Performance of Subcutaneous Implantable Cardioverter Defibrillator (S-ICD) in Chinese Population with Primary Prevention Indications: A Prospective Observational Cohort Study.

BACKGROUND International studies have shown that use of a subcutaneous implantable cardioverter defibrillator (S-ICD) could reduce lead-related complications while maintaining adequate defibrillation performance; however, data from the Chinese population or other Asian groups are limited. MATERIAL AND METHODS SCOPE is a prospective, multicenter, observational cohort study. Two hundred patients with primary prevention indication for sudden cardiac death (SCD), who are candidates for S-ICD, will be enrolled. From the same population, another 200 patients who are candidates for transvenous implantable cardioverter defibrillator (TV-ICD) will be enrolled after being matched for age, sex, SCD high-risk etiology (ischemic cardiomyopathy, and non-ischemic cardiomyopathy, ion channel disease, and other) and atrial fibrillation in a 1: 1 ratio with enrolled S-ICD patients. All the patients will be followed for 18 months under standard of care. RESULTS The primary endpoint is proportion of patients free from inappropriate shock (IAS) at 18 months in the S-ICD group. The lower 95% confidence bound of the proportion will be compared with a performance goal of 90.3%, which was derived from the previous meta-analysis. The comparisons between S-ICD and TV-ICD on IAS, appropriate shock, and complications will be used as secondary endpoints without formal assumptions. CONCLUSIONS This is the first prospective multicenter study focusing on the long-term performance of S-ICD in a Chinese population. By comparing with the data derived from international historical studies and a matched TV-ICD group, data from SCOPE will allow for the assessment of S-ICD in the Chinese population in a contemporary real-world implantation level and programming techniques, which will help us to further modify the device implantation and programming protocol in this specific population in the future.

Outcomes of Upgrading to LBBP in CRT Nonresponders: A Prospective, Multicenter, Nonrandomized, Case-Control Study.

BACKGROUND: Cardiac resynchronization therapy (CRT) nonresponders account for nearly 30% of CRT candidates. Left-bundle branch pacing (LBBP) is an alternative to CRT. OBJECTIVES: This study aimed to evaluate the feasibility, clinical efficacy, and outcomes of upgrading to LBBP in CRT nonresponders, using propensity-score matching (PSM) analysis. METHODS: CRT nonresponders were defined as those with an implantable CRT-pacemaker or CRT-defibrillator for more than 12 months who remained nonresponsive (a decrease in left ventricular end-systolic volume of <15% or a left ventricular ejection fraction [LVEF] absolute increase of <5%) after optimal medical therapy and device optimization compared with baseline. In total, 145 CRT nonresponders were prospectively enrolled and randomly divided into 2 groups: upgraded to LBBP (n = 48), and continuing biventricular pacing (BVP) (control; n = 97). PSM was performed at a 1:1 ratio, and clinical evaluation and echocardiographic assessments were compared at baseline and follow-up in paired cohorts. The primary composite endpoint for clinical outcomes (heart failure-related rehospitalization events, all-cause death, or heart transplantation) was analyzed. RESULTS: Successful upgrading to LBBP was achieved in 48/49 patients (97.96%), with a significant decrease in QRS duration (P < 0.001). In the paired LBBP group, LVEF significantly increased (baseline: 29.75% ± 7.79%; 6 months: 37.78% ± 9.25% [P < 0.001]; 12 months: 38.84% ± 12.13% [P < 0.001]) with 21/44 patients (47.73%) classified as echocardiographically responsive, whereas in the BVP control group, no significant improvement was observed (29.55% ± 6.74% vs 29.22% ± 8.10%; P = 0.840). In a multivariate logistic regression model, LV end-diastolic volume and baseline LBBB QRS morphology were independent predictors of echocardiographic response after upgrading to LBBP. At a median 24 months, the primary composite endpoint was significantly lower in the LBBP group (HR: 0.31; 95% CI: 0.14-0.72; log-rank P = 0.007). CONCLUSIONS: Upgrading to LBBP is feasible and effective in achieving significant heart function improvement and better clinical outcomes in CRT nonresponders, making it a reasonable and promising pacing strategy. (LBBP in CRT Non-Response patients; ChiCTR1900028131).

Effect of left bundle branch pacing on right ventricular function: A 3-dimensional echocardiography study.

