Rapamycin improves the long-term T-cell memory and protective efficacy of tuberculosis subunit vaccine.

The formation of long-lived T-cell memory is a critical goal of vaccines against intracellular pathogens like Mycobacterium tuberculosis (M. tuberculosis). In this study, to access the adjuvant effect of rapamycin on tuberculosis subunit vaccine, we treated mice with rapamycin during the course of vaccination and then monitored the vaccine-specific long-term memory T cell recall responses and protective ability against mycobacterial organisms. Compared with the mice that received vaccine alone, rapamycin treatment enhanced the vaccine induced long-term IFN-γ and IL-2 recall responses, promoted the development of TCM (central memory) like cells and improved the long-term proliferative ability of lymphocytes. Long-duration (total 53 days) of low-dose rapamycin (75 µg/kg/day) treatment generated stronger vaccine-specific memory T cell responses than short-duration treatment (total 25 days). Moreover, rapamycin improved the vaccine's long-term protective efficacy, which resulted in a better reduction of 0.89-log10 CFU of mycobacterial organisms in the lungs compared with control without rapamycin treatment. These findings suggest that rapamycin may be considered in designing TB subunit vaccine regimens or as potential adjuvant to enhance vaccine-induced T cell memory response and to prolong the longevity of vaccine's protective efficacy.

Genetically predicted biomarkers of iron homeostasis and risk of non-ischemic cardiomyopathy: A mendelian randomization study.

BACKGROUND AND AIMS: Both iron overload and iron deficiency have been associated with cardiovascular diseases in observational studies. Previous Mendelian Randomization (MR) studies discovered a protective effect of higher iron status on coronary atrial disease, while a neutral effect on all-cause heart failure. Using two-sample MR, we evaluated how genetically predicted systemic iron status affects the risk of non-ischemic cardiomyopathy and different phenotypes. METHODS AND RESULTS: Two-sample MR analyses were performed to estimate the causal effect of four biomarkers of systemic iron status on diagnosed cardiomyopathy and its subtypes in 242,607 participants from the FinnGen research project. The level of transferrin saturation was significantly associated with an increased risk of cardiomyopathy (OR, 1.17; 95% CI, 1.13-1.38) when using nine separately selected genetic instruments. An increase in genetically determined serum iron (odds ratio [OR] per standard deviation [SD], 1.25; 95% confidence interval [CI], 1.13-1.38) and ferritin (OR, 1.49; 95% CI, 1.02-2.18) were associated with an increased risk of cardiomyopathy. Total iron binding capacity, a marker of reduced iron status, was inversely linked with cardiomyopathy (OR, 0.80; 95% CI, 0.65-0.98). The risk effect of iron status was more evident in hypertrophic cardiomyopathy and related heart failure. CONCLUSIONS: These analyses support the causal effect of increased systemic iron status on a higher risk of non-ischemic cardiomyopathy. A screening test for cardiomyopathy should be considered in patients with evidence of iron overload. Future study is needed for exploring the mechanism of these causal variants on cardiomyopathy.

The combined association of physical activity and alcohol use with long-term mortality: an age-stratified analysis.

BACKGROUND: The combined association of physical activity (PA) and alcohol use (AU) with long-term mortality is yet to be investigated. METHODS: For the current study, 12,621 participants aged ≥ 20 years were enrolled from the National Health and Nutrition Examination Survey (1999-2004). The study endpoint was all-cause mortality. Cox proportional hazards regression models were used to examine the combined effect of PA and AU on long-term mortality. RESULTS: The study population was divided into young (< 60 years, N = 8,258) and old (≥ 60 years, N = 4,363) groups. The median follow-up time was 203 months. In both young and old group, sedentary lifestyle combined with even minimal AU were associated with elevated risk of death (all P < 0.05). In young group, the integration of high volume AU with any degree of PA, including sedentary PA (HR = 2.35, 95% CI 1.24-4.44, P = 0.009), low PA (HR = 1.64, 95% CI 1.01-2.68, P = 0.047), and moderate-to-vigorous PA (HR = 1.99, 95% CI 1.03-3.84, P = 0.041), was associated with an increased risk of mortality. This relationship persisted as significant after adjusting for potential confounders (all P < 0.05). In old group, combining moderate-to-vigorous PA and low volume AU (HR = 0.59, 95% CI 0.37-0.94, P = 0.027) was associated with a reduction in mortality. After adjustment, the combination of moderate-to-vigorous PA and low volume AU was independently associated with favorable prognostic outcomes (all P < 0.05). CONCLUSIONS: In both age groups, combining sedentary lifestyle with even minimal AU was a risk factor for death. In young group, combining any level of PA with high volume AU was associated with increased mortality. In old group, combining moderate-to-vigorous PA with low volume AU was related to reduced mortality.

