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.

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.

Cardiac resynchronization therapy via left bundle branch pacing vs. optimized biventricular pacing with adaptive algorithm in heart failure with left bundle branch block: a prospective, multi-centre, observational study.

AIMS: The purpose of our study was to evaluate the feasibility and efficacy of cardiac resynchronization therapy (CRT) via left bundle branch pacing (LBBP-CRT) compared with optimized biventricular pacing (BVP) with adaptive algorithm (BVP-aCRT) in heart failure with reduced left ventricular ejection fraction ≤35% (HFrEF) and left bundle branch block (LBBB). METHODS AND RESULTS: One hundred patients with HFrEF and LBBB undergoing CRT were prospectively enrolled in a non-randomized fashion and divided into two groups (LBBP-CRT, n = 49; BVP-aCRT, n = 51) in four centres. Implant characteristics and echocardiographic parameters were accessed at baseline and during 6-month and 1-year follow-up. The success rate for LBBP-CRT and BVP-aCRT was 98.00% and 91.07%. Fused LBBP had the greatest reduced QRS duration compared to BVP-aCRT (126.54 ± 11.67 vs. 102.61 ± 9.66 ms, P < 0.001). Higher absolute left ventricular ejection fraction (LVEF) and △LVEF was also achieved in LBBP-CRT than BVP-aCRT at 6-month (47.58 ± 12.02% vs. 41.24 ± 10.56%, P = 0.008; 18.52 ± 13.19% vs. 12.89 ± 9.73%, P = 0.020) and 1-year follow-up (49.10 ± 10.43% vs. 43.62 ± 11.33%, P = 0.021; 20.90 ± 11.80% vs. 15.20 ± 9.98%, P = 0.015, P = 0.015). There was no significant difference in response rate between two groups while higher super-response rate was observed in LBBP-CRT as compared to BVP-aCRT at 6 months (53.06% vs. 36.59%, P = 0.016) and 12 months (61.22% vs. 39.22%, P = 0.028) during follow-up. The pacing threshold was lower in LBBP-CRT at implant and during 1-year follow-up (both P < 0.001). Procedure-related complications and adverse clinical outcomes including heart failure hospitalization and mortality were not significantly different in two groups. CONCLUSIONS: The feasibility and efficacy of LBBP-CRT demonstrated better electromechanical resynchronization and higher clinical and echocardiographic response, especially higher super-response than BVP-aCRT in HFrEF with LBBB.

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.

Pericardial effusion caused by accidently placing a Micra transcatheter pacing system into the coronary sinus.

BACKGROUND: Leadless pacemaker has been acknowledged as a promising pacing strategy to prevent pocket and lead-related complications. Although rare, cardiac perforation remains a major safety concern for implantation of Micra transcatheter pacing system (TPS). CASE PRESENTATION: A 83-year-old female with low body mass index (18.9 kg m-2) on dual anti-platelet therapy, was indicated for Micra TPS implantation due to sinus arrest and paroxysmal atrial flutter. The patient developed mild pericardial effusion during the procedure since the delivery catheter was accidentally placed into the coronary sinus for several times. Cardiac perforation with moderate pericardial effusion and pericardial tamponade was detected 2 h post-procedure. The patient was treated with immediately pericardiocentesis and recovered without further invasive therapy. CONCLUSION: Pericardial effusion caused by accidently placing a delivery catheter into the coronary sinus is rare but should be carefully considered in Micra TPS implantation, especially for those with periprocedural anti-platelet therapy.

Patient-tailored SyncAV algorithm: A novel strategy to improve synchrony and acute hemodynamic response in heart failure patients treated by cardiac resynchronization therapy.

