Risultati per: Probiotici: in vivo vs in vitro

Circulation, Volume 150, Issue Suppl_1, Page A4145424-A4145424, November 12, 2024. Introduction:Dual therapy with clopidogrel and an anticoagulant has become the standard of care for patients on long-term anticoagulation following PCI. However, the impact of initial triple therapy and the selection of optimal P2Y12 inhibitor on ischemic and bleeding events is ambiguous during the first 30 days after PCI.Aim:Explore prescribing patterns and outcomes of patients discharged on dual therapy versus triple therapy post PCI.Methods:We performed a retrospective chart review of all patients receiving PCI at a single institution over a 12-month time frame who were discharged on an anticoagulant. The exposure variable was type of therapy (dual vs. triple) prescribed at discharge as well as anticoagulants and P2Y12 inhibitors prescribed. The outcome was any 30-day event defined as death, stent thrombosis, major bleeding events, and composites of ischemic and bleeding events. Differences were explored using Fisher’s exact test due to the low number of types of events.Results:The study included 124 patients. 41% patients were treated with immediate dual therapy, and 59% were discharged on triple therapy. A greater proportion of patients undergoing non-elective PCI received triple combination therapy (58% vs 31%; P=0.004; Table 1). There was no statistically significant difference in death or composite outcomes between groups (Table 2). Two stent thrombosis events occurred, both in patients receiving dual antithrombotic therapy with clopidogrel (P=0.09). No stent thrombosis events occurred in patients initially started on triple therapy or in patients receiving dual therapy utilizing a more potent P2Y12 inhibitor. Four major bleeding events were noted in patients on triple therapy, and 1 major bleeding event occurred in a patient on dual therapy (P=0.31; Table 2).Conclusion:In this retrospective analysis of patients, a trend toward higher albeit not statistically significant 30-day stent thrombosis event rate was noted in patients started on dual therapy using clopidogrel for P2Y12 inhibition. These findings should be cautiously interpreted, and analysis is ongoing in a larger dataset to better define the relationship between type of therapy and ischemic and bleeding events.

Circulation, Volume 150, Issue Suppl_1, Page A4141050-A4141050, November 12, 2024. Background:Elucidating key mechanisms of cardiac contraction/relaxation can lead to new treatments for heart failure. Intact papillary muscles produce maximum force at much lower [Ca2+] than de-membraned cardiac tissue and show [Ca2+] to force hysteresis relationship. We then hypothesize that cross-bridge (CB) attachments sustain force generation independent of [Ca2+] after [Ca2+] enabling as a key driver of contraction.Methods:We acquired transgenic mouse model with cardiac myocyte specific endogenous fluorescent calcium sensor GCaMP8. GCaMP8 is green fluorescent protein coupled with calmodulin. We made a novel system using commercial parts and in-house software that can quantify GCaMP8-[Ca2+] fluorescence ofin vivobeating heart. We then made simultaneous intra-cardiac pressure and [Ca2+] measurements ofin vivobeating hearts.Results:By echocardiography, GCaMP8 hearts demonstrated similar size, reduced left ventricular ejection fraction, slowed maximal myocardial contraction velocity S, similar maximal myocardial relaxation velocity e’, and similar E/e’ ratio in comparison to WT. Thus, GCaMP8 hearts have depressed systolic function but preserved diastolic function. Western blotting did not show any expression differences in SERCA2a or phospholamban. Simultaneous intracardiac pressure and [Ca2+] measurements showed peak [Ca2+] occurring well before peak pressure. Normalizing delay to adjust for different heart rates, peak pressure occurs at 19%±3%SD delay from peak [Ca2+] of heart-beat duration, p