BACKGROUND: The effect of left bundle branch pacing (LBBP) on right ventricular (RV) function is not well known, and there is conflicting evidence regarding whether cardiac resynchronization therapy improves RV function. OBJECTIVES: The study aimed to investigate the effect of LBBP on RV function and to evaluate the response of RV dysfunction (RVD) to LBBP. METHODS: Sixty-five LBBP candidates were prospectively included in the study and underwent echocardiography at baseline and 6-month follow-up. LBBP response was left ventricular (LV) reverse remodeling, defined as a reduction in LV end-systolic volume of ≥15% at follow-up. RESULTS: Patients were assigned to 2 subgroups on the basis of 3-dimensional echocardiography-derived RV ejection fraction (EF) before LBBP implantation: 30 patients (46%) in the no RVD group and 35 patients (54%) in the RVD group. The RVD group was characterized by higher N-terminal pro-brain natriuretic peptide levels, New York Heart Association functional class, and larger LV/RV size. LBBP induced a significant reduction in QRS duration, LV size, and improvement in LVEF and mechanical dyssynchrony in both the no RVD and RVD groups, and a significant improvement in RV volumes and RVEF in the RVD group (all P<.01). LBBP resulted in a similar percentage reduction in QRS duration, LV dimensions, LV volumes, and percentage improvement in LVEF in RVD and no RVD groups (all P＞.05). LV reverse remodeling (29 of 35 patients vs 27 of 30 patients; P = .323) in the RVD group was similar to that in the no RVD group after LBBP. CONCLUSION: LBBP induces excellent electrical and mechanical resynchronization, with a significant improvement in RV volumes and function. RVD did not diminish the beneficial effects on LV reverse remodeling after LBBP.

Association of Device-Detected Atrial High-Rate Episodes With Long-term Cardiovascular and All-Cause Mortality: A Cohort Study.

BACKGROUND: Device-detected atrial high-rate episodes (AHREs) were associated with an increased thromboembolic risk. Although limited data regarding the long-term prognosis of patients with AHRE were controversial, this study aimed to identify the association of device-detected AHRE with mortality. METHODS: This observational study included patients with implantable cardioverter defibrillator (ICD) or cardiac resynchronization therapy defibrillator (CRT-D) placement and no history of atrial fibrillation (AF), atrial flutter (AFL), or atrial tachycardia (AT). During follow-up, patients with at least 1 day of AHRE duration ≥ 15 minutes were identified. The primary endpoint was cardiovascular mortality, and the secondary endpoint was all-cause mortality. RESULTS: During a mean follow-up period of 4.2 years, AHREs were detected in 124 of 343 (36.2%) patients. Of these, 44 deaths (35.5%) occurred in 124 patients with AHREs, which was significantly higher than those without AHREs (43 of 219; 19.6%; P = 0.001). The multivariate analysis revealed that patients with AHRE had a significantly higher risk of cardiovascular (hazard ratio [HR], 2.40; 95% confidence interval [CI], 1.23-4.67; P = 0.010), and all-cause mortality (HR, 2.31; 95% CI, 1.49-3.59; P < 0.001). Further analysis indicated that this association remained significant in patients with higher burden (≥ 6 hours) but not in patients with lower burden (≥ 15 minutes to 6 hours). Notably, even after excluding the patients diagnosed with clinical AF during follow-up, the remaining patients with AHREs still exhibited a higher risk of cardiovascular and all-cause mortality compared with patients without AHREs. CONCLUSIONS: AHREs were prevalent in ICD or CRT-D recipients with no history of clinical AF, AFL, or AT and were associated with more than twice the risk of cardiovascular and all-cause mortality. CLINICAL TRIAL REGISTRATION: No. ChiCTR-ONRC-13003695.

Cardiac resynchronization therapy from an iliac approach in a patient without superior access: a case report.

Background: Cardiac resynchronization therapy (CRT) has been shown to benefit patients with heart failure and left bundle branch block (LBBB). However, CRT implantation is challenging when the superior venous access is not feasible. Case summary: A 50-year-old man with a history of dilated cardiomyopathy and complete LBBB was referred to our hospital for CRT management. Angiography showed that the left and right brachiocephalic veins were occluded. Cardiac resynchronization therapy was finally implanted via the iliac vein. Follow-up echocardiography showed improved cardiac function, and the pacing system was functioning properly. Discussion: The iliac vein access is feasible for CRT implantation with good stability, which can be a viable alternative to avoid unnecessary risk associated with thoracotomy and epicardial lead placement.

Left Bundle Branch Pacing for Heart Failure and Left Bundle Branch Block Patients With Mildly Reduced and Preserved Left Ventricular Ejection Fraction.

