Citations

Abstract Objective To assess the association of aPL and diffuse alveolar haemorrhage (DAH) in patients with SLE by performing a systematic review and meta-analysis. Methods Multiple databases were systematically searched from inception to February 2024. Studies were eligible if they included patients with SLE (population), reported aPL status (exposure), and DAH (outcome). We pooled the estimates as odds ratio (OR) using fixed-effect models. We examined the association between aPL and DAH, as well as associations based on aPL subtypes or concomitant APS. Results Out of 454 screened studies, nine were included in meta-analysis, encompassing 7746 patients with SLE, of whom 2016 (26.0%) were aPL-positive and 163 (2.1%) had DAH. Patients with SLE and positive aPL (any) were more likely to develop DAH than aPL-negative patients (OR = 1.76, 95% CI 1.24–2.49; I2 = 0%). Patients with SLE and positive LA (OR = 1.76, 95% CI 1.06–2.93, I2 = 35%) or positive anticardiolipin IgG (OR = 1.62, 95% CI 1.13–2.34, I2 = 0%) had a higher likelihood of developing DAH compared with patients that were negative for these aPL. An APS diagnosis was associated with a 2.5-fold increased likelihood of DAH compared with subjects without APS (OR = 2.46, 95% CI 1.23–4.92, I2 = 0%). Positivity of anti-β2 glycoprotein I IgG was not significantly associated with DAH among patients with SLE (OR = 0.78, 95% CI 0.45–1.36, I2 = 0%). Conclusion In patients with SLE, aPL positivity increases the risk of DAH compared with aPL-negative patients, particularly in those positive for LA and anticardiolipin IgG.

BACKGROUND: Patients with heart failure with preserved ejection fraction and obesity have significant disability and frequent exacerbations of heart failure. We hypothesized that tirzepatide, a long-acting agonist of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, would improve a comprehensive suite of clinical end points, including measures of health status, functional capacity, quality of life, exercise tolerance, patient well-being, and medication burden, in these patients. METHODS: We randomized (double-blind) 731 patients with class II to IV heart failure, ejection fraction ≥50%, and body mass index ≥30 kg/m 2 to tirzepatide (titrated up to 15 mg SC weekly; n=364) or placebo (n=367) added to background therapy for a median of 104 weeks (quartile 1, 66; quartile 3, 126 weeks). The primary end points were whether tirzepatide reduced the combined risk of cardiovascular death or worsening heart failure and improved Kansas City Cardiomyopathy Questionnaire Clinical Summary Score. The current expanded analysis included sensitivity analyses of the primary end points, 6-minute walk distance, EQ-5D-5L health state index, Patient Global Impression of Severity Overall Health score, New York Heart Association class, use of heart failure medications, and a hierarchical composite based on all-cause death, worsening heart failure, and 52-week changes in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score and 6-minute walk distance. RESULTS: Patients were 65.2±10.7 years of age; 53.8% (n=393) were female; body mass index was 38.2±6.7 kg/m 2 ; Kansas City Cardiomyopathy Questionnaire Clinical Summary Score was 53.5±18.5; 6-minute walk distance was 302.8±81.7 m; and 53% (n=388) had a worsening heart failure event in the previous 12 months. Compared with placebo, tirzepatide produced a consistent beneficial effect across all composites of death and worsening heart failure events, analyzed as time to first event (hazard ratios, 0.41–0.67). At 52 weeks, tirzepatide increased the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score by 6.9 points (95% CI, 3.3–10.6; P <0.001), 6-minute walk distance 18.3 meters (95% CI, 9.9–26.7; P <0.001), and EQ-5D-5L 0.06 (95% CI, 0.03–0.09; P <0.001). The tirzepatide group shifted to a more favorable Patient Global Impression of Severity Overall Health score (proportional odds ratio, 1.99 [95% CI, 1.44–2.76]) and New York Heart Association class (proportional odds ratio, 2.26 [95% CI, 1.54–3.31]; both P <0.001) and required fewer heart failure medications ( P =0.015). The broad spectrum of effects was reflected in benefits on the hierarchical composite (win ratio, 1.63 [95% CI, 1.17–2.28]; P =0.004). CONCLUSIONS: Tirzepatide produced a comprehensive, meaningful improvement in heart failure across multiple complementary domains; enhanced health status, quality of life, functional capacity, exercise tolerance, and well-being; and reduced symptoms and medication burden in patients with heart failure with preserved ejection fraction and obesity. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04847557.

