential risk factor for SMART Pass deactivation. Careful follow-up and suitable management are required for managing patients with risks of SMART Pass deactivation.

Implantable loop recorder uncovered torsades de pointes in long-QT syndrome type 1 with multi cause of syncope.

An implantable loop recorder (ILR) is now widely used for differential diagnosis of unexplained syncope or recurrent syncope with unknown causes. In the inherited arrhythmia syndromes, ILR may be useful for management of the therapeutic strategies; however, there is no obvious evidence to uncover arrhythmic syncope by ILR in long-QT syndrome (LQTS) patients. Here we experienced a 19-year-old female patient with LQTS type 1 who had recurrent syncope even after beta-blocker therapy but no arrhythmias were documented, and some episodes might be due to non-cardiogenic causes. Implantable cardioverter defibrillator (ICD) therapy was also recommended; however, she could not accept ICD but was implanted with ILR for further continuous monitoring. Two years later, she suffered syncope during a brief run, and ILR recorded an electrocardiogram at that moment. Thus a marked QT interval prolongation as well as T-wave alternance resulting in development of torsades de pointes could be detected. Although ILR is just a diagnostic tool but does not prevent sudden cardiac death, most arrhythmic events in LQTS are transient and sometimes hard to be diagnosed as arrhythmic syncope. ILR may provide direct supportive evidence to select the optimal therapeutic strategy in cases where syncope is difficult to diagnose. Learning objective: Long-QT syndrome (LQTS) patients often suffer recurrent syncope even after beta-blocker therapy, but torsades de pointes (TdP) is not always detected by standard 12­lead electrocardiogram or Holter monitoring, and some syncope might be non-cardiogenic. In this case, implantable loop recorder (ILR) documented the evidence of QT interval prolongation and beat-by-beat T-wave alternance subsequent TdP. Thus, ILR may provide useful evidence for the optimal treatment strategy in LQTS cases where syncope is difficult to diagnose.

Clinical Usefulness of the Active Fixation Quadripolar Left Ventricular Lead Compared With the Passive Fixation Quadripolar Lead in Cardiac Resynchronization Therapy.

BACKGROUND: This study compared the stability of the Medtronic Attain Stability Quad (ASQ), a novel quadripolar active fixation left ventricular (LV) lead with a side helix, to that of conventional quadripolar leads with passive fixation (non-ASQ) and evaluated their LV lead performance. METHODS AND RESULTS: In all, 183 consecutive patients (69 ASQ, 114 non-ASQ) who underwent cardiac resynchronization therapy (CRT) between January 2018 and June 2021 were enrolled. Complications, including elevated pacing capture threshold (PCT) levels, phrenic nerve stimulation (PNS), and LV lead dislodgement, were analyzed during the postimplantation period until the first outpatient visit after discharge. The frequency of LV lead-related complications was significantly lower in the ASQ than non-ASQ group (14% vs. 30%, respectively; P=0.019). Specifically, LV lead dislodgement occurred only in the non-ASQ group, and elevated PCT levels were significantly lower in the ASQ group (7% vs. 23%; P=0.007). Kaplan-Meier analysis confirmed a significantly lower incidence of LV lead-related complications in the ASQ group (log-rank P=0.005). Cox multivariable regression analysis showed a significant reduction in lead-related complications associated with ASQ (hazard ratio 0.44; 95% confidence interval 0.23-0.83; P=0.011). CONCLUSIONS: The ASQ group exhibited fewer LV lead-related complications requiring reintervention and setting changes than the non-ASQ group. Thus, the ASQ may be a favorable choice for CRT device implantation.

Demonstration of Arrhythmia Substrate-Associated Dispersion of Repolarization by Epicardial Unipolar Mapping in Brugada Syndrome.