Circulation, Volume 150, Issue Suppl_1, Page A4145037-A4145037, November 12, 2024. Background and Purpose:Heart failure is associated with renal dysfunction suggesting a pathophysiological link between heart and kidney. Empagliflozin, a SGLT2 inhibitor, showed beneficial effects on both cardiovascular and renal endpoints. However, mechanistically, it is unclear if empagliflozin-dependent kidney protection is mediated via inhibition of tubular SGLT2 or more indirectly via improved cardiac function.We hypothesized that Empagliflozin treatment improves left ventricular ejection fraction (LVEF) and thereby renal function in patients and mice independent of renal SGLT2 inhibition.Methods:We evaluated LVEF and GFR in our patients with HF with reduced (n=32) and preserved ejection fraction (n=59) after 30 and 180 days (prospective, single-arm CINNAMON-study, DRKS00031101). Furthermore, we conducted transverse aortic constriction (TAC) in C57BL/6J (wildtype, WT) and SGLT2 deficient mice (SGLT2-KO). Animals received either Empagliflozin (10 mg/kg bw) or vehicle. Cardiac function was evaluated by echocardiography and kidney function by FITC-Sinistrin measurement (GFR).Results:Empagliflozin treatment improved LVEF in patients with reduced LVEF whereas in patients with preserved LVEF (Fig. A, B) there was no change in LVEF (Fig. C). Interestingly, only in patients with LVEF < 40% there was a parallel improvement in GFR (Fig. D, E), whereas in patients with LVEF > 40% we only observed the well-known transient drop of GFR (Fig. F).In mice after 10 weeks, echocardiography confirmed TAC induced pressure-overload, leading to reduced LVEF, which was attenuated by EMPA (Fig. G). Interestingly, at 10 weeks, TAC also reduced GFR, which was prevented by EMPA (Fig. H). To test if direct inhibition of SGLT2 is mechanistically involved, TAC surgery was repeated in SGLT2-deficient mice (SGLT2-KO). In fact, exposure to TAC resulted in comparable reduction of LVEF in SGLT2-KO and EMPA prevented this deterioration similar to WT mice (Fig. G vs. I). Surprisingly, EMPA also prevented GFR deterioration 10 weeks after TAC in SGLT2-KO mice with comparable magnitude as in WT mice (Fig. J), suggesting that the reno-protective effect of Empagliflozin was independent from SGLT2 inhibition.Conclusion and Outlook:This is the first study investigating the role of SGLT2 in Empagliflozin-dependent kidney protection in patients and of mice with heart failure. Importantly, Empagliflozin treatment prevented deterioration of LVEF and GFR independent of the presence of SGLT2.

Circulation, Volume 150, Issue Suppl_1, Page A4135869-A4135869, November 12, 2024. 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 ablatedin vivowith 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.

Circulation, Volume 150, Issue Suppl_1, Page A4121148-A4121148, November 12, 2024. Background:Cardiomyocyte maturation is a crucial process that involves intricate molecular and structural changes necessary for more vigorous and efficient heart function after birth. Understanding the regulatory mechanisms of this process is essential for leveraging these insights to develop advanced therapies for heart disease. Despite recent advancements, the limitations of currentin vivogenetic and single-cell approaches – such as the low throughput ofin vivogenetics, lack of spatial information in single-cell RNA-seq, and, most importantly, the lack of high-throughput combined use of both approaches – hinder the construction of a comprehensive regulatory network of cardiomyocyte maturation.Methods:Here, we established an experimental pipeline combining time-course single-nucleus RNA sequencing and spatial transcriptomics with our optimizedin vivoPerturb-seq platform to establish the regulatory network underlying heart maturation.Results:Our current study has generated a postnatal murine heart atlas with 67,000 nuclei from postnatal heart. Temporal analysis of the cardiomyocyte transcriptome dynamics identifies Ankrd1+ cardiomyocyte as a transient state between proliferative and matured cardiomyocytes. We constructed a regulatory network consisting of 35 known and novel regulators for cardiomyocyte maturation. Our analysis of postnatal cardiomyocyte interactome elucidated signaling pathways’ stage-specific contribution to cardiomyocyte maturation. With the spatial transcriptomic data, we further identified signaling pathways that played unique roles in the maturation of chamber-specific cardiomyocytes. Using fixed RNAin vivoPerturb-seq established in this study, we have validated 21 novel regulators of postnatal cardiomyocyte maturation out of 53 candidate regulators from previous temporal and spatial analyses.Conclusions:We have not only created a single-cell-resolution temporal and spatial atlas during postnatal heart development but also established anin vivoPerturb-seq platform to allow the functional interrogation of key regulatory genes in a physiologically relevant context. Importantly, the proposed working model unlocks new possibilities for research, no longer limiting to a single gene or pathway, but allowing for the exploration of a network of genes. This high-resolution, high-throughputin vivomapping and screening platform has the potential to revolutionize the way we study organogenesis and disease progression in the heart.