INTRODUCTION: Several automatic algorithms have developed to optimize the timing cycle setting in cardiac resynchronization therapy (CRT). The present study aims to investigate whether the novel device-based SyncAV algorithm could elicit better synchrony and acute hemodynamic response. METHODS AND RESULTS: Thirty five patients undergoing CRT implantation were prospectively studied. The device was programmed to three biventricular (BiV) pacing modes sequentially after the procedure: QuickOpt algorithm (mode I), SyncAV algorithm with default 50 ms offset (mode II), and SyncAV algorithm with optimized offset minimizing QRS duration (QRSd) (mode III). After each setting, electrocardiographic and echocardiographic data were collected. As a result, QRSd was reduced from 172.8 ± 17.9 ms during intrinsic conduction to 153.1 ± 15.9 ms in mode I, further narrowed to 140.5 ± 16.7 ms in mode II, and reached shortest (134.8 ± 16.1 ms) in mode III (P < .01 for all). Besides, significantly shorter QT intervals were observed in mode I (453.2 ± 45.5 ms), mode II (443.9 ± 34.2 ms) and mode III (444.1 ± 28.7 ms), compared with native condition (472.5 ± 51.2 ms) (P < .01). All three BiV modes exhibited comparable Tp Te interval and Tp Te /QT ratio (P > .05). Mode I presented significantly higher aortic velocity time integral than intrinsic conduction (21.0 ± 6.4 cm vs 18.4 ± 5.5 cm; P < .01), which was even higher in mode II (22.0 ± 6.5 cm) and mode III (23.7 ± 6.5 cm). All three BiV modes significantly reduced standard deviation of time to peak contraction of 12-LV segments (Ts-SD) (Mode I: 55.2 ± 16.5 ms, Mode II: 50.2 ± 14.7 ms, Mode III: 45.4 ± 14.4 ms) compared with intrinsic conduction (66.3 ± 18.4 ms) (P < .01), with Mode III demonstrating the smallest (P < .01). CONCLUSION: SyncAV CRT ameliorated electrical and mechanical synchrony as well as acute hemodynamic response beyond conventional QuickOpt optimization. An additional individualized adjustment to the SyncAV offset added to its advantage.

Left bundle branch area pacing is superior to right ventricular septum pacing concerning depolarization-repolarization reserve.

INTRODUCTION: Left bundle branch area pacing (LBBAP) has recently been reported to be a new physiological pacing strategy with clinical feasibility and safety. The present study aims to investigate depolarization-repolarization measures including QT interval, QT dispersion (QTD), and Tpeak-end interval (Tp Te ) in this novel LBBAP strategy. METHODS AND RESULTS: A total of 131 pacing-indicated patients were prospectively enrolled and randomized to the LBBAP group (n = 66) and right ventricular septum pacing (RVSP) group (n = 65). LBBAP was successfully achieved in 61 subjects with stable lead performance and comparable complications (ie, pocket hematoma, lead perforation, and dislodgement) compared with RVSP. Of the 61 patients with successful LBBAP, the mean LV peak activation time was 67.89 ± 6.80 ms, with the LBB potential mapped in 46 cases (75.4%). Electrocardiogram (ECG) indices were compared between these two groups before and after implantation. As a result, LBBAP yielded a narrower paced QRS duration (121.49 ± 9.87 ms vs 145.62 ± 8.89 ms; P < .001), shorter QT interval (434.16 ± 32.70 ms vs 462.66 ± 32.04 ms; P < .001), and QTc interval (472.44 ± 33.30 ms vs 499.65 ± 31.35 ms; P < .001), lower QTD (40.10 ± 8.68 ms vs 46.11 ± 10.85 ms; P = .001), and QTc D (43.57 ± 8.78 ms vs 49.86 ± 11.98 ms; P = .001), and shorter Tp Te (96.59 ± 10.76 ms vs 103.77 ± 10.16 ms; P < .001) than RVSP. However, Tp Te /QT ratio did not differ between these two groups (0.223 ± 0.026 vs 0.225 ± 0.022; P = .733). Furthermore, LBBAP displayed less increased QRS duration, QTc interval, QTD, QTc D, and a more shortened QT interval compared with RVSP (all P < .05). CONCLUSION: LBBAP proves to be a feasible and safe pacing procedure with better depolarization-repolarization reserve, which may predict lower risk of ventricular arrhythmia and sudden cardiac death.

The feasibility and safety of left bundle branch pacing vs. right ventricular pacing after mid-long-term follow-up: a single-centre experience.

