Potential drug targets for gastroesophageal reflux disease and Barrett's esophagus identified through Mendelian randomization analysis.

Gastroesophageal reflux disease (GERD) is a prevalent chronic ailment, and present therapeutic approaches are not always effective. This study aimed to find new drug targets for GERD and Barrett's esophagus (BE). We obtained genetic instruments for GERD, BE, and 2004 plasma proteins from recently published genome-wide association studies (GWAS), and Mendelian randomization (MR) was employed to explore potential drug targets. We further winnowed down MR-prioritized proteins through replication, reverse causality testing, colocalization analysis, phenotype scanning, and Phenome-wide MR. Furthermore, we constructed a protein-protein interaction network, unveiling potential associations among candidate proteins. Simultaneously, we acquired mRNA expression quantitative trait loci (eQTL) data from another GWAS encompassing four different tissues to identify additional drug targets. Meanwhile, we searched drug databases to evaluate these targets. Under Bonferroni correction (P < 4.8 × 10-5), we identified 11 plasma proteins significantly associated with GERD. Among these, 7 are protective proteins (MSP, GPX1, ERBB3, BT3A3, ANTR2, CCM2, and DECR2), while 4 are detrimental proteins (TMEM106B, DUSP13, C1-INH, and LINGO1). Ultimately, C1-INH and DECR2 successfully passed the screening process and exhibited similar directional causal effects on BE. Further analysis of eQTLs highlighted 4 potential drug targets, including EDEM3, PBX3, MEIS1-AS3, and NME7. The search of drug databases further supported our conclusions. Our study indicated that the plasma proteins C1-INH and DECR2, along with 4 genes (EDEM3, PBX3, MEIS1-AS3, and NME7), may represent potential drug targets for GERD and BE, warranting further investigation.

Eliciting α7-nAChR exerts cardioprotective effects on ischemic cardiomyopathy via activation of AMPK signalling.

Our previous studies have reported that agonist of α7 nicotinic acetylcholine receptors prevented electrophysiological dysfunction of rats with ischaemic cardiomyopathy (ICM) by eliciting the cholinergic anti-inflammatory pathway (CAP). Adenosine monophosphate-activated protein kinase (AMPK) signalling is widely recognized exerting cardioprotective effect in various cardiomyopathy. Here, we aimed to investigate whether the protective effects of the CAP are associated with AMPK signalling in ICM. In vivo, coronary artery of rats was ligated for 4 weeks to induce the ICM and then treated with PNU-282987 (CAP agonist) and BML-275 dihydrochloride (AMPK antagonist) for 4 weeks. In vitro, primary macrophages harvested from rats were induced inflammation by Lipopolysaccharide (LPS) treatment and then treated with PNU-282987 and BML-275 dihydrochloride. In vivo, exciting CAP by PUN-282987 elicited an activation of AMPK signalling, alleviated ventricular remodeling, modified the cardiac electrophysiological function, reduced the cardiac expression of collagens and inflammatory cytokines and maintained the integrity of ultrastructure in the ischemic heart. However, the benefits of CAP excitation were blunted by AMPK signaling antagonization. In vitro, excitation of the CAP was observed inhibiting the nuclear transfer of NF-κB p65 of macrophages and promoting the transformation of Ly-6Chigh macrophages into Ly-6Clow macrophages. However, inhibiting AMPK signalling by BML-275 dihydrochloride reversed the CAP effect on LPS-treated macrophages. Finally, our findings suggest that eliciting the CAP modulates the inflammatory response in ICM through regulating AMPK signalling.

Common and distinctive electrocardiographic characteristics and effective catheter ablation of idiopathic ventricular arrhythmias originating from different areas of ventricular septum adjacent to atrioventricular annulus.

