Risultati per: Terapia antibiotica: breve durata vs. lunga durata

Circulation, Volume 150, Issue Suppl_1, Page A4146403-A4146403, November 12, 2024. Introduction:Anticoagulation therapy is crucial in enhancing perioperative outcomes, yet uncertainty persists regarding the optimal use of Direct Oral Anticoagulants (DOACs) and Vitamin K Antagonists (VKAs) in cardiovascular interventions. Key outcomes such as bleeding, thromboembolic events, and mortality are critical. Conducting a thorough review is essential to make well-informed decisions that improve patient quality of life and mitigate complications.Hypothesis:This meta-analysis aimed to investigate whether Direct Oral Anticoagulants (DOACs) reduce perioperative complications such as bleeding, thromboembolic events, and mortality compared to Vitamin K Antagonists (VKAs) in patients undergoing cardiovascular procedures.Methods:The present study was conducted in accordance with PRISMA guidelines. A systematic search was conducted in PubMed, MEDLINE, Scopus, Web of Science, Cochrane, and EMBASE databases on 05/14/2024. Data extraction was rigorously performed, and a random-effects model was used for data synthesis.Results:The review included 25 studies involving a total of 25,754 patients. For bleeding risk, the meta-analysis showed that DOACs are associated with a lower risk compared to VKAs, with a relative risk (RR) of 0.69 (95% CI: 0.51 to 0.94, p = 0.0457, I2= 60%). Thromboembolic events showed no significant difference between DOACs and VKAs (RR: 1.13, 95% CI: 0.74 to 1.73, p = 0.5313, I2= 15%). Mortality outcomes also showed no significant difference (RR: 0.53, 95% CI: 0.20 to 1.43, p = 0.1622, I2= 68%).Conclusion:The systematic review and meta-analysis demonstrate that DOACs are associated with a lower risk of bleeding compared to VKAs, with no significant difference in thromboembolic events and mortality. This evidence supports the substantial benefit of DOACs in cardiovascular interventions. Further research is needed to consolidate these findings and improve patient outcomes. PROSPERO registry— CRD42024547465

Circulation, Volume 150, Issue Suppl_1, Page A4146563-A4146563, November 12, 2024. Background:Secondary atrial fibrillation (AF) is triggered by acute illness and associated with adverse outcomes. Timely follow-up is recommended by the American Heart Association statement on acute AF.Hypotheses:Patients with secondary AF receive less follow-up and cardiac testing than those primarily hospitalized for AF (primary AF).Follow-up is lower for secondary AF patients hospitalized for noncardiac diagnoses.Methods:Population-based cohort study using linked administrative datasets of patients aged ≥66 yrs discharged alive after a new diagnosis of AF while hospitalized in Ontario between Apr 2013 – Mar 2019. Patients were classified as secondary or primary AF using a validated approach based on discharge diagnosis type and followed for 1yr. Outcomes included physician visits (family physicians [FP], internists, cardiologists), and cardiac testing (electrocardiograms [ECG], echocardiograms, ambulatory ECG monitoring). The cumulative incidence function was used to quantify the incidence of outcomes. Cause-specific hazards regression was used to estimate hazard ratios (HR) associated with hospitalization type in secondary AF patients. Regression analyses accounted for competing risks.Results:We studied 13,011 secondary AF (35.2% cardiac surgery, 9.6% cardiac medical, 17% noncardiac surgery, 38.1% noncardiac medical) and 11,065 primary AF patients. Secondary AF was associated with lower age, male sex, less heart failure, and greater prevalence of other comorbidities. Less than 50% of secondary AF patients had visits to internists, cardiologists, echocardiograms or ambulatory ECG monitoring (see Figure). The incidence of all outcomes was significantly lower for secondary than primary AF. Among secondary AF patients, specialist follow-up and cardiac testing rates were lowest after noncardiac diagnoses (see Table).Conclusion:Patients with secondary AF have less specialist follow-up and cardiac testing than primary AF, especially if hospitalized for noncardiac diagnoses.