Joint association of sedentary behavior and vitamin D status with mortality among cancer survivors.

BACKGROUND: Sedentary behavior and vitamin D deficiency are independent risk factors for mortality in cancer survivors, but their joint association with mortality has not been investigated. METHODS: We analyzed data from 2914 cancer survivors who participated in the National Health and Nutrition Examination Survey (2007-2018) and followed up with them until December 31, 2019. Sedentary behavior was assessed by self-reported daily hours of sitting, and vitamin D status was measured by serum total 25-hydroxyvitamin D (25(OH)D) levels. RESULTS: Among 2914 cancer survivors, vitamin D deficiency was more prevalent in those with prolonged daily sitting time. During up to 13.2 years (median, 5.6 years) of follow-up, there were 676 deaths (cancer, 226; cardiovascular disease, 142; other causes, 308). The prolonged sitting time was associated with a higher risk of all-cause and noncancer mortality, and vitamin D deficiency was associated with a higher risk of all-cause and cancer mortality. Furthermore, cancer survivors with both prolonged sitting time (≥ 6 h/day) and vitamin D deficiency had a significantly higher risk of all-cause (HR, 2.05; 95% CI: 1.54-2.72), cancer (HR, 2.33; 95% CI, 1.47-3.70), and noncancer mortality (HR, 1.91; 95% CI, 1.33-2.74) than those with neither risk factor after adjustment for potential confounders. CONCLUSIONS: In a nationally representative sample of U.S. cancer survivors, the joint presence of sedentary behavior and vitamin D deficiency was significantly associated with an increased risk of all-cause and cancer-specific mortality.

Clinical outcome of lesion size index-guided high-power radiofrequency catheter ablation for pulmonary vein isolation in patients with atrial fibrillation: 2-year follow-up.

INTRODUCTION: The long-term efficacy of high-power (50 W) ablation guided by lesion size index (LSI-guided HP) for pulmonary vein isolation (PVI) in patients with atrial fibrillation (AF) remains undetermined. Our study sought to assess the clinical efficacy of LSI-guided HP ablation for PVI in patients with AF and explore the potential predictors associated with clinical outcomes. METHODS: We consecutively included 186 patients with AF who underwent LSI-guided HP (50 W) ablation at Fuwai Hospital from June 2019 to October 2021. The target LSI values of 4.5-5.5 and 4.0-4.5 at the anterior and posterior walls, respectively, were used in our study. The baseline clinical characteristics, procedural and ablation data, and clinical outcomes were evaluated. The independent potential predictors associated with AF recurrence were further evaluated. RESULTS: The incidence rate of first-pass PVI was 83.9% (156/186). A total of 11 883 lesions were analyzed, and compared with posterior walls of pulmonary veins, anterior walls had significantly lower mean contact force (8.2 ± 3.0 vs. 8.3 ± 2.3 g, p = .015), longer mean radiofrequency duration (16.9 ± 7.2 vs. 12.9 ± 4.5 s, p < .001) and higher mean LSI (4.8 ± 0.2 vs. 4.4 ± 0.2, p < .001). The overall incidence of periprocedural complications was 3.7%, and steam pops without pericardial effusion occurred in three patients (1.6%). During a mean follow-up of 24.0 ± 8.4 months, the overall AF recurrence-free survival was 87.1% after a single procedure. Patients with paroxysmal AF had a higher incidence of freedom from AF recurrence than those with persistent AF (91.2% vs. 80.8%, log-rank p = .034). Higher LSI (HR 0.50, p < .001) and paroxysmal AF (HR 0.39, p = .029) were significantly associated with decreased AF recurrence. By receiver operating characteristic analysis, the LSI of 4.7 and 4.3 for the anterior and posterior walls of the PVs had the highest predictive value for AF recurrence, respectively. CONCLUSION: LSI-guided HP (50 W) ablation for PVI was an efficient and safe strategy and led to favorable single-procedure 2-year AF recurrence-free survival in patients with AF. Higher LSI and paroxysmal AF were independent predictors of decreased 2-year AF recurrence. The LSI of 4.7 for the anterior wall and 4.3 for the posterior wall of the PVs were the best cutoff values for predicting AF recurrence after LSI-guided HP ablation.