AIMS: The aim of this study is to prospectively assess the feasibility and safety of left bundle branch pacing (LBBP) when compared with right ventricular pacing (RVP) during mid-long-term follow-up in a large cohort. METHODS AND RESULTS: Patients (n = 554) indicated for pacemaker implantation were prospectively and consecutively enrolled and were non-randomized divided into LBBP group and RVP group. The levels of cTnT and N-terminal pro-B type natriuretic peptide were measured and compared within 2 days post-procedure between two groups. Implant characteristics, procedure-related complications, and clinical outcomes were also compared. Pacing thresholds, sensing, and impedance were assessed during procedure and follow-up. Left bundle branch pacing was feasible with a success rate of 94.8% with high incidence of LBB potential (89.9%), selective LBBP (57.8%), and left deviation of paced QRS axis (79.7%) with mean Sti-LVAT of 65.07 ± 8.58 ms. Paced QRS duration was significantly narrower in LBBP when compared with RVP (132.02 ± 7.93 vs. 177.68 ± 15.58 ms, P < 0.0001) and the pacing parameters remained stable in two groups during 18 months follow-up. cTnT elevation was more significant in LBBP when compared with RVP within 2 days post-procedure (baseline: 0.03 ± 0.03 vs. 0.02 ± 0.03 ng/mL, P = 0.002; 1 day post-procedure: 0.13 ± 0.09 vs. 0.04 ± 0.03 ng/mL, P < 0.001; 2 days post-procedure: 0.10 ± 0.08 vs. 0.03 ± 0.08 ng/mL, P < 0.001). The complications and cardiac outcomes were not significantly different between two groups. CONCLUSION: Left bundle branch pacing was feasible in bradycardia patients associated with stable pacing parameters during 18 months follow-up. Paced QRS duration was significantly narrower than that of RVP. Though cTnT elevation was more significant in LBBP within 2 days post-procedure, the complications, and cardiac outcomes were not significantly different between two groups.

Circulating metabolite profiles to predict response to cardiac resynchronization therapy.

BACKGROUND: Heart failure is associated with ventricular dyssynchrony and energetic inefficiency, which can be alleviated by cardiac resynchronization therapy (CRT) with approximately one-third of non-response rate. Thus far, there is no specific biomarker to predict the response to CRT in patients with heart failure. In this study, we assessed the role of the blood metabolomic profile in predicting the response to CRT. METHODS: A total of 105 dilated cardiomyopathy patients with severe heart failure who received CRT were included in our two-stage study. Baseline blood samples were collected prior to CRT implantation. The response to CRT was defined according to echocardiographic criteria. Metabolomic profiling of serum samples was carried out using ultrahigh performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry. RESULTS: Seventeen metabolites showed significant differences in their levels between responders and non-responders, and these metabolites were primarily involved in six pathways, including linoleic acid metabolism, Valine, leucine and isoleucine biosynthesis, phenylalanine metabolism, citrate cycle, tryptophan metabolism, and sphingolipid metabolism. A combination of isoleucine, tryptophan, and linoleic acid was identified as an ideal metabolite panel to distinguish responders from non-responders in the discovery set (n = 51 with an AUC of 0.981), and it was confirmed in the validation set (n = 54 with an AUC of 0.929). CONCLUSIONS: Mass spectrometry based serum metabolomics approach provided larger coverage of metabolome which can help distinguish CRT responders from non-responders. A combination of isoleucine, tryptophan, and linoleic acid may associate with significant prognostic values for CRT.

The mechanical effects of CRT promoting autophagy via mitochondrial calcium uniporter down-regulation and mitochondrial dynamics alteration.

The mechanism of cardiac resynchronization therapy (CRT) remains unclear. In this study, mitochondria calcium uniporter (MCU), dynamin-related protein-1 (DNM1L/Drp1) and their relationship with autophagy in heart failure (HF) and CRT are investigated. Thirteen male beagle's dogs were divided into three groups (sham, HF, CRT). Animals received left bundle branch (LBB) ablation followed by either 8-week rapid atrial pacing or 4-week rapid atrial pacing and 4-week biventricular pacing. Cardiac function was evaluated by echocardiography. Differentially expressed genes (DEGs) were detected by microarray analysis. General morphological changes, mitochondrial ultrastructure, autophagosomes and mitophagosomes were investigated. The cardiomyocyte stretching was adopted to imitate the mechanical effect of CRT. Cells were divided into three groups (control, angiotensin-II and angiotensin-II + stretching). MCU, DNM1L/Drp1 and autophagy markers were detected by western blots or immunofluorescence. In the present study, CRT could correct cardiac dysfunction, decrease cardiomyocyte's size, alleviate cardiac fibrosis, promote the formation of autophagosome and mitigate mitochondrial injury. CRT significantly influenced gene expression profile, especially down-regulating MCU and up-regulating DNM1L/Drp1. Cell stretching reversed the angiotensin-II induced changes of MCU and DNM1L/Drp1 and partly restored autophagy. CRT's mechanical effects down-regulated MCU, up-regulated DNM1L/Drp1 and subsequently enhanced autophagy. Besides, the mechanical stretching prevented the angiotensin-II-induced cellular enlargement.