BACKGROUND: Left bundle branch block (LBBB) may induce or aggravate heart failure (HF). Few data are available on patients with HF and LBBB with mildly reduced ejection fraction (HFmrEF; left ventricular ejection fraction [LVEF] 40%-50%) and those with preserved EF (HFpEF. LVEF ≥ 50%). We aimed to assess the long-term outcomes of left bundle branch pacing (LBBP) on cardiac function and remodelling in patients with LBBB and symptomatic HFmrEF and HFpEF. METHODS: Nonischemic cardiomyopathy (NICM) patients with HFmrEF and HFpEF (LVEF from 40% to 60% as defined with the use of echocardiography) with LBBB who successfully underwent LBBP (n = 50) were prospectively included from 4 centres. Patient characteristics and echocardiographic and lead parameters were recorded at implantation and during follow-ups of 1, 3, 6, and 12 months. RESULTS: All patients completed 1-year follow up. The LVEF was significantly improved from 46.5 ± 5.2% at baseline to 60.0 ± 6.1% (n = 50; P < 0.001) after 1-year follow up. Higher ΔLVEF and super-response rate were observed in the HFmrEF group (n = 30) than in the HFpEF group (n = 20). CONCLUSIONS: LBBP improved symptoms and reversed remodelling in patients with LBBB and symptomatic HF at 1-year follow-up. Improvement occurred even in HFpEF patients, and the resynchronisation effect was better in HFmrEF group.

Myeloid-specific deletion of Capns1 attenuates myocardial infarction injury via restoring mitochondrial function and inhibiting inflammasome activation.

BACKGROUND: Mitochondrial dysfunction of macrophage-mediated inflammatory response plays a key pathophysiological process in myocardial infarction (MI). Calpains are a well-known family of calcium-dependent cysteine proteases that regulate a variety of processes, including cell adhesion, proliferation, and migration, as well as mitochondrial function and inflammation. CAPNS1, the common regulatory subunit of calpain-1 and 2, is essential for the stabilization and activity of the catalytic subunit. Emerging studies suggest that calpains may serve as key mediators in mitochondria and NLRP3 inflammasome. This study investigated the role of myeloid cell calpains in MI. METHODS: MI models were constructed using myeloid-specific Capns1 knockout mice. Cardiac function, cardiac fibrosis, and inflammatory infiltration were investigated. In vitro, bone marrow-derived macrophages (BMDMs) were isolated from mice. Mitochondrial function and NLRP3 activation were assessed in BMDMs under LPS stimulation. ATP5A1 knockdown and Capns1 knock-out mice were subjected to MI to investigate their roles in MI injury. RESULTS: Ablation of calpain activities by Capns1 deletion improved the cardiac function, reduced infarct size, and alleviated cardiac fibrosis in mice subjected to MI. Mechanistically, Capns1 knockout reduced the cleavage of ATP5A1 and restored the mitochondria function thus inhibiting the inflammasome activation. ATP5A1 knockdown antagonized the protective effect of Capns1 mKO and aggravated MI injury. CONCLUSION: This study demonstrated that Capns1 depletion in macrophages mitigates MI injury via maintaining mitochondrial homeostasis and inactivating the NLRP3 inflammasome signaling pathway. This study may offer novel insights into MI injury treatment.

Association between nighttime heart rate and cardiovascular mortality in patients with implantable cardioverter-defibrillator: A cohort study.

BACKGROUND: Although studies have shown that an increased resting heart rate measured randomly at a single point of the day has been associated with adverse cardiovascular outcomes, the utility of continuous monitoring of nighttime heart rate (NTHR) has remained largely uninvestigated. OBJECTIVE: This study aimed to explore the association between NTHR and cardiovascular mortality. METHODS: The Study of Home Monitoring System Safety and Efficacy in Cardiac Implantable Electronic Device-implanted Patients, which is a prospective cohort study, enrolled patients with implantable cardioverter-defibrillator (ICD) or cardiac resynchronization therapy defibrillator between 2010 and 2015. Baseline NTHR was measured during the programmed sleep period from 30 to 60 days after implantation. The primary outcome was cardiovascular mortality, fitted by a restricted cubic spline function. RESULTS: A total of 534 implantable cardioverter-defibrillator recipients with sinus rhythm during the detection window were included in the study. The mean baseline NTHR was 59.6 ± 8.0 beats/min. During the follow-up period of 60.4 ± 21.8 months, 88 (16.5%) patients experienced cardiovascular mortality. After considering potential confounders, a linear association was observed. Each 1 beat/min increase in NTHR was associated with a 7.8%, 10.1%, and 5.7% increase in the risk of cardiovascular mortality in the total population, patients with heart failure, and patients without heart failure, respectively. CONCLUSION: Continuous monitoring of NTHR may identify patients at high risk of cardiovascular mortality in a timely manner, with the potential for "preemptive" action. TRIAL REGISTRATION: No. ChiCTR-ONRC-13003695.

