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.

Multicenter prospective observational study to clarify the current status and clinical outcome in Japanese patients who have an indication for implantable cardioverter defibrillator (ICD) or wearable cardioverter defibrillator (WCD) (TRANSITION JAPAN-ICD/WCD study): Rationale and design of a prospective, multicenter, observational, comparative study.

Background: Despite the positive impact of implantable cardioverter defibrillators (ICDs) and wearable cardioverter defibrillators (WCDs) on prognosis, their implantation is often withheld especially in Japanese heart failure patients with reduced left ventricular ejection fraction (HFrEF) who have not experienced ventricular tachycardia (VT) or ventricular fibrillation (VF) for uncertain reasons. Recent advancements in heart failure (HF) medications have significantly improved the prognosis for HFrEF. Given this context, a critical reassessment of the treatment and prognosis of ICDs and WCDs is essential, as it has the potential to reshape awareness and treatment strategies for these patients. Methods: We are initiating a prospective multicenter observational study for HFrEF patients eligible for ICD in primary and secondary prevention, and WCD, regardless of device use, including all consenting patients. Study subjects are to be enrolled from 31 participant hospitals located throughout Japan from April 1, 2023, to December 31, 2024, and each will be followed up for 1 year or more. The planned sample size is 651 cases. The primary endpoint is the rate of cardiac implantable electronic device implementation. Other endpoints include the incidence of VT/VF and sudden death, all-cause mortality, and HF hospitalization, other events. We will collect clinical background information plus each patient's symptoms, Clinical Frailty Scale score, laboratory test results, echocardiographic and electrocardiographic parameters, and serial changes will also be secondary endpoints. Results: Not applicable. Conclusion: This study offers invaluable insights into understanding the role of ICD/WCD in Japanese HF patients in the new era of HF medication.

Comparison Between Heart Failure Without Left Ventricular Systolic Dysfunction and Progression to End-Stage in Hypertrophic Cardiomyopathy.

BACKGROUND: The incidence and prognostic predictors of heart failure (HF) without left ventricular systolic dysfunction (LVSD) in hypertrophic cardiomyopathy (HCM), particularly their differences in terms of developing LVSD (progression to end-stage) or sudden cardiac death (SCD), are not fully elucidated.Methods and Results: This study included 330 consecutive HCM patients with left ventricular ejection fraction (LVEF) ≥50%. HF hospitalization without LVSD and development of LVSD were evaluated as main outcomes. During a median follow-up of 7.3 years, the incidence of HF hospitalization without LVSD was 18.8%, which was higher than the incidence of developing LVSD (10.9%) or SCD (8.8%). Among patients who developed LVSD, only 19.4% experienced HF hospitalization without LVSD before developing LVSD. Multivariable analysis showed that predictors for HF hospitalization without LVSD (higher age, atrial fibrillation, history of HF hospitalization, and higher B-type natriuretic peptide concentrations) were different from those of developing LVSD (male sex, lower LVEF, lower left ventricular outflow tract gradient, and higher tricuspid regurgitation pressure gradient). Known risk factors for SCD did not predict either HF without LVSD or developing LVSD. CONCLUSIONS: In HCM with LVEF ≥50%, HF hospitalization without LVSD was more frequently observed than development of LVSD or SCD during mid-term follow-up. The overlap between HF without LVSD and developing LVSD was small (19.4%), and these 2 HF events had different predictors.

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.

Observational study of frailty in older Japanese patients with non-valvular atrial fibrillation receiving anticoagulation therapy.