Cessation of pacing in super-responders of cardiac resynchronization therapy: A randomized controlled trial.

BACKGROUND: The consequence of cessation of biventricular pacing in super-responders of cardiac resynchronization therapy (CRT) has not been fully investigated. METHODS: In this prospective, single-blinded clinical trial, 21 super-responders were randomly assigned to the ceased pacing (CeP, 11 patients) group or the continued pacing (CoP, 10 patients) group. Patients randomized to the CeP group underwent cessation of biventricular pacing. New York Heart Association (NYHA) class, quality of life (QOL) assessed with Minnesota questionnaire, 6-minute walking distance (6MWD), left ventricular end systolic volume (LVESV), left ventricular end-diastolic volume (LVEDV), and left ventricular ejection fraction (LVEF) were compared between groups at 3- and 6-month follow-up. RESULTS: No significant difference was observed between the CeP and CoP groups regarding NYHA class, QOL, 6MWD, LVESV, LVEDV, or LVEF after 3 months (all P > 0.05). After 6 months, there existed no significant difference between the CeP and CoP groups with regard to NYHA class, QOL, 6MWD, LVESV, and LVEDV (all P > 0.05); however, LVEF was significantly lower in the CeP group than that of the CoP group (0.49 ± 0.10 vs 0.60 ± 0.11, P = 0.04), and LVEF was significantly reduced in the CeP group compared with the baseline value at randomization (0.49 ± 0.10 vs 0.54 ± 0.06, P = 0.04). CONCLUSION: LVEF was significantly reduced in super-responders of CRT 6 months after cessation of pacing. Super-responders to CRT should receive continued, long-term pacing to preserve recovered LV function.

Electrocardiographic parameters effectively predict ventricular tachycardia/fibrillation in acute phase and abnormal cardiac function in chronic phase of ST-segment elevation myocardial infarction.

BACKGROUND: Abnormal cardiac repolarization is closely associated with ventricular tachycardia/ventricular fibrillation (VT/VF). Myocardial ischemia and infarction aggravate cardiac repolarization dispersion, and VT/VF could be lethal in the early stage of ST-segment elevation myocardial infarction (STEMI). Unfortunately, VT/VF cannot be effectively predicted in current clinical practice. The present study aimed to assess electrocardiographic parameters of the sinus rhythmic complex in relation to cardiac repolarization, e.g., QT interval and T-peak to T-end interval (TpTe), to independently predict VT/VF in acute STEMI. Additionally, we hypothesized that QT and TpTe of PVC would be also valuable to predict VT/VF in STEMI. METHODS AND RESULTS: A total of 198 cases diagnosed as STEMI with PVC on admission by electrography were included. During hospitalization, VT/VF values were recorded. Logistic analysis was performed between patients with and without VT/VF to validate independent electrocardiographic predictors. QTcPVC interval > 520 ms (OR = 3.2; P = 0.027), TpTe interval > 100 ms (OR = 3.1; P = 0.04), TpTePVC  > 101 ms (OR = 3.6; P = 0.029), TpTe/QT > 0.258 (OR = 5.7; P = 0.003), and TpTe/QTPVC  > 0.253 (OR = 3; P = 0.048). However, QRS duration, QTc interval, coupling interval, and QRSPVC duration did not predict VT/VF. Besides, QRSPVC duration >140 ms (OR = 2.6; P = 0.001) independently predicted LVEF decrease after 1 year or more. CONCLUSIONS: QTcPVC interval, TpTe interval, TpTePVC interval, TpTe/QT ratio, and TpTe/QTPVC ratio are risk factors for ECG independent from other confounding factors in predicting VT/VF in the acute phase of STEMI. In addition, PVC characteristics as risk factors for VT/VF in acute phase and LVEF decrease in chronic phase were firstly reported.