Electrical Resynchronization and Clinical Outcomes During Long-Term Follow-Up in Intraventricular Conduction Delay Patients Applied Left Bundle Branch Pacing-Optimized Cardiac Resynchronization Therapy.

BACKGROUND: Left bundle branch-optimized cardiac resynchronization therapy (LOT-CRT) has shown encouraging results for QRS duration reduction and heart function improvement. However, the feasibility and efficacy of LOT-CRT have not been well established in intraventricular conduction delay patients. This study aims to assess and compare the efficacy and clinical outcome of CRT based on left bundle branch pacing, combined with coronary sinus left ventricular pacing (LOT-CRT) with CRT via biventricular pacing (BiV-CRT) in intraventricular conduction delay patients indicated for CRT. METHODS: Consecutive patients with intraventricular conduction delay and CRT indications were assigned nonrandomized to LOT-CRT (n=30) or BiV-CRT (n=55). Addition of the left bundle branch pacing (or coronary venous) lead was at the discretion of the implanting physician guided by suboptimal paced QRS complex and on clinical grounds. Echocardiographic parameters and clinical characteristics were accessed at baseline and during 2-years' follow-up. RESULTS: Success rate for LOT-CRT and BiV-CRT was 96.8% and 96.4%. LOT-CRT had greater reduction of QRS duration compared with BiV-CRT (42.7±17.4 ms versus 21.9±21.5 ms; P<0.001). Higher left ventricular ejection fraction was also achieved in LOT-CRT than BiV-CRT at 6-month (36.7±9.8% versus 30.5±6.4%; P<0.05), 12-month (34.8±7.6% versus 30.3±6.2%; P<0.05), 18-month (36.3±7.9% versus 28.1±6.6%; P<0.005), and 24-month follow-up (37±9.5% versus 30.5±7%; P<0.05). Adverse clinical outcomes including heart failure rehospitalization and mortality were lower in LOT-CRT group for 24 months follow-up (hazard ratio, 0.33; P=0.035). CONCLUSIONS: LOT-CRT improves ventricular electrical synchrony and may provide greater clinical outcomes as compared with BiV-CRT in intraventricular conduction delay patients. These findings need further evaluation in future randomized controlled trials.

Real-world evidence for the use of subcutaneous implantable cardioverter-defibrillators in China: A single-center experience.

BACKGROUND: Subcutaneous implantable cardioverter-defibrillators (S-ICDs) have been shown to be non-inferior to transvenous ICDs in the prevention of sudden cardiac death (SCD), but there is still a lack of evidence from clinical trials in China. We investigated whether S­ICD implantation in the Chinese population is safe and feasible and should be promoted in the future. METHODS: Consecutive patients undergoing S­ICD implantation at our center were enrolled in this retrospective study. Data were collected within the median follow-up period of 554 days. Data concerning patient selection, implantation procedures, complications, and episodes of shock were analyzed. RESULTS: In total, 70.2% of all 47 patients (median age = 39 years) were included for secondary prevention of SCD with different etiologies. Vector screening showed that 98% of patients were with > 1 appropriate vector in all postures. An intraoperative defibrillation test was not performed on six patients because of the high risk of disease deterioration, while all episodes of ventricular fibrillation induced post implantation were terminated by one shock. As expected, no severe complications (e.g., infection and device-related complications) were observed, except for one case of delayed healing of the incision. Overall, 15 patients (31.9%) experienced appropriate shocks (AS) with all episodes terminated by one shock. Two patients (4.3%) experienced inappropriate shocks (IAS) due to noise oversensing, resulting in a high Kaplan-Meier IAS-free rate of 95.7%. CONCLUSION: Based on appropriate patient selection and standardized implantation procedures, this real-world study confirmed the safety and efficacy of S­ICD in Chinese patients, indicating that it may help to promote the prevention of SCD in China.

Progression of Device-Detected Atrial High-Rate Episodes and the Risk of All-Cause Mortality.