The number of patients with atrial fibrillation is increasing, and frailty prevalence increases with age, posing challenges for physicians in prescribing anticoagulants to such patients because of possible harm. The effects of frailty on anticoagulant therapy in older Japanese patients with nonvalvular atrial fibrillation (NVAF) are unclear. Herein, we prescribed rivaroxaban to Japanese patients with NVAF and monitored for a mean of 2.0 years. The primary endpoint was stroke or systemic embolism. The secondary endpoints were all-cause or cardiovascular death, composite endpoint, and major or non-major bleeding. Frailty was assessed using the Japanese long-term care insurance system. A multiple imputation technique was used for missing data. The propensity score (PS) was obtained to estimate the treatment effect of frailty and was used to create two PS-matched groups. Overall, 5717 older patients had NVAF (mean age: 73.9 years), 485 (8.5%) were classified as frail. After PS matching, background characteristics were well-balanced between the groups. Rivaroxaban dosages were 10 and 15 mg/day for approximately 80% and the remaining patients, respectively. Frailty was not associated with the primary endpoint or secondary endpoints. In conclusion, frailty does not affect the effectiveness or safety of rivaroxaban anticoagulant therapy in older Japanese patients with NVAF.Trial registration: UMIN000019135, NCT02633982.

Effect of empagliflozin on ventricular arrhythmias in patients with type 2 diabetes treated with an implantable cardioverter-defibrillator: the EMPA-ICD trial.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure and cardiovascular death with type 2 diabetes; however, their effect on arrhythmias is unclear. The purpose of this study was to investigate the effects of empagliflozin on ventricular arrhythmias in patients with type 2 diabetes. METHODS: A total of 150 patients with type 2 diabetes who were treated with an implantable cardioverter-defibrillator or cardiac resynchronization therapy defibrillator (ICD/CRT-D) were randomized to once-daily empagliflozin or placebo for 24 weeks. The primary endpoint was the change in the number of ventricular arrhythmias from the 24 weeks before to the 24 weeks during treatment. Secondary endpoints included the change in the number of appropriate device discharges and other values. RESULTS: In the empagliflozin group, the number of ventricular arrhythmias recorded by ICD/CRT-D decreased by 1.69 during treatment compared to before treatment, while in the placebo group, the number increased by 1.79. The coefficient for the between-group difference was - 1.07 (95% confidence interval [CI] - 1.29 to - 0.86; P < 0.001). The change in the number of appropriate device discharges during and before treatment was 0.06 in the empagliflozin group and 0.27 in the placebo group, with no significant difference between the groups (P = 0.204). Empagliflozin was associated with an increase in blood ketones and hematocrit and a decrease in blood brain natriuretic peptide and body weight. CONCLUSIONS: In patients with type 2 diabetes treated with ICD/CRT-D, empagliflozin reduces the number of ventricular arrhythmias compared with placebo. Trial registration jRCTs031180120.

Association Between Adherence to a 3-Month Cardiac Rehabilitation Program and Long-Term Clinical Outcomes in Japanese Patients With Cardiac Implantable Electronic Devices.

PURPOSE: The objective of this study was to evaluate the association between comprehensive cardiac rehabilitation (CCR) completion and long-term clinical outcomes in patients with cardiac implantable electronic devices (CIED). METHODS: This retrospective cohort study included 834 patients with CIED who participated in CCR, which included a cardiopulmonary exercise test or 6-min walk test. Patients with a left ventricular ejection fraction ≤40%, predicted peak oxygen uptake ≤80%, or B-type natriuretic peptide level ≥80 pg/mL were eligible. The primary outcome was all-cause mortality. RESULTS: After excluding 241 patients with duplicate records and 69 who underwent CCR in the outpatient department, the data of 524 patients were analyzed. Mean age was 64 ± 15 yr, 389 (74%) patients were men, left ventricular ejection fraction was 31 ± 15%, and 282 (54%) patients had a history of hospitalization for worsening heart failure. Of the patients referred for CCR, 294 (56%) completed the program, and an additional 230 patients started but did not complete CCR. Over a 3.7-yr median follow-up period, all-cause mortality occurred in 156 (30%) patients. Completers had lower all-cause mortality rates than non-completers (log-rank 15.77, P < .001). After adjusting for prognostic baseline characteristics, completers had 58% lower all-cause mortality risks than non-completers (HR = 0.42; 95% CI, 0.27-0.64, P < .001). CONCLUSIONS: Three-mo CCR program completion was associated with lower mortality risks in patients with CIED. New programs or management methods are needed to decrease mortality risks, especially for those who cannot complete CCR programs.