Circulation, Volume 150, Issue Suppl_1, Page A4138601-A4138601, November 12, 2024. Background:Antiplatelets are important in ischemic heart disease(IHD) patients. We aim to research the efficacy and safety of single(SAPT), dual(DAPT), and triple(TAPT) antiplatelet approaches in IHD patients undergoing PCI.Methods:A systematic review was conducted until April 1st, 2024, and a network meta-analysis using the Netmeta package in R studio 4.3.3 was performed. Primary outcomes were cardiac death, myocardial infarction(MI), stent thrombosis, stroke, and major bleeding(BARC 3-5). A sensitivity analysis was done to explain variables with high heterogeneity.Results:From 25 studies, a total of 65115 patients were included in the analysis. For cardiac death, 17 studies showed TAPT had a lower risk than DAPT compared to SAPT [RR = 0.74; 95%CI (0.40 to 1.35); p-value = 0.33], [RR = 1.01, 95%CI (0.84 to 1.19); p-value = 0.87] respectively. The heterogeneity was insignificant(I2=0%; p-value=0.58. For MI, 23 studies found TAPT had a lower risk than DAPT compared to SAPT [RR = 0.77; 95%CI (0.51 to 1.16); p-value = 0.2047], [RR = 0.81, 95%CI (0.64 to 1.03); p-value = 0.0850] respectively. The heterogeneity was significant (I2 = 53%). For stent thrombosis, 17 studies showed DAPT had a lower risk than TAPT compared to SAPT [RR = 0.74; 95%CI (0.45 to 1.21); p-value = 0.2284], [RR = 0.84, 95%CI (0.27 to 2.59); p-value = 0.7630] respectively. The heterogeneity in this comparison was significant. For stroke, 17 studies showed DAPT had a lower risk than TAPT for stroke in comparison to SAPT [RR = 0.91; 95%CI (0.75 to 1.10); p-value = 0.3209], and [RR = 0.87, 95%CI (0.43 to 1.76); p-value=0.6937], respectively. The heterogeneity was insignificant(I2=0%; p-value=0.8165). For Major bleeding(BARC 3-5), 15 studies showed DAPT had a lower risk than TAPT in comparison to SAPT[RR = 1.43; 95%CI (1.09 to 1.88); p-value = 0.0107], [RR = 2.78, 95%CI (0.90 to 4.78); p-value = 0.0852] respectively. The heterogeneity was significant(I2 = 49.5%).Conclusion:Personalized treatment approaches that consider the benefits and risks of different antiplatelet strategies are crucial for optimal patient management of IHD.

Circulation, Volume 150, Issue Suppl_1, Page A4142309-A4142309, November 12, 2024. Background:Myocardial infarction (MI) initiates an injury response that triggers fibroblast to myofibroblast cell transition and pathological fibrosis, a substrate for arrhythmogenesis. However, there are no methods to image in-vivo development of fibrosis continuously in the murine model other than cardiac MRI which is costly and time-consuming.Objectives:We aimed to develop a novel 3D method to track myofibroblast activity in the heartin vivoand correlate with electrophysiological changes using optical mapping.Methods:Mice with the alpha-Smooth Muscle Actin (α-SMA) promoter for expression of the red fluorescent protein DsRed were used to label myofibroblasts. MI was induced by left anterior descending artery ligation in α-SMA-RFP (n=4) and control C57BL/6 mice (n=5). RFP fluorescence was monitored over time using a PerkinElmer® In Vivo Imaging System (IVIS) before and after MI. 3D IVIS imaging with micro-computed tomography (CT) of 3D cardiac structure was then performed. Ex-vivo heart imaging of RFP followed by 3D panoramic optical mapping of electrical activation via Di-4-ANEPPS was performed and action potential duration (APD) maps generated.Results:After MI α-SMA-RFP mice demonstrate strong myofibroblast RFP signal localized above the heart on IVIS imaging at varying time points from 9 days to 3 months after MI. Myofibroblast RFP signal is not present before MI, and is also absent in control C57 mice. Ex-vivo imaging of hearts confirms myofibroblast RFP signal correlates with the site of infarction as well as increased APD. In α-SMA-RFP mice myofibroblast RFP intensity at the fibrotic infarct site is significantly greater than non-infarcted sites (mean difference 52.9 ± 13.2, p = 0.0088). Control C57 hearts do not demonstrate preferential RFP signal at infarct sites (mean difference -3.28 ± 2.99, p = 0.29). Furthermore, 3D IVIS imaging with CT co-registration demonstrates the localization of RFP signal in space near the heart.Conclusion:IVIS imaging of α-SMA-RFP is able to track myofibroblast activity in living mice up to three months after MI, and can be combined with optical mapping to study electrophysiology (APD, phase, activation maps). This novel approach can offer a method to monitor myofibroblast dynamics in disease states and test treatments that reduce the pathologic myofibroblast persistence that leads to fibrosis, scarring and arrhythmogenesis.