OBJECTIVE: To investigate electrocardiographic (ECG) characteristics and radiofrequency catheter ablation (RFCA) efficacy for premature ventricular complexes (PVCs) and idiopathic ventricular tachycardias (IVTs) originating from ventricular septum areas adjacent to atrioventricular annulus (VS-AVA). METHODS: Among 1,505 consecutive PVCs/IVTs cases, 106 (7.04%) were confirmed as origin of VS-AVA guided by both fluoroscopy and three-dimensional mapping system during RFCA. Characteristics of surface 12-lead ECG were analyzed. RESULTS: The overall success rate for RFCA of PVCs/IVTs originating from VS-AVA was 82.08% (87/106), common ECG characteristics were: mainly positive R wave on lead I; dominant-positive R on aVL (91/106, 85.85%) for most, r (1/106, 0.94%) or qr (14/106, 13.21%) in few; QS or qs on aVR; and decreasing R wave amplitude and increasing S wave depth on II, III, and aVF from superior to inferior septum; and S wave on at least one inferior lead (generally III). Distinctive ECG features were: precordial transition zone before or after V2 for septum adjacent to mitral (MA, 19/19, 100.0%) or tricuspid (TA, 74/87,85.05%) annulus origin; initial r wave and rS on V1 for superior septum near TA (above His bundle) origin (9/10, 90.0%) with no initial r wave for most other origins; and QS on V1 for mid-inferior septum near TA origin (73/77, 94.81%) and QR (Qr, qR or qr) on V1 for septum near MA origin (17/19, 89.47%). CONCLUSION: Distinctive ECG characteristics of PVCs/IVTs originating from VS-AVA aid in origin localization guiding effective RFCA.

Comparing safety and efficacy: MemoLefort versus watchman for left atrial appendage closure.

BACKGROUND: The MemoLefort is a new plug occluder for left atrial appendage closure (LAAC) in patients with atrial fibrillation (AF). This study compares the safety and efficacy of MemoLefort and the well-established Watchman occluder for LAAC. METHODS: Between January 2021 and September 2022, a cohort of 189 consecutive patients who underwent LAAC with MemoLefort or Watchman at The Second Affiliated Hospital of Wenzhou Medical University were included. Patients with MemoLefort or Watchman devices were compared in terms of the primary safety endpoints encompassing major periprocedural complications and major bleeding events at follow-up, the primary efficacy endpoint of all-cause stroke, systemic embolism and cardiovascular/unexplained death, and the combined hazard endpoint, a composite of all the above-mentioned hazards. RESULTS: Of the MemoLefort group (n = 83) and Watchman group (n = 106), the mean age, CHA2DS2-VASc score, and HAS-BLED score were 67.6 ± 9.2 vs. 69.0 ± 10.6 years, 3.9 ± 1.9 vs. 3.8 ± 1.9, and 1.6 ± 1.0 vs. 1.7 ± 1.2, respectively. After a median follow-up duration of 198 (99-329) vs. 334 (171-497) days, the primary endpoints of efficacy [2/49, 4.1% (MemoLefort) vs. 2/97, 2.1% (Watchman); hazard ratio (HR), 1.50; 95% confidence interval (CI), 0.20-11.08; P = 0.68] and safety (1/49, 2.0% vs. 5/97, 5.2%; HR, 0.26; 95% CI, 0.05-1.31; P = 0.19), as well as the combined hazard endpoint (3/49, 61% vs. 6/97, 6.2%; HR, 0.70; 95% CI, 0.18-2.58; P = 0.59) were similar between groups. CONCLUSIONS: In the short term, LAAC with MemoLefort provided similar efficacy, safety, and net clinical benefit in comparison to Watchman devices.

Twice-daily rivaroxaban after percutaneous left atrial appendage closure for atrial fibrillation.

Background and aim: Rivaroxaban is an emerging oral anticoagulant for postoperative anticoagulation after percutaneous left atrial appendage closure (LAAC). Because a once-daily dosing regimen of rivaroxaban causes fluctuations in the drug plasma concentration, we studied the feasibility and safety of twice-daily rivaroxaban as a postoperative anticoagulation regimen for patients with atrial fibrillation (AF) undergoing LAAC. Methods: This study involved patients with AF who underwent LAAC and took rivaroxaban postoperatively. A total of 326 patients who received a standard total dose (15 or 20 mg) of rivaroxaban based on their creatinine clearance rate were divided into the twice-daily (BID) rivaroxaban group (n = 208) and once-daily (QD) rivaroxaban group (n = 118) according to their anticoagulation strategy. Transesophageal echocardiography was recommended at 3-6 months postoperatively to check for device-related thrombosis (DRT). Clinical outcomes were evaluated during postoperative anticoagulation. Results: The median CHA2DS2-VASc score (4 [3, 5] vs. 4 [3, 5], p = 0.28) and HAS-BLED score (2 [2, 3] vs. 2 [2, 3], p = 0.48) were not significantly different between the groups. During the anticoagulation period (4.1 ± 0.7 vs. 4.1 ± 0.9 months, p = 0.58), 148 (71.2%) patients in the BID group and 75 (63.6%) in the QD group underwent follow-up transesophageal echocardiography. There were no statistically significant differences between the two groups in terms of DRT (1.4% vs. 2.7%, p = 0.60), minor bleeding (8.2% vs. 11.0%, p = 0.39), thromboembolic events (1.0% vs. 0.8%, p = 1.00), major bleeding (0.5% vs. 0.8%, p = 1.00), or death. Conclusion: A short course of twice-daily rivaroxaban following LAAC is a feasible alternative regimen with a low rate of major bleeding events, DRT, and thromboembolic events for patients with AF.