BACKGROUND: Epicardial unipolar mapping has not been thoroughly investigated in Brugada syndrome (BrS). OBJECTIVES: This study aims to examine the characteristics of epicardial unipolar potentials in BrS and investigate the differences from overt cardiomyopathy. METHODS: Epicardial mapping was performed in 8 patients with BrS and 6 patients with cardiomyopathy. We investigated the J-wave amplitudes using unipolar recordings at delayed potential (DP) sites via bipolar recordings. The repolarization time (RT) at and around the DP recording sites was measured, and maximum dispersion of the RT divided by the distance was defined as the RT dispersion index. RESULTS: Epicardial mapping at baseline revealed significantly higher J-wave amplitude with bipolar DP in patients with BrS than in patients with cardiomyopathy. J-wave amplitude ≥0.42 mV had 99.1% sensitivity and 100% specificity for diagnosing BrS. The RT dispersion index was significantly higher in patients with BrS than in patients with cardiomyopathy at baseline. In all patients with BrS, coved-type unipolar electrograms without negative T waves (short RT) appeared close to coved-type electrograms with negative T waves (long RT) at the DP recording sites after pilsicainide administration. Thus, a steep RT dispersion was observed in this region, and ventricular arrhythmias emerged from this shorter RT area in all 3 patients with BrS in whom ventricular arrhythmias were induced. CONCLUSIONS: Bipolar DP-related prominent unipolar J waves and steep repolarization gradients may be more specific for characterizing BrS than for overt cardiomyopathy. Ventricular arrhythmias in BrS are associated with a steep repolarization gradient, indicating phase 2 re-entry as a possible cause.

Brugada syndrome in Japan and Europe: a genome-wide association study reveals shared genetic architecture and new risk loci.

BACKGROUND AND AIMS: Brugada syndrome (BrS) is an inherited arrhythmia with a higher disease prevalence and more lethal arrhythmic events in Asians than in Europeans. Genome-wide association studies (GWAS) have revealed its polygenic architecture mainly in European populations. The aim of this study was to identify novel BrS-associated loci and to compare allelic effects across ancestries. METHODS: A GWAS was conducted in Japanese participants, involving 940 cases and 1634 controls, followed by a cross-ancestry meta-analysis of Japanese and European GWAS (total of 3760 cases and 11 635 controls). The novel loci were characterized by fine-mapping, gene expression, and splicing quantitative trait associations in the human heart. RESULTS: The Japanese-specific GWAS identified one novel locus near ZSCAN20 (P = 1.0 × 10-8), and the cross-ancestry meta-analysis identified 17 association signals, including six novel loci. The effect directions of the 17 lead variants were consistent (94.1%; P for sign test = 2.7 × 10-4), and their allelic effects were highly correlated across ancestries (Pearson's R = .91; P = 2.9 × 10-7). The genetic risk score derived from the BrS GWAS of European ancestry was significantly associated with the risk of BrS in the Japanese population [odds ratio 2.12 (95% confidence interval 1.94-2.31); P = 1.2 × 10-61], suggesting a shared genetic architecture across ancestries. Functional characterization revealed that a lead variant in CAMK2D promotes alternative splicing, resulting in an isoform switch of calmodulin kinase II-δ, favouring a pro-inflammatory/pro-death pathway. CONCLUSIONS: This study demonstrates novel susceptibility loci implicating potentially novel pathogenesis underlying BrS. Despite differences in clinical expressivity and epidemiology, the polygenic architecture of BrS was substantially shared across ancestries.

Novel Compound Heterozygous Variants in Trans-2,3-Enoyl-Coenzyme A Reductase-Like Gene Associated With Catecholaminergic Polymorphic Ventricular Tachycardia.

A 10-year-old female patient experienced syncope while swimming, and electrocardiography revealed polymorphic ventricular tachycardia, leading to a diagnosis of catecholaminergic polymorphic ventricular tachycardia. No pathogenic variant was identified in RYR2. Additional comprehensive genetic testing revealed novel compound heterozygous variants in trans-2,3-enoyl-coenzyme A reductase-like gene, which caused a recessive form of catecholaminergic polymorphic ventricular tachycardia.

An international multicenter cohort study on implantable cardioverter-defibrillators for the treatment of symptomatic children with catecholaminergic polymorphic ventricular tachycardia.

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) may cause sudden cardiac death (SCD) despite medical therapy. Therefore, implantable cardioverter-defibrillators (ICDs) are commonly advised. However, there is limited data on the outcomes of ICD use in children. OBJECTIVE: The purpose of this study was to compare the risk of arrhythmic events in pediatric patients with CPVT with and without an ICD. METHODS: We compared the risk of SCD in patients with RYR2 (ryanodine receptor 2) variants and phenotype-positive symptomatic CPVT patients with and without an ICD who were younger than 19 years and had no history of sudden cardiac arrest at phenotype diagnosis. The primary outcome was SCD; secondary outcomes were composite end points of SCD, sudden cardiac arrest, or appropriate ICD shocks with or without arrhythmic syncope. RESULTS: The study included 235 patients, 73 with an ICD (31.1%) and 162 without an ICD (68.9%). Over a median follow-up of 8.0 years (interquartile range 4.3-13.4 years), SCD occurred in 7 patients (3.0%), of whom 4 (57.1%) were noncompliant with medications and none had an ICD. Patients with ICD had a higher risk of both secondary composite outcomes (without syncope: hazard ratio 5.85; 95% confidence interval 3.40-10.09; P < .0001; with syncope: hazard ratio 2.55; 95% confidence interval 1.50-4.34; P = .0005). Thirty-one patients with ICD (42.5%) experienced appropriate shocks, 18 (24.7%) inappropriate shocks, and 21 (28.8%) device-related complications. CONCLUSION: SCD events occurred only in patients without an ICD and mostly in those not on optimal medical therapy. Patients with an ICD had a high risk of appropriate and inappropriate shocks, which may be reduced with appropriate device programming. Severe ICD complications were common, and risks vs benefits of ICDs need to be considered.