Circulation, Volume 150, Issue Suppl_1, Page A4136181-A4136181, November 12, 2024. Background:The sympathetic nervous system (SNS) is a critical regulator of cardiovascular function. Whereas acute SNS activation elicits positive inotropy and confers survival advantage, persistent SNS hyperactivity is maladaptive and can lead to arrhythmias, cardiac arrest and heart failure.Hypothesis:Automated optogenetic modulation of the sympathetic stress responsein vivoenhances neurocardiac function while avoiding sympathetic hyperactivity-mediated pathological effects.Methods:In normal guinea pigs, we virally transduced excitatory and/or inhibitory channelrhodopsins to the stellate ganglia (SG), the primary sympathetic input to the heart. We studiedin situeffects of graded activation of SG opsins (e.g., phasic vs tonic) on cardiac function (e.g., ECG, heart rate) with and without perfusing agents (e.g., β-blockers, antioxidants).In vivostudies used novel implanted µLED devices for wireless body signal streaming (e.g., ECG) and neurophotonic SG opsin modulation closed-loop to dynamic analyses of physiological demand versus ECG-based cardiac risk prediction.Results:Compared to baseline heart rate (218±16 bpm), pulsed activation of inhibitory opsins reduced heart rate by ~25% (156±12; delta=67±14 bpm; p

Circulation, Volume 150, Issue Suppl_1, Page A4144103-A4144103, November 12, 2024. Introduction:microRNAs (miRs) are small single stranded RNAs capable of targeting expression of several genes. Circulating miRs can be important biomarkers of disease progression. Children with dilated cardiomyopathy (DCM) experience multiple outcomes including recovered-normalization, stable disease, and progression to death/ need for transplant. We hypothesized that circulating miRs are differentially expressed among these cohorts and may serve as useful prognostic biomarkers in pediatric DCM patients.Methods:RNA-sequencing was used to detect and quantify circulating miRs. Samples were collected within 3 months of a new diagnosis of DCM. Inclusion criteria included