Circulation, Volume 150, Issue Suppl_1, Page A4141390-A4141390, November 12, 2024. Background:Appropriate direct oral anticoagulants (DOAC) dosing could improve their safety and effectiveness. To address this, we developed an intervention to improve on-label dosing using academic detailing and a quality improvement intervention.Methods:This was a cluster RCT with clusters at the site level. There were 2 arms, academic detailing (AD) and AD plus Learn. Engage. Act. Process. (AD/LEAP).Interventions:Primary care doctors and anticoagulation pharmacists from all participating sites were invited to participate in academic detailing, a 1:1 educational and motivational coaching program, about ways to improve DOAC prescribing safely.Intervention arm sites were also invited to participate in LEAP, a quality improvement program based on plan-do-study-act cycles.Sites:8 VA medical centersInclusion criteria:All patients on DOACs at participating sites.Analysis:Generalized Estimating Equations with logit links and clusters at the facility level using aggregated proportion data. Models were weighted by the size of the denominator within each facility and longitudinal measurements were modeled with an autoregressive working correlation matrix. For difference-in-difference modeling, the 6-month pre- and post-period data were included and entered into the model as a fixed effect plus an interaction with the treatment arm.Outcomes:The primary outcome was the percentage of DOAC prescribing that was off-label, including under- and over-dosing for that individual and using for inappropriate indications.Results:Over the full length of the study, there were 34,127 patients on DOACs across the 8 sites. The percentage of prescriptions that met the primary outcome increased from 5.65 to 6.43 in the AD arm and from 5.9 to 6.43 in the AD+LEAP arm, yielding a difference-in-difference of -0.25 (95% CI -1.57- 1.06). An as-treated analysis, which dropped the two sites that did not finish their LEAP programs, also found no effect, as did sub-groups of impacts on patients whose reason for using DOACs was atrial fibrillation vs. thromboembolism.Discussion:A quality improvement intervention did not improve safe DOAC prescribing when added to an academic detailing intervention. We hypothesize the primary reason was insufficient engagement with the intervention.

Circulation, Volume 150, Issue Suppl_1, Page A4145901-A4145901, November 12, 2024. Introduction:Current guidelines recommend preprocedural fasting for at least 6 hours for solid food and 2 hours for clear liquids before cardiac transcatheter procedures. However, the supporting data are limited.Research Question:Does non-fasting impact (NF) patient safety and comfort compared to fasting (F) in transcatheter cardiac procedures?Aims:To compare the effects of fasting vs. non-fasting on patient outcomes in cardiac transcatheter procedures.Methods:We searched the Cochrane, Embase, and Medline databases for RCTs comparing fasting versus non-fasting states for cardiac transcatheter procedures. Risk ratios (RRs) and standardized mean difference (SMD) with 95% confidence intervals (CIs) were pooled for binary and continuous outcomes, respectively, using a random-effects model. Endpoints were hunger, thirst, incidence of aspiration, nausea/vomiting, acute kidney injury (AKI), length of stay, and patient satisfaction.Results:Our meta-analysis included 8 studies with 2,930 patients. Hunger sensation was significantly lower in the NF group (SMD -0.91; 95% CI: -1.71 to -0.11; P = 0.026; I2 = 96%; Figure 1A), with no difference in thirst. The incidence of aspiration (RR 2.20; 95% CI 0.29–17.02; P = 0.449; I2 = 0%; Figure 1B), nausea/vomiting (RR 1.09; 95% CI 0.67-1.78; P = 0.723; I2 = 0%), and AKI (RR 1.90; 95% CI 0.84–4.31; P = 0.126; I2 = 0%) were not significantly different between groups. Similarly, length of stay (MD -0.01 days; 95% CI -0.39 to 0.36; P = 0.940; I2 = 3%; Figure 2A), and patient satisfaction (SMD -0.74; 95% CI: -1.54 to -0.07; P = 0.073; I2 = 98%; Figure 2B) were also similar in both groups.Conclusions:Our study suggests a non-fasting strategy is a safe option before transcatheter cardiac procedures.