Ivabradine inhibits the production of proinflammatory cytokines and inducible nitric oxide synthase in acute coxsackievirus B3-induced myocarditis.

The role of ß-adrenergic stimulation on viral myocarditis has been investigated in animal models. The beneficial action of the ß-blocker carvedilol in murine viral myocarditis can be explained partly by the resulting heart rate reduction and the inhibition of proinflammatory cytokine production. The modulation of myocardial necrosis and contractile dysfunction by proinflammatory cytokines may be partially mediated by the production of nitric oxide (NO). The selective I(f) current inhibitor ivabradine reduces the heart rate without affecting cardiac contractility and has been shown to be cardioprotective in failing hearts. However, little is known about the effects of ivabradine in viral myocarditis, and in particular, its effects on inducible NO synthase (iNOS) have not been investigated. This study was therefore designed to examine the effects of ivabradine in murine viral myocarditis. In a coxsackievirus B3 murine myocarditis model, the effects of ivabradine and carvedilol on the myocardial histopathological changes and fibrosis, NO production, iNOS protein and cytokine levels were studied. Both ivabradine and carvedilol similarlyattenuated myocardial lesions and fibrosis, inhibited NO synthesis by iNOS, and decreased the production of TNF-α and IL-6. These results show that ivabradine has a therapeutic benefit in murine CVB3-induced myocarditis. The beneficial effects of ivabradine in viral myocarditis are partially mediated by the inhibition of both the production of proinflammatory cytokines and the synthesis of NO by iNOS.

Intravenous Contrast Material Administration at High-pitch Dual-source CT Coronary Angiography: Bolus-tracking Technique with Shortened Time of Respiratory Instruction Versus Test Bolus Technique.

Objective To investigate the feasibility of acquiring the similar homogeneous enhancement using bolus-tracking techniques with shortened respiratory time in prospectively electrocardiogram-gated high-pitch spiral acquisition mode (Flash mode) coronary computed tomography angiography (CCTA) compared with test bolus technique. Methods One hundred and eighty-four consecutive patients with mean heart rate ≤65 beats per minute undergoing CCTA were prospectively included in this study. The patients were randomly divided into two groups. Patients in the group A (n=92) instructed to shorten respiratory time received CCTA using bolus-tracking technique with high-pitch spiral acquisition mode (Flash mode), while those in the group B (n=92) underwent CCTA with test bolus technique. The attenuation in the ascending aorta, image noise, contrast-to-noise ratio and radiation doses of the two groups were assessed. Results There were no significant differences in the mean attenuation values in the ascending aorta (483.18±59.07 HU vs. 498.7±83.51 HU, P=0.183), image noise (21.4±4.5 HU vs. 20.9±4.3 HU, P=0.414), contrast-to-noise ratio (12.1±4.2 vs. 13.8±5.1, P=0.31) between the groups A and B. There were no significant differences in the radiation dose of dynamic monitoring scans (0.056±0.026 mSv vs. 0.062±0.018 mSv, P=0.068) and radiation dose of angiography (0.94±0.07 mSv vs. 0.96±0.15 mSv, P=0.926) between the two groups, while 15 mL less contrast material volume was administered in the group A than the group B. Conclusion Bolus-tracking technique with shortened time of respiratory in Flash mode of dual-source CT yields the similar homogeneous enhancement with less contrast material in comparison to the test bolus technique.

Excessive Dietary Salt Intake Exacerbates Cognitive Impairment Progression and Increases Dementia Risk in Older Adults.