A novel approach for developing left bundle branch pacing and left bundle branch block in a canine model.

BACKGROUND AND OBJECTIVE: Left bundle branch pacing (LBBP) has shown the benefits in the treatment of dyssynchronous heart failure (HF). The purpose of this study was to develop a novel approach for LBBP and left bundle branch block (LBBB) in a canine model. METHODS: A "triangle-center" method by tricuspid valve annulus angiography for LBBP implantation was performed in 6 canines. A catheter was then applied for retrograde His potential recording and left bundle branch (LBB) ablation simultaneously. The conduction system was stained to verify the "triangle-center" method for LBBP and assess the locations of the LBB ablation site in relation to the left septal fascicle (LSF). RESULTS: The mean LBB potential to ventricular interval and stimulus-peak left ventricular activation time were 11.8 ± 1.2 and 35.7 ± 3.1 ms, respectively. The average intrinsic QRS duration was 44.7 ± 4.7 ms. LBB ablation significantly prolonged the QRS duration (106.3 ± 8.3 ms, p < .001) while LBBP significantly shortened the LBBB-QRS duration to 62.5 ± 5.3 ms (p < .001). After 6 weeks of follow-up, both paced QRS duration (63.0 ± 5.4 ms; p = .203) and LBBB-QRS duration (107.3 ± 7.4 ms; p = .144) were unchanged when comparing to the acute phase, respectively. Anatomical analysis of 6 canine hearts showed that the LBBP lead-tip was all placed in LSF area. CONCLUSION: The new approach for LBBP and LBBB canine model was stable and feasible to simulate the clinical dyssynchrony and resynchronization. It provided a useful tool to investigate the basic mechanisms of underlying physiological pacing benefits.

Effectiveness of adding a defibrillator with cardiac resynchronization therapy in heart failure according to the modified Model for End-stage Liver Disease-Albumin score.

Current guidelines lack clear recommendations between the implantation of cardiac resynchronization therapy (CRT) with defibrillator (CRT-D) and CRT with pacemaker (CRT-P). We hypothesized that modified model for end-stage liver disease score including albumin (MELD-Albumin score), could be used to select patients who may not benefit from CRT-D. We consecutively included patients with CRT-P or CRT-D implantation between 2010 and 2022. The primary endpoint was the composite of all-cause mortality or worsening heart failure. We performed multivariable-adjusted Cox proportional hazard regression. We assessed the interaction between the MELD-Albumin score and the effect of adding a defibrillator with CRT.A total of 752 patients were included in this study, with 291 implanted CRT-P. During a median follow-up of 880 days, 205 patients reached the primary endpoint. MELD-Albumin score was significantly associated with the primary endpoint in the CRT-D group [HR 1.16 (1.09-1.24); P < 0.001] but not in the CRT-P group [HR 1.03 (0.95-1.12); P = 0.49]. There was a significant interaction between the MELD-Albumin score and the effect of CRTD (P = 0.013). The optimal cut-off value of the MELD-Albumin score was 12. For patients with MELD-Albumin ≥ 12, CRT-D was associated with a higher occurrence of the primary endpoint [HR 1.99 (1.10-3.58); P = 0.02], whereas not in patients with MELD-Albumin < 12 [HR 1.19 (0.83-1.70); P = 0.35). Our findings suggest that CRT-D is associated with an excess risk of composite clinical endpoints in HF patients with higher MELD-Albumin score.

High antipersister activity of a promising new quinolone drug candidate in eradicating uropathogenic Escherichia coli persisters and persistent infection in mice.