Circulation, Volume 150, Issue Suppl_1, Page A4144727-A4144727, November 12, 2024. Introduction:Dilated cardiomyopathy (DCM) is a common cardiomyopathy characterized by ventricular dilatation and systolic dysfunction. The TNNT2-R141W mutation is known to cause DCM in both humans and mice and is associated with Ca2+desensitization and reduced contractility. However, there are no reports of utilizing patient-derived induced pluripotent stem cells (iPSCs) carrying the TNNT2-R141W mutation, looking at functional improvement after gene replacement. Here, we describe the characteristics of TNNT2-R141W mutant iPSC-derived cardiomyocytes (iPSC-CMs)in vitro.Methods:Two human iPSC lines were derived from pediatric DCM patient samples, with the TNNT2-R141W mutation (R141W-iPSC), and a R141W-iPSC derived TNNT2 overexpression line (TNNT2-OE iPSC) for comparison. The Ca2+handling and sarcomere structures of the differentiated hiPSC-CMs were then assessed.Results:In TNNT2-OE iPSC-CMs, the expression level ofTNNT2was significantly higher than R141W-iPSC-CMs. Evaluation of Ca2+handling revealed that R141W-iPSC-CMs exhibited a significant decrease in maximum fluorescence intensity (amplitude) and a prolongation of time to maximum fluorescence intensity (time to peak), which are characteristic of failing heart tissue (Figure 1a, b, and c). Ca2+reuptake efficacy during relaxation, measured by Ca2+decay tau, or the time taken for an 80% signal reduction, was also significantly prolonged in R141W-iPSC-CMs (Figure 1d). In addition, R141W-iPSC-CMs displayed abnormality in sarcomere alignment (Figure 2). These properties were corrected in TNNT2-OE iPSC-CMs, indicating that R141W-iPSC-CMs reflect DCM phenotypesin vitro.Conclusions:R141W-iPSC-CMs exhibited Ca2+desensitization and abnormal sarcomere structure, further suggesting that gene therapy with normal TNNT2 may be a future therapeutic approach for DCM with TNNT2 mutations.

Circulation, Volume 150, Issue Suppl_1, Page A4139258-A4139258, November 12, 2024. Introduction:Antiplatelet therapy plays a significant role in the management of patients with coronary artery disease (CAD) to prevent cardiovascular events. Current guidelines recommend 6-12 months of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) followed by either aspirin or clopidogrel monotherapy indefinitely. Previous meta-analyses have suggested a potential superiority of clopidogrel over aspirin. However, given the evolving landscape of cardiovascular medicine, there is a need for updated evidence to inform clinical practice.Hypothesis:This systematic review and meta-analysis, to our knowledge the most up-to-date, aims to compare the effectiveness and safety of aspirin versus clopidogrel as monotherapy in patients with coronary artery disease (CAD).Methods:We searched PubMed, Embase, and Cochrane Library databases for relevant randomized controlled trials (RCTs) and Non (RCTs) Studies published up to April 2024. The primary outcomes were Major Adverse Cardiovascular and Cerebrovascular Events, myocardial infarction, stroke, and Death, while secondary outcomes included major bleeding events, target vessel revascularization, repeated revascularization, and stent thrombosis. heterogeneity analysis, and pooled analysis conducted by RevMan 5.3 software.Results:A total of eleven (11) studies involving 26324 patients, of whom 11435 (43.4%) received clopidogrel met the inclusion criteria. Mean follow-up was 12-36 months. Duration of DAPT before antiplatelet monotherapy was 1-18 months. The meta-analysis revealed a significant reduction with Clopidogrel monotherapy in all the following compared to Aspirin monotherapy; myocardial infarction [ 0.77 -95%CI -(0.64 – 0.93)], stroke [ 0.59 -95%CI- (0.48 – 0.74)], major bleeding events [ 0.66 -95%CI- (0.53 – 0.84)], and repeated revascularization [ 0.88 – 95% CI ( 0.77 – 0.99 )]. There was no significant difference in the risk of major adverse cardiovascular and cerebrovascular events, death and cardiac death.Conclusion:Clopidogrel monotherapy may be associated with a lower risk of major bleeding, MI, stroke and repeated revascularization compared to aspirin monotherapy in patients with CAD. This supports the use of clopidogrel over aspirin in patients with CAD who require secondary prevention with long-term antiplatelet monotherapy.