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

Circulation, Volume 150, Issue Suppl_1, Page A4143363-A4143363, November 12, 2024. Background:Various temporary mechanical circulatory support device (t-MCS) options are available for supporting patients in cardiogenic shock. While each device has a different physiological impact on the heart, limited studies compare genetic changes in the heart t-MCS. Here, we compare the impact of a percutaneous left ventricular assist device (pVAD) vs an Intra-aortic balloon pump (IABP) on miRNA expression of the left ventricle in patients being bridged to cardiac replacement.Hypothesis:Difference in genetic signature exists between patients treated with pVAD vs IABPMethods:Myocardial tissue was collected at the time of cardiac surgery from 4 patients bridged with a pVAD (Impella 5.5) and 4 bridged with IABP. Samples from each strategy of support were combined. Bulk sequencing was performed on an Illumina Hiseq 4000. Raw data was processed to identify unique sequences with lengths of 18-26 nucleotides and were mapped to miRBase to identify known and novel microRNAs (miRs).Results:The top upregulated (Fig. 1A) and downregulated (Fig. 1B) miRs had functionality related to endothelial pathology and cell transitions (miR 422,378 &92a, miR-653, miR-144). For example, miR 21 has been shown to represent a pathogenic state in cancer and cardiac disease and was found to be significantly lower in heart failure patients supported with pVAD when compared to patients supported with IABP. Gene set enrichment analysis of all the downregulated miRs was performed using miRNA enrichment analysis and annotation tool (miEAA). UpSet plots (Fig. 1C) of the downregulated miRs exhibited a regulatory role in inflammatory and cancer-based genes. KEGG enrichment analysis oftarget genesof the differentially expressed miRs exhibited that 1000 genes were associated with metabolic pathways (hsa01100), followed by 500 genes in cancer pathways (hsa05200) (Fig. 1D).Conclusion:Our results suggest that direct cardiac unloading using a p-VAD might have a better improvement of the pathological milieu of heart failure when compared to counter-pulsation unloading. The choice of t-MCS to support myocardial recovery might be important. Our future work will include a prospective study with temporal evaluation of patient’s blood for miRNA profiling.

Circulation, Volume 150, Issue Suppl_1, Page A4144137-A4144137, November 12, 2024. Background:The optimal management of angiotensin-converting enzyme (ACE) inhibitors during elective surgeries remains uncertain. While some studies suggest that continuing ACE inhibitors increase the risk of perioperative hypotension, others argue that discontinuation may heighten the risk of significant clinical events. This meta-analysis aims to clarify the clinical outcomes associated with continuation compared to discontinuation of ACE inhibitors in surgical settings.Methods:We conducted a systematic search of MEDLINE, Cochrane, and Embase for clinical trials comparing the effects of continuing versus discontinuing ACE inhibitors during surgery. Outcomes evaluated included death, stroke, myocardial injury (MI), intraoperative hypotension, postoperative hypotension, and acute kidney injury (AKI). Data were synthesized using odds ratios (OR) with 95% confidence intervals (CI). Heterogeneity was assessed with I2 statistics, and a random-effects model was applied. Statistical analyses were performed using R software version 4.3.2.Results:From 865 identified studies, 15 studies involving 11,519 patients met the inclusion criteria. Not all studies had outcomes available for comparison between them. The average age was 65.75 years, with 86.45% having hypertension and 13.13% with heart failure. Continuing ACE inhibitors was associated with a higher risk of intraoperative hypotension (OR 1.33; 95% CI 1.16-1.53). No significant differences were found between groups for mortality (OR 1.06; 95% CI 0.68-1.65), stroke (OR 0.99; 95% CI 0.47-2.09), MI (OR 0.98; 95% CI 0.72-1.31), postoperative hypotension (OR 1.27; 95% CI 0.74-2.17), and AKI (OR 0.88; 95% CI 0.66-1.16).Conclusion:Discontinuation of ACE inhibitors before non-cardiac surgery may lower the risk of intraoperative hypotension without significantly affecting mortality, stroke, MI, postoperative hypotension, or AKI. Further research with greater power and better design is needed to confirm these findings.