AIMS: To develop more potent drugs that eradicate persister bacteria and cure persistent urinary tract infections (rUTIs). METHODS AND RESULTS: We synthesized eight novel clinifloxacin analogs and measured minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), the time-kill curves in uropathogenic Escherichia coli (UPEC) UTI89, and applied the candidate drugs and combinations against biofilm bacteria in vitro and in mice. Transcriptomic analysis was performed for UPEC after candidate drug treatment to shed light on potential mechanism of action. We identified Compound 2, named Qingdafloxacin (QDF), which was more potent than clinafloxacin and clinically used levofloxacin and moxifloxacin, with an MIC of < 0.04 µg ml-1 and an MBC of 0.08∼0.16 µg ml-1. In drug combination studies, QDF + gentamicin + nitrofuran combination but not single drugs completely eradicated all stationary phase bacteria containing persisters and biofilm bacteria, and all bacteria in a persistent UTI mouse model. Transcriptome analysis revealed that the unique antipersister activity of QDF was associated with downregulation of genes involved in bacterial stress response, DNA repair, protein misfolding repair, pyrimidine metabolism, glutamate, and glutathione metabolism, and efflux. CONCLUSIONS: QDF has high antipersister activity and its drug combinations proved highly effective against biofilm bacteria in vitro and persistent UTIs in mice, which may have implications for treating rUTIs.

Combined association of triglyceride-glucose index and systolic blood pressure with all-cause and cardiovascular mortality among the general population.

BACKGROUND: The combined association of triglyceride-glucose (TyG) index and different systolic blood pressure (SBP) levels with all-cause and cardiovascular mortality among the general population remains unclear. METHODS: In this study, 6245 individuals were from the National Health and Nutrition Examination Survey (1999-2002). The study endpoints were all-cause and cardiovascular mortality. Multivariate Cox proportional hazards regression models were used to explore the combined association of TyG index and different SBP levels with all-cause and cardiovascular mortality. RESULTS: During a mean follow-up period of 66.8 months, a total of 284 all-cause deaths (331/100000 person-years) and 61 cardiovascular deaths (66/100000 person-years) were recorded. Multivariate Cox regression analysis revealed that the combination of low TyG index and low SBP (< 120 mmHg and < 130 mmHg) was associated with a reduced risk of all-cause and cardiovascular mortality than others. However, survival benefit was not observed in the combined group with the low TyG index and SBP < 140 mmHg. Furthermore, the mortality rate in the combined group of low TyG index and low SBP gradually increased with the elevation of SBP level. CONCLUSION: The combination of low TyG index and low SBP (< 120 mmHg and < 130 mmHg) was associated with a lower risk of all-cause and cardiovascular mortality. However, no survival benefit was observed in the combined group of low TyG index and SBP < 140 mmHg.

Global and regional cardiac dysfunction quantified by 18F-FDG PET scans can predict ventricular arrhythmia in patients with implantable cardioverter defibrillator.

BACKGROUND: A low appropriate therapy rate indicates that a minority of patients will benefit from their implantable cardioverter defibrillator (ICD). Quantitative measurements from 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) may predict ventricular arrhythmia (VA) occurrence after ICD placement. METHODS: We performed a prospective observational study and recruited patients who required ICD placement. Pre-procedure image scans were performed. Patients were followed up for VA occurrence. Associations between image results and VA were analyzed. RESULTS: In 51 patients (33 males, 53.9 ± 17.2 years) analyzed, 17 (33.3%) developed VA. Compared with patients without VA, patients with VA had significantly larger values in scar area (17.7 ± 12.4% vs. 7.0 ± 7.9%), phase standard deviation (51.4° ± 14.0° vs. 34.0° ± 15.0°), bandwidth (172.9° ± 39.8° vs. 128.7° ± 49.9°), sum thickening score (STS, 29.5 ± 11.1 vs. 17.8 ± 13.2), and sum motion score (42.9 ± 11.5 vs. 33.0 ± 19.0). Cox regression analysis and receiver operating characteristic curve analysis showed that scar size, dyssynchrony, and STS were associated with VA occurrence (HR, 4.956, 95% CI 1.70-14.46). CONCLUSION: Larger left ventricular scar burden, increased dyssynchrony, and higher STS quantified by 18F-FDG PET may indicate a higher VA incidence after ICD placement.

Electrical characteristics of pacing different portions of the His bundle in bradycardia patients.