Atrial high-rate episodes (AHREs) are prevalent in approximately 1/3 of patients with cardiac implanted electronic devices and are associated with an increased risk of several adverse outcomes. This study aimed to explore the factors associated with AHRE progression and the risk of all-cause mortality. At least 1 day with AHRE burden ≥15 minutes was identified in 124 of 343 recipients (36.2%) of an implantable cardioverter defibrillator or cardiac resynchronization therapy device. We included patients whose AHRE burden at the time of first detection was ≥15 minutes but <24 hours (n = 107). Various cut-off values (15 minutes, 6 hours, and 24 hours) of daily AHRE burden were analyzed. During an average follow-up of 4.2 years, 60 patients (56.1%) experienced ≥1 progression to greater AHRE burden. Patients with hypertension or greater AHRE burden at first detection were associated with faster progression. In addition, 27 deaths (45%) occurred among 60 patients with AHRE progression, compared with 25.5% (12 of 47) for those without progression. After multivariable adjustment, AHRE progression was independently associated with all-cause mortality (hazard ratio 2.56, 95% confidence interval 1.23 to 5.35, p = 0.012). Notably, AHRE progression within 1 month after their first detection was associated with an increased risk for all-cause mortality (hazard ratio 4.01, 95% confidence interval 1.76 to 9.16, p = 0.001) compared with patients without progression. However, a similar risk was not observed among patients with AHRE progression occurring after 1 month after their first detection. In conclusion, >1/2 of the patients with AHRE progressed to a greater burden over time. Continuous monitoring of the AHRE burden may help identify patients at great risk for death.

Trimetazidine Affects Mitochondrial Calcium Uniporter Expression to Restore Ischemic Heart Function via Reactive Oxygen Species/NFκB Pathway Inhibition.

ABSTRACT: Studies have demonstrated the roles of trimetazidine beyond being an antianginal agent in ischemic heart disease (IHD) treatment associated with mechanisms of calcium regulation. Our recent studies revealed that mitochondrial calcium uniporter (MCU, the pore-forming unit responsible for mitochondrial calcium entrance) inhibition provided cardioprotective effects for failing hearts. Because trimetazidine and MCU are associated with calcium homeostasis, we hypothesized that trimetazidine may affect MCU to restore the failing heart function. In the present study, we tested this hypothesis in the context of cardiac ischemia in vivo and in vitro. The IHD model was established in male C57BL/6 mice followed by trimetazidine administration intraperitoneally at 20 mg/kg q.o.d for 8 weeks. In vitro studies were performed in a hypoxia model using primary rat neonate cardiomyocytes. The mice survival outcomes and heart function, pathohistologic, and biological changes were analyzed. The results demonstrated that trimetazidine treatment resulted in longer life spans and heart function improvement accompanied by restoration of mitochondrial calcium levels and increase in ATP production via MCU down-regulation. Studies in vitro further showed that trimetazidine treatment and MCU inhibition decreased reactive oxygen species (ROS) production, inhibited the NFκB pathway, and protected the cardiomyocytes from hypoxic injury, and vice versa. Thus, the present study unveils a unique mechanism in which trimetazidine is involved in ameliorating the ischemic failing heart via MCU down-regulation and the following mitochondrial calcium homeostasis restoration, ROS reduction, and cardiomyocyte protection through NFκB pathway inhibition. This mechanism provides a novel explanation for the treatment effects of trimetazidine on IHD.

GAS-STING signaling plays an essential pathogenetic role in Doxorubicin-Induced Cardiotoxicity.

BACKGROUND: The severe unfavorable effects of doxorubicin on the heart restrict its clinical usage. Numerous investigations document that cyclic GMP-AMP synthase (cGAS) activator of interferon genes (STING) cascade influences inflammation along with the immune response in a variety of diseases. The pathophysiological function of the cGAS-STING cascade in Doxorubicin-induced cardiomyopathy (DIC) is, nevertheless, unknown. METHODS: In vivo, cardiotoxicity was triggered by a single dose of intra-peritoneal inoculation of doxorubicin (15 mg/kg) in wild-type C57BL/6J mice and STING knockdown animals. Adeno-associated virus 9 (AAV9) was utilized to silence STING. qPCR along with Western blotting were adopted to assess alterations in the cGAS/STING cascade. To assess cardiac function, we employed echocardiography coupled with histology, as well as molecular phenotyping. In vitro, HL-1 cardiomyocytes were introduced as test models. RESULTS: In wild type mice, doxorubicin stimulation significantly activated the cGAS/STING pathway. STING silencing increased rate of survival along with heart function in mice, as well as diminished myocardial inflammatory cytokines along with apoptosis. These observations were also confirmed by utilizing siRNA of STING in vitro studies. CONCLUSION: This research premise established that STING inhibition could alleviate Dox-triggered cardiotoxicity in mice. As a result, preventing DIC by repressing STING in cardiomyocytes might be a possible treatment approach.

Device-evaluated autonomic nervous function for predicting ventricular arrhythmias and all-cause mortality in patients who underwent cardiac resynchronization therapy-defibrillator.