OBJECTIVES: To investigate excessive dietary salt intake as an independent risk factor of cognitive impairment and dementia in older adults. DESIGN: Prospective, population-based cohort study. SETTINGS AND PARTICIPANTS: Two thousand forty-one community residents aged ≥60 years were recruited between April 2007 and August 2009 from the Shandong area of China. MEASUREMENTS: Participants were classified into low, mild, moderate, and high salt intake groups according to urinary sodium measurements for 7 consecutive days. Global cognitive function was assessed at baseline and biennially thereafter using the Mini Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Dementia Rating Scale (DRS), and Informant Questionnaire on Cognitive Decline in the Elderly. Demographics and apolipoprotein E (APOE) genotype were also obtained for each participant. Participants were monitored for 11.4 ± 2.0 years. RESULTS: During follow-up, MMSE, MoCA, and DRS scores decreased progressively faster with increasing salt intake (Padjustment < 0.05 among all intake groups). In total, 319 participants (13.74 per 1000 person-years) developed cognitive impairment. Compared with the low salt intake group, cognitive impairment risk was increased by 75% in the mild group (Padjustment = 0.027), 180% in the moderate group (Padjustment < 0.001), and 330% in the high group (Padjustment < 0.001) after adjustment for age, education, mean, and variability in visit-to-visit systolic and diastolic blood pressure, and APOE genotype. The hazard ratio for cognitive impairment increased by 1.59 (95% CI 1.40-1.79) with each 1-SD increment in salt intake after confounder adjustment (Padjustment < 0.001). CONCLUSIONS AND IMPLICATIONS: Excessive dietary salt impairs cognitive function and increases cognitive impairment risk in older adults independently of known risk factors, including hypertension and APOE genotype.

Electrocardiogram features of premature ventricular contractions/ventricular tachycardia originating from the left ventricular outflow tract and the treatment outcome of radiofrequency catheter ablation.

BACKGROUND: Radiofrequency catheter ablation (RFCA) has been used for the ablation of premature ventricular contractions (PVCs) or ventricular tachycardia (VT). To date, the mapping and catheter ablation of the arrhythmias originating from the left ventricular outflow tract (LVOT) has not been specified. This study investigates the electrocardiogram (ECG) feature of PVCs or VT originating from the LVOT. Moreover, the treatment outcome of RFCA is analyzed. METHODS: Mapping and ablation were performed on the supravalvular or subvalvular aorta in 52 cases with PVCs/VT originating from the LVOT. The data were compared with those from 104 patients with PVCs/VT originating from the right ventricular outflow tract (RVOT). A differential procedure was prepared based on the comparison of the ECG features of PVCs/VT originating from the RVOT, LVOT, and their different parts. RESULTS: Among 52 cases with PVCs originating from the LVOT, 47 were successfully treated by RFCA, with a success rate of 90.38%. Several differences among the 12-lead ECG features were observed from the RVOT and LVOT in the left and right coronary sinus groups, as well as under the left coronary sinus group (left fibrous trigone): (1) If the precordial leads transition 0 are considered as the diagnostic parameters of PVCs/VT originating from the LVOT, then the sensitivity, specificity, as well as positive and negative predictive values are 94.12%, 93.00%, 87.27%, and 96.88%, respectively; (2) The analysis of different subgroups of the LVOT are as follows: (a) A mainly positive wave of r or m pattern was recorded in the lead I in 72.73% of patients in the right coronary sinus group, versus 12.90% of patients in the left coronary sinus group, and 0% in the under left coronary sinus group. (b) All patients in the right coronary sinus group presented waves of RII>RIII and QSaVR>QSaVL, whereas most patients in the other two groups showed waves of RIII>RII and QSaVL>QSaVR. (c) Most patients in the under left coronary sinus group in lead V1 had a mainly positive wave (R) (77.78%), whereas those in the right (81.82%) and left (62.50%) coronary sinus groups had mainly negative waves (rS). CONCLUSIONS: RFCA is a safe and effective curative therapy for PVCs/VT originating from the LVOT. The 12-lead ECG features of the LVOT from different origins exhibit certain distinctions.

Ablation of atrioventricular nodal reentrant tachycardia in a patient with reversal of slow and fast pathways inputs into the atrioventricular node.

We report a case of atrioventricular nodal reentrant tachycardia (AVNRT) coexistent with His bundle anomaly and atrial septal defects. The His-bundle potential was recorded at the coronary sinus (CS) ostium. Fractionated atrial potentials and an A:V electrogram ratio 1:3 were recorded at the anterior septum of the tricuspid annulus approximately 2 cm from CS ostium. Radiofrequency catheter ablation at the anterior septum of the tricuspid annulus effectively eliminated AVNRT.

Excessive Visit-to-Visit Small and Dense Low-Density Lipoproteins Elevate Cerebral Small Vessel Disease Progression Risk in the Elderly.