Abstract Background Nicotinamide adenosine dinucleotide phosphate oxidases (NOX) play important roles in mediating stress-induced depression. Three NOX isotypes are expressed mainly in the brain: NOX2, NOX3 and NOX4. In this study, the expression and cellular sources of these NOX isoforms was investigated in the context of stress-induced depression. Methods Chronic restraint stress (CRS)-induced depressive-like behaviour and cognitive deficits were evaluated by tail suspension tests, forced swimming tests and the Morris water maze test. Hippocampal NOX expression was determined by immunofluorescence staining and western blotting. The hippocampal levels of the brain-derived neurotrophic factor (BDNF) mRNA were determined via quantitative real-time –polymerase chain reaction. Glucocorticoid levels in the hippocampus were measured using ELISA kits. Results In the mouse CRS model, a significant increase in NOX2 expression was observed in the hippocampus, whereas no significant changes in NOX3 and NOX4 expression were detected. Next, NOX2 expression was primarily localised to neurons (NeuN+) but not microglia (Iba-1+) or astrocytes (GFAP+). Treatment with gp91ds-tat, a specific NOX2 inhibitor, effectively mitigated the behavioural deficits induced by CRS. The decreased expression of the BDNF mRNA in the hippocampus of CRS mice was restored upon gp91ds-tat treatment. A positive correlation was identified between neuronal NOX2 expression and serum glucocorticoid levels. Conclusions Our study indicated that neuronal NOX2 may be a critical mediator of depression-like behaviours and spatial cognitive deficits in mice subjected to CRS. Blockade of NOX2 signalling may be a promising therapeutic strategy for depression.

Background: About 25% of patients with acute myocardial infarction complicated by cardiogenic shock (AMI-CS) have chronic total occlusion (CTO) at non-culprit artery. However, the prognostic impact of CTO in these patients is still unclear. Aims: We aimed to investigate the impact of CTO at non-culprit artery on 1-year mortality in patients with AMI-CS using the multicenter registry of cardiogenic shock. Methods: A total of 1,247 patients presented with cardiogenic shock (CS) were enrolled in the SMART-RESCUE registry between January 2014 and December 2018. After exclusion of non-ischemic cause shock, ischemic cardiomyopathy, failed or no revascularization, vasospasm, and patients undergoing coronary artery bypass surgery, 695 patients underwent percutaneous coronary intervention (PCI). Among these, we analyzed 536 patients with multivessel disease (MVD) according to the presence of CTO at non-culprit artery. The study endpoint was a 1-year all-cause mortality. We also examined the incidence of 1-year cardiac death, and in-hospital death or renal replacement therapy (RRT). Results: A 141 patients (26.3%) of study population had CTO lesion at non-culprit artery. The CTO group had more patients with diabetes mellitus, and lesser patients with ST-elevation myocardial infarction. Although initial left ventricular ejection fraction was lower in CTO group (28.5 vs. 34.1%, P=0.005), initial systolic blood pressure (73.8 vs. 73.2 mmHg, P=0.822) and the level of lactate (6.6 vs. 6.4 mmol/L, P=0.804) were similar in both groups. Venoarterial extracorporeal membrane oxygenation was applied in 206 patients (38.4%), and its use rate was comparable in 2 groups (40.4 vs. 37.7%, P=0.571). Pre- (32.9 vs. 22.9, P <0.001) and post-PCI SYNTAX score (16.7 vs. 5.3, P <0.001) was significantly higher in CTO group. In CTO group, 53 patients (37.6%) had CTO at left main or left anterior descending artery, and only 19 patients (13.5%) in CTO group received PCI for CTO. In multivariate analysis, all-cause mortality at 1-year was significantly higher in CTO group (51.8 vs. 40.5%, hazard ratio [HR] 1.44, 95% confidence interval [CI] 1.09-1.90, P=0.011). The incidences of 1-year cardiac death (45.4 vs. 32.4%, HR 1.55, 95% CI 1.15-2.10, P=0.004) and in-hospital death or RRT (46.8 vs. 36.5%, P=0.031) were also higher in CTO group. Conclusions: Non-culprit CTO lesion was associated with higher 1-year mortality in patients with AMI-CS and multivessel disease.

Heart disease continues to be the leading cause of death globally, even with the development and implementation of numerous pharmacological and surgical treatments. Transplanting cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CMs) shows potential for repairing heart damage. However, tracking and quantifying these cells after transplantation in large animals remains challenging. This study aimed to develop a hiPSC line that overexpresses ferritin heavy chain (FHC) to enable tracking of transplanted hiPSC-CMs via magnetic resonance imaging (MRI). Using the CRISPR/dCas9 activation system, we increased FHC expression in hiPSCs and hiPSC-CMs. Both mRNA and protein levels of FHC were significantly elevated following transfection. Cell viability was unaffected by iron chloride concentrations between 0 μM and 2000 μM. hiPSCs and hiPSC-CMs overexpressing FHC (hiPSC-FHC OE and hiPSC-CM-FHC OE ) showed enhanced iron chloride uptake without changes in their electrophysiological properties compared to control hiPSC-CMs. Additionally, hiPSC-CM-FHCOE cells provided strong contrast and lower T 2 * values, indicating their effectiveness for cardiac MRI. When hiPSC-CM-FHCOE cells were injected into mouse hearts and imaged three days later, MRI revealed distinct signals from these cells with lower T 2 * values and rapid signal decay. Overall, endogenous FHC labeling in hiPSC-CMs could significantly improve the precision of cardiac MRI, marking a crucial advancement in assessing the success of hiPSC-CM transplantation in large animal models and enhancing cardiac regenerative therapies.