Introduction: Autonomic nervous system (ANS) function quantified by heart rate variability (HRV) was associated with long-term prognosis, but it was rarely used in the evaluation of patients with heart failure, especially those with cardiac resynchronization therapy-defibrillator (CRT-D) implantation. This study aimed to describe the changes in ANS function among patients who underwent CRT-D with remote home monitoring function, and explore predictive value of HRV for ventricular tachyarrhythmias (VTAs) and all-cause mortality. Method: Patients who underwent CRT-D implantation were included. Device-measured all-day HR, night-time HR, and HRV (measured by the standard deviation of the atrial-atrial sensed intervals) were used to quantify ANS function. Multivariate Cox proportional hazards models were fitted to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) of VTAs or all-cause mortality in relation to ANS function at baseline and 6 months post-implantation. The cutoff value was determined using restrictive cubic splines. Multivariable logistic regression was further established to determine factors influencing postoperative HRV. Results: A total of 170 patients treated with CRT-D were eligible for analysis. During a median follow-up period of 50.8 months, 61 patients died and 69 patients experienced at least one spontaneous episode of VTAs. At 6 months after CRT implantation, 114 patients showed improvement in HRV, increasing from 66.4 ± 19.4 ms to 76.7 ± 21.2 ms. The postoperative HRV was associated with both all-cause mortality (HRs: 0.983; 95% CI: 0.968 to 0.998, p = 0.012) and VTAs (HRs: 0.973; 95% CI: 0.954 to 0.993, p = 0.008), and the relative risk would significantly increase when the postoperative HRV lower than 75 ms. After adjusting for basic ANS function and possible influencing factors, patients without diabetes (p = 0.018) and with higher daily physical activity (p = 0.041) could maintain higher postoperative HRV after CRT implantation. Conclusion: More than two-thirds of heart failure patients showed improvement in ANS function following CRT treatment. However, patients with diabetes and low daily physical activity levels have difficulty maintaining a higher postoperative HRV, which is associated with a worse clinical outcome.

Sex Differences in the Relationship between Abdominal Obesity and Cardiovascular Death in Elderly Patients with Permanent Pacemakers Implantation: A Retrospective Cohort Study.

Objectives: This study aims to investigate the association between waist circumference (WC) and cardiovascular death in patients with permanent pacemakers (PPMs). Methods: This is a retrospective cohort study that enrolled patients who underwent PPM implantation in Fuwai Hospital from May 2010 to April 2014, according to the BIOTRONIK Home Monitoring database. The WC was treated as sex-specific quartiles, and patients were divided into three groups according to body mass index (BMI): normal (≤22.9 kg/m2), overweight (23-24.9 kg/m2), and obese (≥25 kg/m2). Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals for cardiovascular death according to WC and BMI in patients. Results: 492 patients with PPMs implantation were analyzed (mean age: 71.9 ± 10.8 years; 55.1% men (n = 271)). Data showed that after a mean follow-up 67.2 ± 17.5 months, 24 (4.9%) patients had experienced cardiovascular death and 71 (14.4%) were cases of all-cause mortality. Men in the third quartile of WC had an HR of 10.67 (Model 4, 95% CI: 1.00-115.21, p trend = 0.04) for cardiovascular death. However, the association disappeared in female patients (Model 4, HR = 3.99, 95% CI: 0.37-42.87, p trend = 0.25). There was no association between BMI and cardiovascular death or all-cause mortality in both male and female patients. Conclusions: Abdominal obesity was associated with an increased risk of cardiovascular death in patients with PPMs, and this relationship was only in male patients.

Left Bundle Branch Area Pacing versus Biventricular Pacing for Cardiac Resynchronization Therapy on Morbidity and Mortality.

BACKGROUND: Left bundle branch area pacing (LBBAP) has emerged as an alternative to biventricular pacing (BVP) for cardiac resynchronization therapy (CRT). We aimed to compare the morbidity and mortality associated with LBBAP versus BVP in patients undergoing CRT implantation. METHODS: Consecutive patients who received CRT from two high-volume implantation centers were retrospectively recruited. The primary endpoint was a composite of all-cause death and heart failure hospitalization, and the secondary endpoint was all-cause death. RESULTS: A total of 491 patients receiving CRT (154 via LBBAP and 337 via BVP) were included, with a median follow-up of 31 months. The primary endpoint was reached by 21 (13.6%) patients in the LBBAP group, as compared with 74 (22.0%) patients in the BVP group [hazard ratio (HR) 0.70, 95% confidence interval (CI) 0.43-1.14, P = 0.15]. There were 10 (6.5%) deaths in the LBBAP group, as compared with 31 (9.2%) in the BVP group (HR 0.91, 95% CI 0.44-1.86, P = 0.79). No significant difference was observed in the risk of either the primary or secondary endpoint between LBBAP and BVP after multivariate Cox regression (HR 0.74, 95% CI 0.45-1.23, P = 0.24, and HR 0.77, 95% CI 0.36-1.67, P = 0.51, respectively) or propensity score matching (HR 0.72, 95% CI 0.41-1.29, P = 0.28, and HR 0.69, 95% CI 0.29-1.65, P = 0.40, respectively). CONCLUSION: LBBAP was associated with a comparable effect on morbidity and mortality relative to BVP in patients with indications for CRT.