Objective: Small and dense low-density lipoprotein (sdLDL) elevation may be among the most sensitive early biomarkers for nascent cardiovascular disease. This study, therefore, investigated the association between visit-to-visit changes in sdLDL and cerebral small vessel disease (CSVD) progression in older individuals, and the influence of Apolipoprotein E (APOE) genotype on this association. Methods: Between April 2007 and July 2009, 1,143 participants ≥60 years old were recruited from the Shandong region of China, and sdLDL was measured at baseline and at each follow-up visit. White matter hyperintensities (WMHs), lacunes, microbleeds, and enlarged perivascular spaces (EPVSs) were assessed by magnetic resonance imaging. The APOE genotype was determined and participants were stratified as ε4-positive or ε4-negative. Results: During an average follow-up of 86.0 months, 225 participants (19.7%) developed WMH progression, 193 (16.9%) lacune progression, 170 (14.9%) microbleed progression, and 185 (16.2%) EPVS progression. Compared with patients in the first (lowest) tertile of visit-to-visit mean sdLDL, those in the second and third tertiles demonstrated significantly greater risks of WMH progression (53.5 and 105.3% higher), lacune progression (53.3 and 60.8%), microbleed progression (47.2 and 127.6%), and EPVS progression (54.0 and 135.0%) after adjustment for confounders (all adjusted P values for trends <0.001). Compared with patients in the first tertile of visit-to-visit sdLDL SD, those in the second and third tertiles also demonstrated significantly greater risks of WMH progression (49.9% and 143.6%), lacune progression (75.3 and 178.0%), microbleed progression (12.7 and 64.7%), and EPVS progression (41.7 and 114.6%) after adjustment (all P < 0.001). There were significant and positive visit-to-visit mean sdLDL × visit-to-visit sdLDL SD, visit-to-visit mean sdLD×ε4-positive, visit-to-visit sdLDL SD×ε4-positive, and visit-to-visit mean sdLDL×visit-to-visit sdLDL SD×ε4-positive interactions influencing CSVD progression after confounder adjustment (all P < 0.05). Conclusion: Large and variable visit-to-visit changes in sdLDL are independent predictors of aggressive CSVD progression, and this association is strongly influenced by APOE ε4 allele genotype.

Low shear stress inhibits endothelial mitophagy via caveolin-1/miR-7-5p/SQSTM1 signaling pathway.

BACKGROUND AND AIMS: Mitophagy plays a crucial role in mitochondrial homeostasis and is closely associated with endothelial function. However, the mechanism underlying low blood flow shear stress (SS), detrimental cellular stress, regulating endothelial mitophagy is unclear. This study aimed to investigate whether low SS inhibits endothelial mitophagy via caveolin-1 (Cav-1)/miR-7-5p/Sequestosome 1 (SQSTM1) signaling pathway. METHODS: Low SS in vivo modeling was induced using a perivascular SS modifier implanted in the carotid artery of mice. In vitro modeling, low and physiological SS (4 and 15 dyn/cm2, respectively) were exerted on human aortic endothelial cells using a parallel plate chamber system. RESULTS: Compared with physiological SS, low SS significantly inhibited endothelial mitophagy shown by down-regulation of SQSTM1, PINK1, Parkin, and LC 3II expressions. Deficient mitophagy deteriorated mitochondrial dynamics shown by up-regulation of Mfn1 and Fis1 expression and led to decreases in mitochondrial membrane potential. Cav-1 plays a bridging role in the process of low SS inhibiting mitophagy. The up-regulated miR-7-5p expression induced by low SS was suppressed after Cav-1 was silenced. The results of dual-luciferase reporter assays showed that miR-7-5p targeted inhibiting the SQSTM1 gene. Oxidative stress reaction shown by the elevation of reactive oxygen species and O2●- and endothelial dysfunction by the decrease in nitric oxide and the increase in macrophage chemoattractant protein-1 were associated with the low SS inhibiting endothelial mitophagy process. CONCLUSIONS: Cav-1/miR-7-5p/SQSTM1 signaling pathway was the mechanism underlying low SS inhibiting endothelial mitophagy that involves mitochondrial homeostasis impairment and endothelial dysfunction.

Overcoming High Impedance in the Transitional Area of the Distal Great Cardiac Vein during Radiofrequency Catheter Ablation of Ventricular Arrhythmia.