AIMS: His-bundle pacing (HBP) can be achieved in either atrial-side HBP (aHBP) or ventricular-side HBP (vHBP). The study compared the pacing parameters and electrophysiological characteristics between aHBP and vHBP in bradycardia patients. METHODS AND RESULTS: Fifty patients undergoing HBP implantation assisted by visualization of the tricuspid valvular annulus (TVA) were enrolled. The HBP lead position was identified by TVA angiography. Twenty-five patients were assigned to undergo aHBP and compared with 25 patients who underwent vHBP primarily in a prospective and randomized fashion. Pacing parameters and echocardiography were routinely assessed at implant and 3-month follow-up. His-bundle pacing was successfully performed in 45 patients (90% success rate with 44.4% aHBP and 55.6% vHBP). The capture threshold was lower in vHBP than aHBP at implant (vHBP: 1.1 ± 0.5 vs. aHBP: 1.4 ± 0.4 V/1.0 ms, P = 0.014) and 3-month follow-up (vHBP: 0.8 ± 0.4 vs. aHBP: 1.7 ± 0.8 V/0.4 ms, P < 0.001). The R-wave amplitude was higher in vHBP than in aHBP at implant (vHBP: 4.5 ± 1.4 vs. aHBP: 2.0 ± 0.8 mV, P < 0.001) and at 3-month follow-up (vHBP: 4.4 ± 1.5 vs. aHBP: 1.8 ± 0.7 mV, P < 0.001). No procedure-related complications and aggravation of tricuspid valve regurgitation were observed in most patients and echocardiographic assessment of cardiac function remained in the normal range in all patients during the follow-up. CONCLUSION: This study demonstrates that vHBP features a low and stable pacing capture threshold and high R-wave amplitude, suggesting better pacing mode management and battery longevity can be achieved by HBP in the ventricular side.

Multipolar mapping for catheter ablation of premature ventricular complexes originating from papillary muscles in the structurally normal heart: a case series.

BACKGROUND: Previous studies on radiofrequency catheter ablation of premature ventricular complexes (PVCs) arising from the left ventricle (LV) papillary muscles (PM) show a modest procedural success rate with higher recurrence rate. Our study sought to explore the utility of using a multipolar mapping with a steerable linear duodecapolar catheter for ablating the PM PVCs. METHODS: Detailed endocardial multipolar mapping was performed using a steerable linear duodecapolar catheter in 6 consecutive PM PVCs patients with structurally normal heart. The clinical features and procedural data as well as success rate were analysed. RESULTS: LV endocardial electroanatomic mapping was performed in all patients via a retrograde aortic approach using a duodecapolar mapping catheter. All patients displayed a PVC burden with 16.2 ± 5.4%. Duodecapolar catheter mapping demonstrated highly efficiency with an average procedure time (95.8 ± 7.4 min) and fluoroscopy time (14.2 ± 1.5 min). The mean number of ablation applications points was 6.8 ± 1.9 with an average overall ablation duration of 6.1 ± 3.0 min. The values of earliest activation time during mapping using duodecapolar catheter were 37.8 ± 7.2 ms. All patients demonstrated acute successful ablation, and the PVC burden in all patients after an average follow-up of 8.5 ± 2.0 months was only 0.7%. There were no complications during the procedures and after follow-up. CONCLUSIONS: Mapping and ablation of PM PVCs using a duodecapolar catheter facilitated the identification of earliest activation potentials and pace mapping, and demonstrated a high success rate during follow-up.

A prognostic nomogram for event-free survival in patients with atrial fibrillation before cardiac resynchronization therapy.

BACKGROUND: Atrial fibrillation (AF), one of the most common comorbidities of heart failure (HF), is associated with worse long-term prognosis in HF patients receiving cardiac resynchronization therapy (CRT). However, there is still no convenient tool to identify CRT candidates with AF who are at high risk of mortality and hospitalization due to HF. METHODS: We included 152 consecutive patients with AF for CRT in our hospital from January 2009 to July 2019. Multiple imputation was used for missing values. With imputed datasets, a multivariate Cox regression model was performed for variable selection using the backward stepwise method to predict all-cause mortality and HF readmissions. A nomogram and nomogram-based scoring system were constructed from the selected predictors. Then, internal validation and calibration were achieved by the bootstrap method, deriving the corrected concordance index and calibration curves. Sensitivity analysis was also performed to validate our selected predictors. RESULTS: Five predictors were incorporated in the nomogram, including N-terminal pro brain natriuretic protein (NT-proBNP) > 1745 pg/mL, history of syncope, previous pulmonary hypertension, moderate or severe tricuspid regurgitation, thyroid-stimulating hormone (TSH) > 4 mIU/L. The concordance index (0.70, 95% CI 0.62-0.77), corrected concordance index (0.67, 95% CI 0.59-0.74) and calibration curve showed optimal discrimination and calibration of the established nomogram. A significant difference in overall event-free survival was recognized by the nomogram-derived scores for patients with high risk (> 50 points), intermediate risk (21-50 points) and low risk (0-20 points) before CRT. CONCLUSION: Our internally validated nomogram may be an applicable tool for the early risk stratification of CRT candidates with AF.