Left Bundle Branch Pacing Versus Biventricular Pacing for Acute Cardiac Resynchronization in Patients With Heart Failure.

BACKGROUND: Left bundle branch pacing (LBBP) has emerged as an alternative to biventricular pacing (BVP) for delivering cardiac resynchronization therapy. We sought to compare the acute improvement of electrical and mechanical synchrony, and hemodynamics between LBBP and BVP in patients with heart failure and left bundle branch block. METHODS: LBBP and BVP were performed and compared in a crossover fashion in patients with heart failure and left bundle branch block undergoing cardiac resynchronization therapy implantation. Electrical synchrony was assessed by QRS duration and area, mechanical synchrony by the SD of time to peak velocity of 12 left ventricular segments (Ts-SD) and interventricular mechanical delay, and hemodynamics by the maximum rate of left ventricular pressure rise (dP/dtmax). RESULTS: Twenty-one patient with heart failure and left bundle branch block (mean age 67±10 years, 48% male, and 90% nonischemic cause) were included. Both LBBP and BVP provided significant improvements in electrical and mechanical synchrony, and hemodynamics compared to the baseline. Compared with BVP, LBBP achieved a larger reduction in QRS duration (-11 ms [95% CI, -17 to -4 ms]; P=0.003) and QRS area (-85 µVs [95% CI, -113 to -56 µVs]; P<0.001); LBBP achieved a greater decrease in Ts-SD (-14 ms [95% CI, -21 to -7 ms]; P=0.001), with no significant difference in interventricular mechanical delay (-2 ms [95% CI, -13 to 8 ms]; P=0.63). The increase in dP/dtmax from LBBP was significantly higher than that from BVP (6% [95% CI, 2%-9%]; P=0.002). CONCLUSIONS: LBBP delivers greater acute electrical and mechanical resynchronization and hemodynamic improvement than BVP in predominantly nonischemic heart failure patients with left bundle branch block. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04505384.

The mediation function of resting heart rate in how physical activity improves all-cause mortality: Continuous and automatic measurement via cardiac implantable electronic devices.

Background: Physical activity (PA) and resting heart rate (RHR) are connected with all-cause mortality. Moreover, there was an inverse correlation between PA and RHR. However, the causal relationship between PA, RHR, and long-term mortality has been rarely evaluated and quantified, particularly the mediation effect of RHR in the association between PA and all-cause mortality. Objective: To describe the relationship between PA and RHR when consistently measured via cardiac implantable electronic devices (CIED) and further explore the mediation effect of PA on all-cause mortality through RHR. Materials and methods: Patients who underwent CIED implantation and received remote home monitoring services were included. During the first 30-60 days after CIED implantation, daily PA and RHR were continuously measured and automatically transmitted by CIED. The primary endpoint was all-cause mortality. The multiple linear regression model was used to confirm the relationship between PA and RHR. The predictive values of both PA and RHR for all-cause mortality were assessed by multivariable Cox proportional hazards models. The causal mediation model was further established to verify and quantify the mediation effect of RHR in the association between PA and all-cause mortality. Results: A total of 730 patients with CIED were included. The mean daily PA and RHR were 10.7 ± 5.7% and 61.3 ± 9.1 bpm, respectively. During a mean follow-up period of 55.8 months, 187 (26.5%) death was observed. A negative linear relationship between PA and RHR was demonstrated in the multiple regression model (ß = -0.260; 95% CI: -0.377 to -0.143, p < 0.001). Multivariable Cox proportional hazards analysis showed that both lower levels of PA (HR = 0.907; 95% CI: 0.878-0.936, p < 0.001) and higher RHR (HR = 1.016; 95% CI: 1.001-1.032, P = 0.031) were independent risk factors of all-cause mortality. Causal mediation analysis further confirmed and quantified the mediation function of RHR in the process of PA improving all-cause mortality (mediation proportion = 3.9%; 95% CI: 0.2-10.0%, p = 0.036). Conclusion: The effects of the higher level of PA on improving life prognosis may be partially mediated through RHR among patients with CIED. It indicates that changes in the autonomic nervous function during postoperative rehabilitation exercises should get more attention.

Translocation of gasdermin D induced mitochondrial injury and mitophagy mediated quality control in lipopolysaccharide related cardiomyocyte injury.