Atrial transseptal left ventricular lead implantation for cardiac resynchronization therapy using arteriovenous loop technique.

To date, several techniques for transseptal left ventricular (LV) endocardial pacing for cardiac resynchronization therapy (CRT) have been proposed in patients for whom routine transvenous LV pacing is infeasible. These techniques are of varying difficulty and complexity, and some requires devices not easily accessible. We herein report a simple, safe and effective approach of atrial transseptal LV lead implantation using arteriovenous loop technique in a patient for whom transvenous LV implantation lead had failed.

The gene polymorphism of LOX1 predicts the incidence of LVH in patients with essential hypertension.

BACKGROUND: Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) has been shown to play an important role in cardiac remodeling under different pathologic conditions. The role of genetic polymorphisms in the LOX1 gene, however, remains unclear in the development of left ventricular hypertrophy (LVH) for patients with hypertension. METHODS: A total of 536 patients diagnosed with essential hypertension (EH) were recruited in this study. Patients were assigned to the LVH+ (n=143) and LVH- (n=393) groups, respectively. The serum LOX1 level was measured and three single nucleotide polymorphisms (SNPs), i.e. intron 4 (G→A), intron 5(T→G), and 3' UTR (T→C) of the LOX1 gene were genotyped. RESULTS: The genotype frequencies of intron 4 G>A and 3'UTR T>C were not significantly different between the LVH+ and LVH- groups (both P>0.05), however, frequencies of 501G>C were significantly different between those two groups (P=0.007). The 501CC genotype carriers had a markedly higher serum LOX1 level and an increased risk to develop LVH (adjusted OR=2.444, adjusted P=0.002). There was a positive correlation between serum LOX1 level and left ventricular mass index (r=0.907, P<0.001); a cutoff value of 1.0 ng/mL for sLOX-1 was applied to significantly differentiate the LVH+ patients from the LVH- patients with 84% sensitivity and 86% specificity. CONCLUSION: Our data suggest that both the 501>C SNP in the LOX1 gene and the serum LOX1 level may be used to predict the development of LVH among EH patients.

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).

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.

Current of injury is an indicator of lead depth and performance during left bundle branch pacing lead implantation.

BACKGROUND: Monitoring of lead depth is crucial to achieve left bundle branch pacing (LBBP) with a low capture threshold and avoid septal perforation, but lacks informative approach. OBJECTIVE: We aimed to prospectively assess the predictive value of current of injury on the occurrence of inadequate left bundle branch (LBB) capture threshold and acute septal perforation. METHODS: Consecutive patients who received LBBP were enrolled. ST-segment elevation ≥ 25% of intrinsic R-wave amplitude on the unipolar intracardiac electrogram was defined as a sign of distinct current of injury. An LBB capture threshold of <1.5 V/0.5 ms was considered acceptable. RESULTS: LBBP was attempted 513 times in 212 patients. The LBB capture threshold was more likely to improve to an acceptable level after 10 minutes in leads with initial (33 of 47 vs 0 of 8, with vs without) and residual (29 of 33 vs 4 of 14, with vs without) current of injury recorded on the tip electrode (P < .0001). Lead perforation during the procedure has occurred in 11 patients who had no current of injury noted on the tip electrode. The ratio of current of injury recorded on the tip electrode to that on the ring electrode was correlated to the lead depth determined by sheath angiography (Spearman correlation coefficient -0.624; P < .0001), and microperforation is highly possible when the ratio is decreased to <1 (sensitivity 100%; specificity 96.6%). CONCLUSION: Current of injury is a useful tool in forecasting LBBP lead depth and septal perforation, and it could facilitate the decision-making process when the initial LBB capture threshold is undesirable.

Evaluation of electrophysiological characteristics and ventricular synchrony: An intrapatient-controlled study during His-Purkinje conduction system pacing versus right ventricular pacing.