Circulation, Volume 150, Issue Suppl_1, Page A4144488-A4144488, November 12, 2024. Background:Oral anticoagulants (OAC) including Vitamin K antagonists such as warfarin and direct oral anticoagulants like Apixaban, Rivaroxaban, and Edoxaban, have long been the standard treatment for stroke prevention in patients with atrial fibrillation (AF). However, they increase the risk of bleeding, making them unsuitable for certain patient populations, particularly those with a personal history of bleeding, elderly individuals prone to falls or those with high-risk occupation with safety hazards. In cases of non-valvular AF, where thrombi typically form in the left atrial appendage, mechanical left atrial appendage closure (LAAC) has come out as an alternative for selected patients. Numerous studies have shown that LAAC is comparable to OAC in preventing strokes while significantly reducing major bleeding events. This meta-analysis aims to compare the 4–5-year outcomes of these two treatment strategies in non-valvular AF.Methods:4 studies (3 randomized controlled trials and 1 observational study) comparing the 4–5-year outcomes of LAAC versus OAC in patients with AF were included in this meta-analysis. These studies were identified after a thorough search of PUBMED, COCHRANE, and MEDLINE databases from inception till May 2024. The outcomes of interest were MACE (composite of stroke, embolism, and death), ischemic stroke, major bleeding episodes, cardiovascular (CV) deaths, and all-cause death. The results were reported as Risk Ratio (RR) with 95% confidence intervals (CI), using a random effects model.Results:6,012 patients were identified from the 4 studies. After a median follow-up of 4–5 years, LAAC was associated with a clinically significant reduction in MACE (RR: 0.76, 95% CI: 0.61-0.94, p=0.01), all-cause mortality (RR: 0.77, 95% CI: 0.62-0.96, p=0.02), and CV mortality (RR: 0.64, 95% CI: 0.45-0.90, p=0.01). Additionally, a significant reduction in major bleeding episodes (RR: 0.63, 95% CI: 0.44-0.91, p=0.01) was also noted between the two treatment strategies favoring LAAC treatment group. There was no significant difference in the incidence of ischemic stroke (RR: 1.07, 95% CI: 0.62-1.85, p=0.80) between the two groups.Conclusion:Over a median follow-up of 4-5 years, LAAC was found to be as effective as OAC in preventing ischemic strokes, while also showing lower incidence of MACE, all-cause, CV mortality and major bleeding episodes. More RCTs are needed to further assess the long-term outcomes between the two strategies.

Circulation, Volume 150, Issue Suppl_1, Page A4137688-A4137688, November 12, 2024. Introduction:Endotrophin, a collagen type VI–derived signaling peptide, has been linked to cardiac metabolic dysregulation, inflammation, and fibrosis. Several matrix metalloproteinases (MMPs), incl. MMP2 and MMP9, have been shown to cleave collagen 6A3 and release endotrophin. Baseline plasma endotrophin levels in heart failure with preserved ejection fraction (HFpEF) patients were shown to be strongly and independently associated with increased risk of poor outcomes (death or HF-admissions).VS-041 is a novel drug candidate for HFpEF that inhibits key MMPs implicated in cardiac fibrosis and diastolic dysfunction. Previously, VS-041 demonstrated robust efficacy in the Dahl Salt Sensitive rat model of hypertension and HFpEF, improving diastolic function and dose-proportionally reducing left ventricle (LV) fibrosis.Hypothesis:Inhibition of endotrophin release by VS-041 could contribute to its anti-fibrotic mechanism and serve as a potential biomarker of MMP inhibition (target engagement) in patients.Methods and Results:The effect of VS-041 on production of endotrophin was investigated in a “Scar-in-a-Jar” model using primary human cardiac fibroblasts isolated from adult healthy ventricles. Fibroblasts were treated with 10 ng/mL platelet-derived growth factor (PDGF) AB in the presence of 0.03, 0.3, or 3 µM VS-041, or DMSO control. The concentration of endotrophin in the medium was assessed via the ELISA nordicPRO-C6TM(Nordic Bioscience A/S). After 4 days of treatment, VS-041 at 0.3 µM and 3 µM significantly inhibited PDGF AB-stimulated production of endotrophin. Cumulative inhibitory effects of VS-041 could still be observed after 12 days of culture. The antifibrotic activity of VS-041 was also tested in a model of extensive cardiac fibrosis in 16-months old C57BL/6 mice exacerbated by angiotensin II infusion at 1 mg/kg/day for 28 days. Oral treatment with VS-041 at 75 mg/kg BID resulted in a 62% reduction (p