Evaluation of synchronized left ventricular pacing rate over biventricular pacing in cardiac resynchronization therapy.

BACKGROUND: The adaptive cardiac resynchronization therapy (aCRT) algorithm enables synchronized left ventricular pacing (sLVP) to achieve fusion with intrinsic right ventricular activation. Although sLVP presents benefits over biventricular pacing, the adequate sLVP rate for better clinical outcomes remains unclear. We aimed to assess the association between sLVP rates and clinical outcomes. METHODS: Our study cohort included 271 consecutive patients, who underwent CRT implantation between April 2016 and August 2021. RESULTS: We evaluated 63 patients on whom we applied the aCRT algorithm [48 men, mean age: 64 ±â€¯14 years; median follow-up period: 316 days (interquartile range: 212-809 days)]. At the 6-month follow-up after CRT implantation, the frequency of CRT responders was 71 % (n = 45). The sLVP rate was significantly higher in responders than in non-responders (75 ±â€¯30 % vs. 47 ±â€¯40 %, p = 0.003). Receiver operating characteristics curve analysis revealed that the optimal cut-off value during the sLVP rate was 59.4 % for the prediction of CRT responders (area under the curve, 0.70; sensitivity, 80 %; specificity, 61 %; positive predictive value, 84 %; and negative predictive value, 55 %). Kaplan-Meier analysis demonstrated that the higher-sLVP group (sLVP ≧59.4 %, n = 43) had a better prognosis (cardiac death and heart failure hospitalization) than the lower-sLVP group (sLVP <59.4 %, n = 20) (log-rank p < 0.001). Multivariate Cox hazard analysis revealed that a higher sLVP rate was associated with a good prognosis (p < 0.001). CONCLUSIONS: sLVP was associated with CRT response, and a higher sLVP rate (≧59.4 %) was important for good prognosis in patients with aCRT.

Effect of adaptive cardiac resynchronization therapy in heart failure patients with pacemaker dependency.

BACKGROUND: An adaptive cardiac resynchronization therapy (aCRT) algorithm allows continuous adjustments of pacing timings of atrioventricular delays by periodic automatic evaluation of electrical conduction. This applies to patients with an atrioventricular block and is effective in cardiac resynchronization therapy (CRT) devices; however, whether this algorithm benefits patients with pacemaker dependency is uncertain. METHODS: This study examined the clinical impact of an aCRT algorithm in patients diagnosed with heart failure with reduced ejection fraction and pacemaker dependency. A total of 359 patients underwent CRT between January 2016 and December 2022. Patients undergoing pacemaker-dependent CRT with the aCRT algorithm function were selected. Sixty-four patients with pacemaker dependency (31 with aCRT algorithm and 33 without) were included. Pacemaker dependency was defined as the absence of spontaneous ventricular activity during the sensing test at VVI 30 bpm or prolonged atrioventricular delay (> 300 ms). The primary endpoint was the composite clinical outcome of all-cause death or hospitalization for heart failure. RESULTS: No significant differences were observed in baseline characteristics between groups. During a median follow-up of 1,067 days (interquartile range 553-1,776 days), aCRT reduced the risk of composite clinical outcomes in patients with pacemaker dependency (log-rank P = 0.028). In addition, using the aCRT algorithm was an independent predictor of the composite clinical outcomes in the multivariate analysis (hazard ratio 0.34, 95% confidence interval: 0.12-0.94, P = 0.038). CONCLUSION: The aCRT algorithm significantly reduced the risk of adverse clinical outcomes in patients with pacemaker dependency. This algorithm may be an important tool for managing such patients.

Right Atrial Septal Lead Enhances the Favorable Effects of the Adaptive Cardiac Resynchronization Therapy Algorithm.