OBJECTIVES TO BACKGROUND: To compare electromechanical ventricular synchrony when pacing from different sites, including right ventricular apex pacing (RVAP), right ventricular septum pacing (RVSP), His bundle pacing (HBP), left bundle branch pacing (LBBP), and RVSP during unipolar pacing from the ring electrode of LBBP lead (RVSPring ) in each patient and evaluate the correlations between electrophysiological characteristics and ventricular synchrony. METHODS: Twenty patients with complete atrioventricular block indicated for dual-chamber pacemaker implantation were included in the study. Unipolar pacing at different sites, including RVAP, RVSP, HBP, LBBP, and RVSPring , was successively performed in each patient. The pacing characteristics and echocardiogram parameters were collected and compared among intrinsic rhythm and pacing at different sites. RESULTS: Similar to HBP (114.84 ± 18.67 ms), narrower paced QRSd was found in LBBP (116.15 ± 11.60 ms) as compared to RVSPring (135.11 ± 13.68 ms), RVSP (141.65 ± 14.26 ms), and RVAP (160.15 ± 19.35 ms) (p < .001). LBBP showed comparable pacing parameters to RVAP or RVSP and was significantly better than HBP, with maintained cardiac function. TS-12-SD was significantly improved in LBBP (41.80 ± 20.97 ms) than RVAP (69.70 ± 32.42 ms, p = .003) and RVSP (63.30.56 ± 32.53 ms, p = .018) but similar to HBP (51.50 ± 25.67 ms, p = .283) or RVSPring (57.80 ± 25.65 ms, p = .198). Among these pacing strategies, negative values of interventricular mechanical delay (IVMD) were only identified in LBBP (-19.25 ± 18.43 ms), significantly different from RVAP (35.00 ± 30.72 ms), RVSP (22.85 ± 22.05 ms), HBP (5.20 ± 18.64 ms), and RVSPring (16.00 ± 26.76 ms (all p < .05). Using Pearson's analysis, Sti-LVAT was positively correlated with QRS duration, IVMD, TS-12-SD, LVEDV, and LVESV, while a negative relationship could be observed for left ventricular ejection fraction. CONCLUSIONS: His-Purkinje conduction system pacing (HPCSP) achieved better electrical and mechanical synchrony than conventional RV pacing. For interventricular synchrony, only LBBP initiated earlier LV activation than RV, in accordance with the right bundle branch block (RBBB) pattern of paced QRS during LBBP. Sti-LVAT might be a good parameter correlating with LV systolic function and mechanical synchrony.

Risk factors of pacing dependence and cardiac dysfunction in patients with permanent pacemaker implantation.

AIMS: Right ventricular pacing (RVP) dependence could impair left ventricular ejection fraction (LVEF). This study aimed to illuminate the relationship between RVP proportion and LVEF, as well as disclosing independent predictors of RVP dependence. METHODS AND RESULTS: Patients indicated for permanent pacemaker implantation were included (2016-2020). The ventricular pacing lead was placed in right ventricular apex or septum. Pacing mode programming followed universal standard. Electrocardiographic, echocardiographic, and serological parameters were collected. RVP dependence was defined according to its influence on LVEF. This study was of case-control design. Included patients were matched by potentially confounding factors through propensity score matching. A total of 1183 patients were included, and the mean duration of follow-up was 24 months. Percentage of RVP < 80% hardly influenced LVEF; however, LVEF tended to decrease with higher RVP proportion. High degree/complete atrioventricular block (AVB) [odds ratio (OR) = 5.71, 95% confidence interval (CI): 3.66-8.85], atrial fibrillation (AF) (OR = 2.04, 95% CI: 1.47-2.82), percutaneous coronary intervention (PCI) (OR = 2.89, 95% CI: 1.24-6.76), maximum heart rate (HRmax ) < 110 b.p.m. (OR = 2.74, 95% CI: 1.58-4.76), QRS duration > 120 ms (OR = 2.46, 95% CI: 1.42-4.27), QTc interval > 470 ms (OR = 2.01, 95% CI: 1.33-3.05), and pulmonary artery systolic pressure (PASP) > 40 mmHg (OR = 1.93, 95% CI: 1.46-2.56) were proved to predict RVP dependence. CONCLUSIONS: High RVP percentage (>80%) indicating RVP dependence significantly correlates with poor prognosis of cardiac function. High degree/complete AVB, AF, ischaemic aetiology, PCI history, HRmax  < 110 b.p.m., QRS duration > 120 ms, QTc interval > 470 ms, and PASP > 40 mmHg were verified as independent risk factors of RVP dependence.

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.