BACKGROUNDS: Inflammation underlies the mechanism of different kinds of heart disease. Cytoplasmic membrane localized N-terminal fragment of gasdermin-D (GSDMD-N) could induce inflammatory injury to cardiomyocyte. However, effects and dynamic changes of GSDMD during the process of lipopolysaccharide (LPS) related inflammatory stress induced cardiomyocyte injury are barely elucidated to date. In this study, LPS related cardiomyocyte injury was investigated based on potential interaction of GSDMD-N induced mitochondrial injury and mitophagy mediated mitochondria quality control. METHODS: HL-1 cardiomyocytes were treated with LPS and Nigericin to induce inflammatory stress. The dual-fluorescence-labelled GSDMD expressed HL-1 cardiomyocytes were constructed to study the translocation of GSDMD. The mitochondrial membrane potential (MMP) was measured by JC-1 staining. Mitophagy and autophagic flux were recorded by transmission electron microscopy and fluorescent image. RESULTS: GSDMD-N showed a time-dependent pattern of translocation from mitochondria to cytoplasmic membrane under LPS and Nigericin induced inflammatory stress in HL-1 cardiomyocytes. GSDMD-N preferred to localize to mitochondria to permeablize its membrane and dissipate the MMP. This effect couldn't be reversed by cyclosporine-A (mPTP inhibitor), indicating GSDMD-N pores as alternative mechanism underlying MMP regulation, in addition to mitochondrial permeability transition pore (mPTP). Moreover, the combination between GSDMD-N and autophagy related Microtubule Associated Protein 1 Light Chain 3 Beta (LC3B) was verified by co-immunoprecipitation. Besides, mitophagy alleviating GSDMD-N induced mitochondrial injury was proved by pre-treatment of autophagy antagonist or agonist in GSDMD-knock out or GSDMD-overexpression cells. A time-dependent pattern of GSDMD translocation and mitochondrial GSDMD targeted mitophagy were verified. CONCLUSION: Herein, our study confirmed a crosstalk between GSDMD-N induced mitochondrial injury and mitophagy mediated mitochondria quality control during LPS related inflammation induced cardiomyocyte injury, which potentially facilitating the development of therapeutic target to myocardial inflammatory disease. Our findings support pharmaceutical intervention on enhancing autophagy or inhibiting GSDMD as potential target for inflammatory heart disease treatment.

Interaction between electrical storm and left ventricular ejection fraction as predictors of mortality in patients with implantable cardioverter defibrillator: A Chinese cohort study.

Aims: To determine the interaction of electrical storm (ES) and impaired left ventircular ejection fraction (LVEF) on the mortality risk of patients with implantable cardioverter defibrillator (ICD). Methods and results: A total of 554 Chinese ICD recipients from 2010 to 2014 were retrospectively included and the mean follow-up was 58 months. The proportions of dilated cardiomyopathy and the hypertrophic cardiomyopathy were 26.0% (144/554) and 5.6% (31/554), respectively. There were 8 cases with long QT syndrome, 6 with arrhythmogenic right ventricular cardiomyopathy and 2 with Brugada syndrome. Patients with prior MI accounted for 15.5% (86/554) and pre-implantation syncope accounted for 23.3% (129/554). A total of 199 (35.9%) patients had primary prevention indications for ICD therapy. Both ES and impaired LVEF (<40%) were independent predictors for all-cause mortality [hazard ratio (HR) 2.40, 95% CI 1.57-3.68, P < 0.001; HR 1.94, 95% CI 1.30-2.90, P = 0.001, respectively] and cardiovascular mortality (HR 4.63, 95% CI 2.68-7.98, P < 0.001; HR 2.56, 95% CI 1.47-4.44, p = 0.001, respectively). Compared with patients with preserved LVEF (≥40%) and without ES, patients with impaired LVEF and ES had highest all-cause and cardiovascular mortality risks (HR 4.17, 95% CI 2.16-8.06, P < 0.001; HR 11.91, 95% CI 5.55-25.56, P < 0.001, respectively). In patients with impaired LVEF, ES increased the all-cause and cardiovascular mortality risks (HR 1.84, 95% CI 1.00-3.37, P = 0.034; HR 4.86, 95% CI 2.39-9.86, P < 0.001, respectively). In patients with ES, the deleterious effects of impaired LVEF seemed confined to cardiovascular mortality (HR 2.54, 95% CI 1.25-5.14, p = 0.038), and the HR for all-cause mortality was not significant statistically (HR 1.14, 95% CI 0.54-2.38, P = 0.735). Conclusion: Both ES and impaired LVEF are independent predictors of mortality risk in this Chinese cohort of ICD recipients. The interaction of ES and impaired LVEF in patients significantly amplifies the deleterious effects of each other as distinct disease.