A novel ryanodine receptor 2 inhibitor, M201-A, enhances natriuresis, renal function and lusi-inotropic actions: Preclinical and phase I study.

BACKGROUND AND PURPOSE: The ryanodine receptor 2 (RyR2) is present in both the heart and kidneys, and plays a crucial role in maintaining intracellular Ca2+ homeostasis in cells in these organs. This study aimed to investigate the impact of M201-A on RyR2, as well as studying its effects on cardiac and renal functions in preclinical and clinical studies. EXPERIMENTAL APPROACH: Following the administration of M201-A (1,4-benzothiazepine-1-oxide derivative), we monitored diastolic Ca2+ leak via RyR2 and intracellular Ca2+ concentration in isolated rat cardiomyocytes and in cardiac and renal function in animals. In a clinical study, M201-A was administered intravenously at doses of 0.2 and 0.4 mg·kg-1 once daily for 20 min for four consecutive days in healthy males, with the assessment of haemodynamic responses. KEY RESULTS: In rat heart cells, M201-A effectively inhibited spontaneous diastolic Ca2+ leakage through RyR2 and exhibited positive lusi-inotropic effects on the rat heart. Additionally, it enhanced natriuresis and improved renal function in dogs. In human clinical studies, when administered intravenously, M201-A demonstrated an increase in natriuresis, glomerular filtration rate and creatinine clearance, while maintaining acceptable levels of drug safety and tolerability. CONCLUSIONS AND IMPLICATIONS: The novel drug M201-A inhibited diastolic Ca2+ leak via RyR2, improved cardiac lusi-inotropic effects in rats, and enhanced natriuresis and renal function in humans. These findings suggest that this drug may offer a potential new treatment option for chronic kidney disease and heart failure.

Syncope Due to Iatrogenic Cava Vein Obstruction: Rare Complication of Cardiac Implantable Electronic Device Leads.

A 77-year-old female patient with multiple pacemaker leads experienced hypotension and syncope during right heart catheterization. Imaging studies revealed a stenotic inferior vena cava with superior vena cava obstruction and well-developed retrograde collateral vessels, suggesting that balloon obstruction of the sole venous return site caused low cardiac output leading to syncope.

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.

Impact of High-Voltage Device Implantation in Elderly Japanese Patients With Heart Failure as Primary Prevention　- Post Hoc Analysis of HINODE.

BACKGROUND: Despite an increased incidence of chronic heart failure (HF) and sudden cardiac death (SCD), the use of implantable cardioverter-defibrillators (ICDs) and cardiac resynchronization therapy (CRT) is much lower in Japan than in Western countries. The HF Indication and SCD Prevention Trial Japan (HINODE) prospectively assessed the mortality rate, appropriately treated ventricular arrhythmias (VA), and HF in Japanese patients with a higher risk of HF.Methods and Results: HINODE consisted of ICD, CRT-defibrillator (CRT-D), pacing, and non-device treatment cohorts. This subanalysis evaluated the impact of the implantation of high-voltage devices (HVD; ICD and CRT-D) in 171 Japanese patients. We compared all-cause mortality, VA, and HF events between elderly (age >70 years at study enrollment) and non-elderly HVD recipients. The estimated survival rate through 24 months in the HVD cohort was 85.8% (97.5% lower control limit 77.6%). The risk of all-cause mortality was increased for the elderly vs. non-elderly (hazard ratio [HR] 2.82; 95% confidence interval [CI] 1.01-7.91; P=0.039), but did not differ after excluding ICD patients with CRT-D indication (HR 2.32; 95% CI 0.79-6.78; P=0.11). There were no differences in VA and HF event-free rates between elderly and non-elderly HVD recipients (P=0.73 and P=0.55, respectively). CONCLUSIONS: Although elderly patients may have a higher risk of mortality in general, the benefit of HVD therapy in this group is comparable to that in non-elderly 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.

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.