The adaptive cardiac resynchronization therapy (CRT) algorithm provides synchronized left ventricular pacing (sLVP). However, ensuring a high sLVP rate is challenging. We assessed the association between the sLVP rate and pacing sites in the right atrium. We evaluated 71 patients who underwent CRT and in whom the adaptive CRT algorithm was applied (53 men; mean age, 66 ± 14 years; median follow-up period, 301 days; IQR: 212-596 days). The atrial pacing leads were positioned in the right atrial (RA) septum in 17 patients (septal group) and in the RA appendage in 54 patients (RA appendage group), with significantly higher sLVP rates in the septal group compared with the RA appendage group (81% ± 30% vs 63% ± 37%; P = 0.045). In patients with first-degree atrioventricular blocks, the sLVP rates tended to be higher in the septal group. Therefore, RA septal pacing increased sLVP rates in patients undergoing CRT.

Local dispersion of repolarization in the occurrence of ventricular fibrillation in Brugada syndrome: Possibility of phase 2 reentry?

To date, there have been no reports of recording epicardial electrograms at the onset of spontaneous ventricular fibrillation (VF) in patients with Brugada syndrome (BrS). In the case of BrS, unipolar and bipolar electrogram recording on the right ventricular epicardium revealed that dispersion of repolarization with delayed potential was associated with spontaneous occurrence of VF. Phase 2 reentry associated with shortening and dispersion of action potential could have been recorded for the first time in BrS. Epicardial unipolar mapping can guide accurate and appropriate ablation for the elimination of arrhythmia substrate in J wave syndrome.

Implications of ventricular arrhythmia after cardiac resynchronization therapy.

BACKGROUND: Conflicting data are available on whether ventricular arrhythmia (VA) or shock therapy increases mortality. Although cardiac resynchronization therapy (CRT) reduces the risk of VA, little is known about the prognostic value of VA among patients with CRT devices. OBJECTIVES: The purpose of this study was to evaluate the implications of VA as a prognostic marker for CRT. METHODS: We investigated 330 CRT patients within 1 year after CRT device implantation. The primary endpoint was the composite endpoint of all-cause death or hospitalization for heart failure. RESULTS: Forty-three patients had VA events. These patients had a significantly higher risk of the primary endpoint, even among CRT responders (P = .009). Fast VA compared to slow VA was associated with an increased risk of the primary endpoint (hazard ratio [HR] 2.14; 95% confidence interval [CI] 1.06-4.34; P = .035). Shock therapy was not associated with a primary endpoint (shock therapy vs antitachycardia pacing: HR 1.49; 95% CI 0.73-3.03; P = .269). The patients with VA had a lower prevalence of response to CRT (23 [53%] vs 202 [70%]; P = .031) and longer left ventricular paced conduction time (174 ± 23 ms vs 143 ± 36 ms; P = .003) than the patients without VA. CONCLUSION: VA occurrence within 1 year was related to paced electrical delay and poor response to CRT. VA could be associated with poor prognosis among CRT patients.

Clinical Significance of Atrial Tachyarrhythmia Duration for Ventricular Arrhythmia in Patients With Cardiac Resynchronization Therapy.

BACKGROUND: Atrial tachyarrhythmias (ATAs) are reportedly associated with ventricular arrhythmias (VAs). However, little is known about the association between ATA duration and the risk of VA. We investigated the relationship between ATA duration and subsequent VA in patients with a cardiac resynchronization therapy defibrillator (CRT-D).Methods and Results: We investigated associations between the longest ATA duration during the first year after cardiac resynchronization therapy (CRT) implantation and VA and VA relevant to ATA (VAATA) in 160 CRT-D patients. ATAs occurred in 63 patients in the first year. During a median follow-up of 925 days from 1 year after CRT implantation, 40 patients experienced 483 VAs. Kaplan-Meier analysis showed a significantly higher risk of VA in patients with than without ATA in the first year (log rank P=0.0057). Hazard ratios (HR) of VA (HR 2.36, 2.10, and 3.04 for ATA >30s, >6 min and >24 h, respectively) and only VAATA (HR 4.50, 5.59, and 11.79 for ATA >30s, >6 min and >24 h, respectively) increased according to the duration of ATA. In multivariate analysis, ATA >24 h was an independent predictor of subsequent VA (HR 2.42; P=0.02). CONCLUSIONS: Patients with ATA >24 h in the first year after CRT had a higher risk of subsequent VA and VAATA. The risk of VA, including VAATA, increased with the longest ATA duration.