Circulation, Volume 150, Issue Suppl_1, Page A4138076-A4138076, November 12, 2024. Background&Objective:Recurrent stroke is a common event following a previous transient ischemic attack (TIA) or minor to moderate ischemic stroke. Dual antiplatelet therapy (DAPT) with clopidogrel and aspirin may provide greater protection against subsequent stroke than aspirin monotherapy. We aim to study the effects on using DAPT vs. aspirin alone in patients with TIAs or mild to moderate ischemic strokes within 72 hours of symptoms.Methods:We conducted a meta-analysis synthesizing randomized controlled trials (RCTs), which were retrieved by searching PubMed, EMBASE, Web of Science, SCOPUS, and Cochran. We used mean difference (MD) to pool continuous outcomes presented and the risk ratio (RR) for the dichotomous outcomes, with the corresponding 95% confidence interval (CI).Results:We included seven RCTs with a total of 20,992 patients. DAPT was more effective in reducing combined ischemic and hemorrhagic strokes recurrence (RR = 0.77, 95% CI (0.70, 0.84), P < 0.00001)Fig-A, ischemic strokes (RR = 0.74, 95% CI (0.67, 0.82), P < 0.00001)Fig-B, early neurologic deterioration (RR= 0.46, 95% CI (0.24, 0.88), P = 0.04)Fig-C, poor functional outcome (RR = 0.89, 95% CI (0.81, 0.98), P = 0.02)Fig-D, and composite of ischemic stroke, myocardial infarction, death from ischemic vascular causes, and major hemorrhage [RR = 0.80, 95% CI (0.73, 0.88), P < 0.00001]Fig-E. However, DAPT led to more bleeding events occurrence (RR = 1.74, 95% CI (1.23, 2.48), P = 0.002)Fig-F.Conclusion:DAPT is a viable option for stroke recurrence prevention, leading to better functional outcomes, and less early neurologic deterioration; however, it increases the overall bleeding.

Circulation, Volume 150, Issue Suppl_1, Page A4142913-A4142913, November 12, 2024. Background:NSTEMI accounts for the majority of the in-hospital MI. However, whether differences exist between in-hospital NSTEMI patients referred to cardiology and those who are not remains unclear.AimsThis study aims to compare the characteristics and prognosis of in-hospital NSTEMI patients referred to cardiology with those who are not.Methods:Data for this study were obtained from a retrospective cohort comprising patients from 72 hospitals between 2010 and 2023. Patients who developed NSTEMI during hospitalization were identified and classified into the referral and the non-referral group based on whether they were referred to cardiology. The primary endpoint was Major Adverse Cardiovascular and Cerebrovascular Events (MACCE), comprising cardiovascular death(CD), recurrent MI, stroke, and repeat revascularization at 1 year. The secondary endpoints were in-hospital all-cause mortality, 1-year all-cause mortality, CD, and Net Adverse Clinical Events (NACE), including CD, recurrent MI, BARC≥3 bleeding events, and repeat revascularization. Kaplan-Meier curves were used to depict survival between the two groups. A multivariable Cox regression model, adjusted for age, sex, Killip classification, and medical history, was utilized to analyze the association between referral and 1-year outcomes. Additionally, multivariate logistic regression analysis was employed to examine the factors related to in-hospital mortality.Results:The study included 6218 patients were in the non-referral group (mean age 73 years, 43.4% women) and 1260 in the cardiology referral group (mean age 70.8 years, 43.4% women). The non-referral group was less likely to take antiplatelet drugs, statins, or undergoing PCI (p

Circulation, Volume 150, Issue Suppl_1, Page A4141344-A4141344, November 12, 2024. Background:Leadless pacemakers offer a safe and effective alternative pacing strategy, crucial for patients with end-stage renal disease (ESRD) overcoming vascular access isues. However, there is limited data available on their use in this population.Methods:We utilized the Nationwide Readmission Database to extract data on all adult patients with ESRD who received either traditional transvenous or leadless pacemaker implantation from 2016 to 2021. We then compared in-hospital mortality, in-hospital complications, healthcare resource utilization, and 30-day readmission rates between these two groups.Results:A total of 6,384 patients (81.2%) were included in the transvenous pacemaker cohort, while 1,481 patients (18.8%) were in the leadless pacemaker cohort. In ESRD patients, leadless pacemaker implantation was associated with higher in-hospital complications compared to transvenous pacemakers, including cardiac complications (aOR 4.12, CI 1.70-9.98, p