A novel risk model for mortality and hospitalization following cardiac resynchronization therapy in patients with non-ischemic cardiomyopathy: the alpha-score.

BACKGROUND: Non-ischemic cardiomyopathy (NICM) has been associated with a better left ventricle reverse remodeling response and improved clinical outcomes after cardiac resynchronization therapy (CRT). The aims of our study were to identify the predictors of mortality and heart failure hospitalization in patients treated with CRT and design a risk score for prognosis. METHODS: A cohort of 422 consecutive NICM patients with CRT was retrospectively enrolled between January 2010 and December 2017. The primary endpoint was all-cause mortality and heart transplantation. RESULTS: In a multivariate analysis, the predictors of all-cause death were left atrial diameter [Hazard ratio (HR): 1.056, 95% confidence interval (CI): 1.020-1.093, P = 0.002]; non-left bundle branch block [HR: 1.793, 95% CI: 1.131-2.844, P = 0.013]; high sensitivity C-reactive protein [HR: 1.081, 95% CI: 1.029-1.134 P = 0.002]; and N-terminal pro-B-type natriuretic peptide [HR: 1.018, 95% CI: 1.007-1.030, P = 0.002]; and New York Heart Association class IV [HR: 1.018, 95% CI: 1.007-1.030, P = 0.002]. The Alpha-score (Atrial diameter, non-LBBB, Pro-BNP, Hs-CRP, NYHA class IV) was derived from each independent risk factor. The novel score had good calibration (Hosmer-Lemeshow test, P > 0.05) and discrimination for both primary endpoints [c-statistics: 0.749 (95% CI: 0.694-0.804), P < 0.001] or heart failure hospitalization [c-statistics: 0.692 (95% CI: 0.639-0.745), P < 0.001]. CONCLUSION: The Alpha-score may enable improved discrimination and accurate prediction of long-term outcomes among NICM patients with CRT.

Introducing RpsA Point Mutations Δ438A and D123A into the Chromosome of Mycobacterium tuberculosis Confirms Their Role in Causing Resistance to Pyrazinamide.

Pyrazinamide (PZA) is a unique frontline drug for shortening tuberculosis (TB) treatment, but its mechanisms of action are elusive. We previously found one PZA-resistant strain that harbors an alanine deletion at position 438 (Δ438A) in RpsA, a target of PZA associated with PZA resistance, but its role in causing PZA resistance has been inconclusive. Here, we introduced the RpsA Δ438A mutation along with the D123A mutation into the Mycobacterium tuberculosis chromosome and demonstrated that these RspA mutations are indeed responsible for PZA resistance.

The effect of posture, exercise, and atrial pacing on atrioventricular conduction in systolic heart failure.

BACKGROUND: Optimization of atrioventricular (AV) intervals for cardiac resynchronization therapy (CRT) programming is typically performed in supine patients at rest, which may not reflect AV timing in other conditions. OBJECTIVE: To evaluate the effects of posture, exercise, and atrial pacing on intrinsic AV intervals in patients with CRT devices. METHODS: Rate-dependent A-V delay by exercise was a multicenter, prospective trial of patients in sinus rhythm following CRT implantation. Intracardiac electrograms were recorded to analyze atrial to right ventricular (ARV), atrial to left ventricular (ALV), and RV to LV (VV) time intervals. Heart rate was increased with incremental atrial pacing in different postures, followed by an exercise treadmill test. RESULTS: This study included 36 patients. At rest, AV intervals changed minimally with posture. With atrial pacing, AV interval immediately increased compared with sinus rhythm, with ARV slopes being 8.1 ± 7.7, 8.8 ± 13.4, and 6.8 ± 6.5 milliseconds per beat per minute (ms/bpm) and ALV slopes being 8.2 ± 7.7, 9.1 ± 12.8, and 7.0 ± 6.5 ms/bpm for supine, standing and sitting positions, respectively. As the paced heart rate increased, ARV and ALV intervals increased more gradually with similar trends. Interventricular conduction times changed less than 0.2 ms/bpm with atrial pacing. During exercise, the direction of change of intrinsic ARV intervals, as heart rate increased, was variable between patients with relatively small overall group changes (0.1 ± 1.4 and 0.2 ± 1.2 ms/bpm for ARV and ALV, respectively). CONCLUSION: Posture and exercise have a smaller effect on AV timing compared with atrial pacing. However, individualized optimization and dynamic rate related changes may be needed to maintain optimal fusion with left ventricular (LV) stimulation.