(1) Background: Radiofrequency catheter ablation (RFCA) is an essential treatment for ventricular arrhythmia (VA). However, high impedance in the transitional area of the distal great cardiac vein (TAODGCV) often leads to ablation failure. This study aimed to explore the factors influencing impedance and identify effective ways to reduce impedance. (2) Methods: A total of 156 patients with VA arising from the TAODGCV received RFCA therapy at our center from October 2009 to August 2021 and were retrospectively analyzed. Local impedance variation during RFCA was monitored, recorded, and analyzed. (3) Results: The impedance increased from the proximal to distal portions of the TAODGCV and decreased by increasing the saline flow rate at the same site. To overcome high impedance, we implemented the following strategies: (1) Reset the upper limit impedance to 300 Ω and accelerate the saline flow rate to 60 mL/min (effective in 118 of 144 patients); (2) turn off the upper limit impedance (effective in eleven of 21 patients); (3) use high-flow-rate irrigation devices (effective in five of 15 patients); and (4) increase the upper limit temperature (effective in six of ten patients). (4) Conclusions: In the TAODGCV, local impedance is mainly influenced by the target site location and saline flow rate. We concluded several methods to overcome the high impedance and contribute to a successful ablation.

Combined atrial fibrillation ablation and left atrial appendage closure: Watchman vs. LAmbre devices.

Background: Left atrial appendage closure (LAAC) combined with radiofrequency catheter ablation is an emerging one-stop hybrid procedure for non-valvular atrial fibrillation (AF). This study was performed to compare the efficacy and safety of the Watchman device vs. the LAmbre device for this combined procedure. Methods: Two hundred and thirty two patients with AF who underwent the combined procedure were enrolled and divided into two subgroups depending on the device choice: the Watchman-combined group (n = 118) and the LAmbre-combined group (n = 114). The periprocedural and follow-up adverse events in both groups were documented. Results: The mean CHA2DS2-VASc score and HAS-BLED score in the Watchman-combined group and LAmbre-combined group were 3.7 ± 1.5 vs. 3.8 ± 1.5 and 2.5 ± 1.1 vs. 2.3 ± 1.1, respectively (all P > 0.05). Successful LAAC was achieved in all patients. The rate of major periprocedural complications and AF recurrence at 6 months post-procedure were similar between the Watchman-combined group and LAmbre-combined group (0.8 vs. 0.9%, P = 1.00; 22.0 vs. 15.8%, P = 0.23). During 2.6 ±0 .7 vs.1.6 ± 1.6 years follow-up, the rate of major clinical adverse events, including stroke and major bleeding, were comparable between the Watchman-combined group and the LAmbre-combined group (2.6 vs. 1.1% per 100 patient-years, P = 0.33). The intraprocedural peri-device leakage (PDL) rate was similar between the Watchman-combined group and the LAmbre-combined group (5.1 vs. 6.1%, P = 0.73), but the PDL rate was significantly higher at 3-6 months transesophageal echocardiography (TEE) follow-up than the intraprocedural PDL rate in both groups (21.6 vs. 5.1%; 36.6 vs. 6.1%, respectively), with a more obvious increase in minimal PDL rate in the LAmbre-combined group than the Watchman-combined group (36.6 vs. 21.6%, P < 0.05). Conclusion: The Watchman and LAmbre devices were comparable in efficacy and safety for the combined procedure. The minimal PDL rate at short-term TEE follow-up was higher in the LAmbre-combined group than the Watchman-combined group.

Percutaneous left atrial appendage closure using the LAmbre device in patients with atrial fibrillation and left atrial appendage thrombus.

Background: Left atrial appendage closure (LAAC) is considered a valid alternative for the prevention of thromboembolic stroke in patients with persistent left atrial appendage thrombus (LAAT) despite adequate anticoagulation. However, the data on LAAC using the LAmbre device for patients with LAAT is limited. This study was performed to explore efficacy and safety as well as to share the experience of the modified LAAC procedure with the LAmbre device. Materials and methods: A total of 7 patients with persistent LAAT despite adequate anticoagulation underwent modified LAAC with the LAmbre device between November 2019 and April 2022. Transesophageal echocardiography was performed 3 months postoperatively to detect device-related thrombosis and peridevice leak. The patients' clinical events were evaluated during the perioperative and follow-up periods. Results: The median age, CHA2DS2-VASc score, and HAS-BLED score of all patients were 71 [53-73], 3 [2-4], and 2 [2-3], respectively. In the procedure, a cerebral protection system was used in two patients. LAAC with the LAmbre device was successfully performed in all patients without perioperative events. During the median follow-up of 383 [325-865] days, postoperative transesophageal echocardiography was performed in six (85.7%) patients. Device-related thrombosis was detected in one (16.7%) patient, and no significant peridevice leak was observed. No thromboembolic event or bleeding event occurred in any patients. Conclusion: LAAC with the LAmbre device is effective and safe when performed by experienced operators in highly selected patients with LAAT after adequate anticoagulation.