Background: Pulsed field ablation (PFA) is an innovative modality for treating arrhythmias that is mostly non-thermal and renders myocardial tissue non-viable by creating pores in cardiac cell membranes. The impact of contact force (CF) on PFA efficacy is not well characterized. Hypothesis: We hypothesize that, while contact is necessary for PFA, increasing CF will not have a significant effect on in vivo ablation lesion size. Aim: We seek to investigate the effects of CF on acute PFA lesions in a beating porcine heart model. Methods: The ventricles of 7 porcine animals were ablated in vivo with PFA (500V, at 20μs for 50 pulses separated by 200ms) using a focal bipolar irrigated ablation catheter and BTX 830 electroporation generator (Harvard Apparatus). CF was measured before and after each PFA application using CARTO 3. Lesions were divided into standard CF (5-15g), high CF (16-30g), and very high CF (>31g). Results: A total of 46 lesions were analyzed. Gross pathology showed no significant difference in maximum width, lesion depth, and lesion volume between the three groups ( Figure 1A-B ). Linear regression showed a decrease of 0.003 mm in depth (depth = -0.003 × CF + 1.8, R = 0.05), an increase of 0.01 mm in width (width = 0.01 × CF + 5.7, R = 0.09), and a decrease of 0.05 mm 3 in volume (volume = -0.05 × CF + 26.8, R = 0.03) for each additional gram of CF ( Figure 1C ). Conclusion: While contact is necessary, increasing CF did not have a significant effect on in-vivo PFA lesion dimensions in a beating porcine heart model.

Background: Pulsed field ablation (PFA) has emerged as an innovative technology for treating cardiac arrhythmias. PFA increases cell permeability, which can lead to apoptosis. Greater PFA energy may be necessary to ablate ventricular myocardium for ventricular tachycardia circuits, but this carries risks of side effects such as gaseous formation (microbubbles) and hemolysis. Ethanol (EtOH) infusion has been used to ablate pathologic myocardial tissues in hypertrophic cardiomyopathy and for refractory arrhythmias. Hypothesis: We hypothesize that PFA in the ventricle can increase EtOH uptake through PFA-generated pores, thereby enhancing ablation efficacy, even at low powers, by utilizing the cell permeability effects of PFA. Aim: The aim of this study is to investigate the effect of local EtOH infusion after PFA on lesion size in porcine ventricles. Methods: The ventricles of five porcine subjects were ablated in vivo with a PFA low power setting (750 V, at 20 μs for 50 pulses separated by 200 ms) using a focal bipolar irrigated ablation catheter and BTX 830 electroporation generator (Harvard Apparatus). After PFA was performed, 2 ml of 90 % EtOH vs. saline (control) was infused through the catheter tip to the site of ablation. We compared the electrograms voltage amplitude reduction before and after PFA, and the ablation lesion characteristics. Results: A total of 10 lesions in the control group and 9 lesions in the EtOH group were analyzed. For the controls, the voltage after PFA was not reduced. In contrast, for the EtOH group, the voltage after PFA was significantly reduced ( Figure 1A ). On gross pathology, there were significant differences in ablation lesion depths and volumes between the 2 lesion sets ( Figure 1A-B ). Conclusion: Local EtOH infusion after ventricular PFA enhanced acute efficacy of electroporation. Concurrent PFA with local EtOH infusion has the potential to improve efficacy without requiring higher energy parameters, thereby reducing PFA risks. Future studies on chronic efficacy are warranted.

Abstract The DNA damage response (DDR) and the blood tumor barrier (BTB) restrict chemotherapeutic success for primary brain tumors like glioblastoma (GBM). Coherently, GBM almost invariably relapse with fatal outcome. We here show that interaction of GBM and myeloid cells simultaneously induces chemoresistance on the genetic and the vascular level by activating GP130 receptor signaling, which can be addressed therapeutically. We performed transcriptomic and immunohistochemical screens with human brain material, pharmacological experiments with a humanized organotypic GBM model, proteomics and cell-based assays and observed that nanomolar concentrations of the signaling peptide Humanin promoted TMZ resistance through DDR activation. GBM mouse models recapitulating intratumoral Humanin-release showed accelerated BTB formation. Genetic analysis of pericyte to endothelial cell signaling in transgenic mice revealed increased GP130 activation in Humanin releasing tumors as compared to controls. GP130 blockade attenuated both DDR activity and BTB formation resulting in improved preclinical chemotherapeutic efficacy. Altogether, we describe an overarching mechanism for TMZ resistance and outline a translatable strategy with predictive markers to improve chemotherapy for GBM.