Visualization of tricuspid valve annulus for implantation of His bundle pacing in patients with symptomatic bradycardia.

BACKGROUND: His bundle pacing (HBP) is a physiological pacing modality, but HBP implantation remains a challenge. OBJECTIVE: This study explored the feasibility of using visualization of the tricuspid valve annulus (TVA) to locate the site for HBP. METHODS: During the lead placement in eight patients with symptomatic bradycardia, the TVA and tricuspid septal leaflet was revealed by contrast injection in the right ventricle under the fluoroscopic right anterior oblique view, and the target site for HBP was identified near the intersection of the tricuspid septal leaflet and the interventricular septum. On the basis of the imaging marker, the pacing lead was placed for HBP at either the atrial (aHBP) or ventricular side (vHBP). RESULTS: During the implantation, the pacing lead placement was attempted for aHBP in two patients, vHBP in five patients, and first for aHBP then vHBP in one patient. The aHBP was selective and had a capture threshold of 1.6 ± 0.5 V@ 1.0ms and R-wave amplitude of 1.2 ± 0.4 mV. Ventricular-side His bundle capture was selective in four patients and nonselective in two patients. The vHBP capture threshold was 0.8 ± 0.4 V@ 1.0ms (P < .05 vs aHBP) and R-wave amplitude was 4.1 ± 1.5 mV (P < .05 vs aHBP). At the final pacing programming of 3.0 V@ 1.0ms, vHBP was nonselective in all six patients and aHBP remained selective in two patients. Pacing parameters remained stable at 3 months. CONCLUSION: The location of the TVA and tricuspid septal leaflet revealed by right ventriculography can be used as a landmark to identify the HBP site.

Left bundle branch pacing from distal His-bundle region by tricuspid valve annulus angiography.

A 78-year-old man presenting with amaurosis was admitted to the outpatient clinic 1 week ago. His baseline electrocardiogram showed Mobitz type II atrioventricular block and right bundle branch block. The patient's heart rate from Holter was only 32 bpm and therefore the indication for pacemaker implantation.

Electrocardiographic characteristics of distal His bundle pacing in a patient with left bundle branch block.

This case demonstrates the feasibility of placing the pacing lead helix at the His bundle distal to the region of left bundle branch block and reveals three types of electrocardiographic characteristics of distal His bundle pacing during correction of left bundle branch block in a patient. As the pacing lead helix was placed distal to the block, left bundle branch block correction was achieved by pacing with a low and stable capture threshold.

The Orally Active Noncompetitive AMPAR Antagonist Perampanel Attenuates Focal Cerebral Ischemia Injury in Rats.

Inhibition of ionotropic glutamate receptors (iGluRs) is a potential target of therapy for ischemic stroke. Perampanel is a potent noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor (AMPAR) antagonist with good oral bioavailability and favorable pharmacokinetic properties. Here, we investigated the potential protective effects of perampanel against focal cerebral ischemia in a middle cerebral artery occlusion (MCAO) model in rats. Oral administration with perampanel significantly reduced MCAO-induced brain edema, brain infarct volume, and neuronal apoptosis. These protective effects were associated with improved functional outcomes, as measured by foot-fault test, adhesive removal test, and modified neurological severity score (mNSS) test. Importantly, perampanel was effective even when the administration was delayed to 1 h after reperfusion. The results of enzyme-linked immunosorbent assay (ELISA) showed that perampanel significantly decreased the expression of pro-inflammatory cytokines IL-1ß and TNF-α, whereas it increased the levels of anti-inflammatory cytokines IL-10 and TGF-ß1 after MCAO. In addition, perampanel treatment markedly decreased the expression of inducible nitric oxide synthase (iNOS) and neuronal nitric oxide synthase (nNOS), and also inhibited nitric oxide (NO) generation in MCAO-injured rats at 24 and 72 h after reperfusion. In conclusion, this study demonstrated that the orally active AMPAR antagonist perampanel protects against experimental ischemic stroke via regulating inflammatory cytokines and NOS pathways.