COVID-19-related myocarditis and cholinergic anti-inflammatory pathways.

Coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2, is currently in a pandemic outbreak and has become a global health issue. In addition to the primarily involvement of the respiratory system, myocarditis is considered an important and fatal lesion in patients with COVID-19. However, effective therapeutic methods are currently lacking. The cholinergic anti-inflammatory pathway (CAP) has been demonstrated to suppress pro-inflammatory cytokine production and control inflammation in sepsis and other medical conditions. Therefore, the CAP may be a potential and effective therapeutic method for COVID-19-related myocarditis. This article reviews the relationship between COVID-19-related myocarditis and the CAP and discusses the CAP as a potential therapeutic modality in the treatment of COVID-19-related myocarditis.

Effects of early intensive blood pressure-lowering treatment on the growth of hematoma and perihematomal edema in acute intracerebral hemorrhage: the Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT).

BACKGROUND AND PURPOSE: The Intensive Blood Pressure Reduction In Acute Cerebral Haemorrhage Trial (INTERACT) study suggests that early intensive blood pressure (BP) lowering can attenuate hematoma growth at 24 hours after intracerebral hemorrhage. The present analyses aimed to determine the effects of treatment on hematoma and perihematomal edema over 72 hours. METHODS: INTERACT included 404 patients with CT-confirmed intracerebral hemorrhage, elevated systolic BP (150 to 220 mm Hg), and capacity to start BP-lowering treatment within 6 hours of intracerebral hemorrhage. Patients were randomly assigned to an intensive (target systolic BP 140 mmHg) or standard guideline-based management of BP (target systolic BP 180 mm Hg) using routine intravenous agents. Baseline and repeat CTs (24 and 72 hours) were performed using standardized techniques with digital images analyzed centrally. Outcomes were increases in hematoma and perihematomal edema volumes over 72 hours. RESULTS: Overall, 296 patients had all 3 CT scans available for the hematoma and 270 for the edema analyses. Mean systolic BP was 11.7 mm Hg lower in the intensive group than in the guideline group during 1 to 24 hours. Adjusted mean absolute increases in hematoma volumes (mL) at 24 and 72 hours were 2.40 and 0.15 in the guideline group compared with -0.74 and -2.31 in the intensive group, respectively, an overall difference of 2.80 (95% CI, 1.04 to 4.56; P=0.002). Adjusted mean absolute increases in edema volumes (mL) at 24 and 72 hours were 6.27 and 10.02 in the guideline group compared with 4.19 and 7.34 in the intensive group, respectively, for an overall difference of 2.38 (95% CI, -0.45 to 5.22; P=0.10). CONCLUSIONS: Early intensive BP-lowering treatment attenuated hematoma growth over 72 hours in intracerebral hemorrhage. There were no appreciable effects on perihematomal edema.

MG-132 attenuates cardiac deterioration of viral myocarditis via AMPK pathway.

BACKGROUND: Coxsackievirus B3 (CVB3) is the primary cause of infectious myocarditis. Aggressive immunological activation and apoptosis of myocytes contributes to progressive dysfunction of cardiac contraction and poor prognosis. MG-132, a proteasome inhibitor, regulates mitochondrial-mediated intrinsic myocardial apoptosis and downregulates NF-κB-mediated inflammation. Here, we determined whether AMPK pathway participates in MG-132-mediated myocardial protection in viral-induced myocarditis. METHODS AND RESULTS: Acute viral myocarditis models were established by intraperitoneal inoculation of CVB3 in male BALB/c mice. Myocarditis and age-matched control mice were administered MG-132 and/or BML-275 dihydrochloride (BML) (AMPK antagonist) intraperitoneally daily from the day following CVB3 inoculation. MG-132 improved hemodynamics and inhibited the structural remodeling of the ventricle in mice with myocarditis, while BML largely blunted these effects. TUNEL staining and immunochemistry suggested that MG-132 exerts anti-apoptotic and anti-inflammatory effects against CVB3-induced myocardial injuries. BML attenuated the effects of MG-132 on anti-apoptosis and anti-inflammation. CONCLUSION: MG-132 modulated apoptosis and inflammation, improved hemodynamics, and inhibited the structural remodeling of ventricles in a myocarditis mouse model via regulation of the AMPK signal pathway.

An electrocardiographic sign of idiopathic ventricular tachycardia ablatable from the distal great cardiac vein.

BACKGROUND: Idiopathic ventricular arrhythmias (IVAs) can originate from the distal great cardiac vein (DGCV). However, inadequate distinction sometimes occurs when electrocardiographic (ECG) characteristics are used to distinguish ventricular arrhythmias (VAs) arising from the DGCV from those arising from the adjacent left ventricular endocardium (LV ENDO). OBJECTIVE: The purpose of this study was to identify distinct ECG features in patients with idiopathic IVAs originating from the DGCV. METHODS: A total of 32 patients with IVAs originating from the DGCV were identified from a consecutive group of 874 patients undergoing IVAs ablation. Patients with IVAs from the DGCV were compared with a consecutively chosen series of 40 patients with IVAs in whom the site of origin was the adjacent LV ENDO. RESULTS: Of the 32 patients with IVAs arising from the DGCV, 13 had distinct ECG characteristics compared with the LV ENDO group. Notches in both the upstroke and downstroke of the R wave in lead III were found in all 13 patients. However, the characteristic ECG pattern in lead III was found in 1 of 40 patients in the LV ENDO group. The ECG characteristic of both early notch and late notches in lead III has sensitivity of 40.6%, specificity of 97.5%, negative predictive value of 67.2%, and positive predictive value of 92.9% to predict VAs arising from the DGCV. CONCLUSION: The distinct ECG characteristics of VAs originating from the DGCV can help differentiate from adjacent LV ENDO sites of origin.

Intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT): a randomised pilot trial.

BACKGROUND: There is much uncertainty about the effects of early lowering of elevated blood pressure (BP) after acute intracerebral haemorrhage (ICH). Our aim was to assess the safety and efficiency of this treatment, as a run-in phase to a larger trial. METHODS: Patients who had acute spontaneous ICH diagnosed by CT within 6 h of onset, elevated systolic BP (150-220 mm Hg), and no definite indication or contraindication to treatment were randomly assigned to early intensive lowering of BP (target systolic BP 140 mm Hg; n=203) or standard guideline-based management of BP (target systolic BP 180 mm Hg; n=201). The primary efficacy endpoint was proportional change in haematoma volume at 24 h; secondary efficacy outcomes included other measurements of haematoma volume. Safety and clinical outcomes were assessed for up to 90 days. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00226096. FINDINGS: Baseline characteristics of patients were similar between groups, but mean haematoma volumes were smaller in the guideline group (12.7 mL, SD 11.6) than in the intensive group (14.2 mL, SD 14.5). From randomisation to 1 h, mean systolic BP was 153 mm Hg in the intensive group and 167 mm Hg in the guideline group (difference 13.3 mm Hg, 95% CI 8.9-17.6 mm Hg; p<0.0001); from 1 h to 24 h, BP was 146 mm Hg in the intensive group and 157 mm Hg in the guideline group (10.8 mm Hg, 95% CI 7.7-13.9 mm Hg; p<0.0001). Mean proportional haematoma growth was 36.3% in the guideline group and 13.7% in the intensive group (difference 22.6%, 95% CI 0.6-44.5%; p=0.04) at 24 h. After adjustment for initial haematoma volume and time from onset to CT, median haematoma growth differed between the groups with p=0.06; the absolute difference in volume between groups was 1.7 mL (95% CI -0.5 to 3.9, p=0.13). Relative risk of haematoma growth >or=33% or >or=12.5 mL was 36% lower (95% CI 0-59%, p=0.05) in the intensive group than in the guideline group. The absolute risk reduction was 8% (95% CI -1.0 to 17%, p=0.05). Intensive BP-lowering treatment did not alter the risks of adverse events or secondary clinical outcomes at 90 days. INTERPRETATION: Early intensive BP-lowering treatment is clinically feasible, well tolerated, and seems to reduce haematoma growth in ICH. A large randomised trial is needed to define the effects on clinical outcomes across a broad range of patients with ICH. FUNDING: National Health and Medical Research Council of Australia.