Circulation, Volume 150, Issue Suppl_1, Page A4137423-A4137423, November 12, 2024. Background:Elevated lipoprotein(a) [Lp(a)] is an inherited, currently non-modifiable risk marker that increases lifetime ASCVD risk. Guidance vary on Lp(a) levels at which risk increases; hence prevalence of “elevated” Lp(a) depends on putative thresholds e.g. >1.3 billion people globally have Lp(a)≥125 nmol/L. Lp(a) levels are >90% genetically determined and stable throughout life; hence measurement once in adulthood is recommended. Awareness of Lp(a) levels may change patient management with more intensive control of traditional risk factors. However, testing all adults is costly and the test is not universally available.Research Question:Can Machine Learning (ML) models reduce the number needed to screen (NNS) compared to population universal screening for identifying individuals with elevated Lp(a)?Aims&Objectives:To derive a model from ML to help prioritise individuals likely to have high levels for Lp(a) testing and compare its yield to universal screening at different Lp(a) cut-points. This approach could enable automatic screening of large databases like EHRs for Lp(a) testing.Method:We conducted a cross-sectional predictive analysis using UK Biobank, including individuals ≥40 years old with Lp(a) measurements, split into feature importance, derivation, and validation datasets. Eight ML classification algorithms were used for feature importance analysis and model derivation. Models’ performance was evaluated in the validation set using sensitivity and NNS in comparison with the discrimination ability of the following guidelines across different populations: The 2019’s Heart UK and European Atherosclerosis Society (EAS) and Society of Cardiology guidelines, the 2022 EAS Consensus Statement, and threshold used in clinical trial —respective cut-offs: 90,430,125,200nmol/L.Results:438,579 patients were included. The best ML models were neural networks with different weights. Regardless of the Lp(a) threshold used, ML models resulted in higher rates of high Lp(a) cases identified per million tests with lower NNS compared to universal screening (Table 1). Using higher Lp(a) thresholds (200-430nmol/L) increased models sensitivity with far fewer tests required to identify those with high Lp(a).Conclusion:ML models could reduce the number of tests needed to identify individuals with high Lp(a), increasing efficiency and potentially helping to prioritize Lp(a) testing, with a potentially scalable cost-effective option for health systems.Work supported by Novartis

Circulation, Volume 150, Issue Suppl_1, Page A4146376-A4146376, November 12, 2024. Background:Although observational studies have shown a higher rate of atrial arrhythmia recurrences in patients with atrial fibrillation (AF) undergoing delayed catheter ablation as compared with early ablation, a recent randomized controlled trial (RCT) did not show any such difference. We aimed to perform an updated meta-analysis of the available studies.Methods:Multiple online databases were searched for studies comparing early ablation (< 1 year) to delayed ablation ( > 1 year) in patients diagnosed with AF. The outcome of interest was atrial arrhythmia recurrence at the longest follow up available. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using a random-effects model.Results:A total of 8 studies (1 RCT and 7 observational) with 5,171 patients (early ablation n=1,636, delayed ablation n=3,535) were included. Around 70% patients were men, mean age was 61 years and mean duration of follow up was 28 months. Patients with AF undergoing early catheter ablation had a lower rate of atrial arrhythmia recurrence when compared with the delayed ablation group (OR 0.57, 95% CI 0.44 to 0.73, p < 0.0001). Substantial level of heterogeneity was present between the studies (I2 = 67%).Conclusion:Performing catheter ablation early (within 1 year of diagnosis) in patients with AF may lead to significant reduction in atrial arrhythmia recurrence as compared with delayed ablation. The results of this meta-analysis, however, are subject to potential bias and heterogeneity.

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 A4142661-A4142661, November 12, 2024. Introduction:Although ECG devices with non-conventional form factors, such as wearable patches, offer enhanced convenience and comfort for users, they can introduce variability in signal characteristics, posing challenges for clinicians and ECG analysis software. To ensure accuracy and support informed decision-making, ECG software must process even the most difficult signals effectively.Aims:To compare the signal characteristics of a standard lead II configuration with those of a modified lead II (MLII) patch configuration and to evaluate the differential impact of these configurations on the performance of ECG processing software.Methods:Five-minute ECGs were recorded on 43 adult participants (63% male, mean age: 34.5 ± 9.1 years) using Bittium Faros cardiac monitors in two configurations: i) standard Einthoven lead II with electrodes placed across the chest cavity, and ii) a MLII patch configuration with electrodes 10 cm apart on the upper left chest. Average QRS amplitudes for both configurations were compared, using a paired T-test to determine statistical significance. ECG signals were processed with HeartKey software, and the accuracy of QRS beat detection was calculated against manual annotations. Heart rate (HR) detection accuracy was assessed using Bland-Altman analysis.Results:The average QRS amplitude was significantly lower in the MLII patch configuration compared to the standard lead II configuration (2.3 ± 1.0 mV vs. 1.2 ± 0.7 mV,p99.1% and a mean positive predictive value of >99.9% across both configurations. HR detection accuracy was high across both configurations, with an absolute mean HR difference of 0.4 bpm (95% CI: -0.5 bpm to 1.3 bpm) for the standard lead II and 0.24 bpm (95% CI: -1.4 bpm to 1.9 bpm) for the MLII patch configuration.Conclusion(s):Despite the notable decrease in QRS amplitude with the MLII patch configuration compared to the standard Lead II configuration, HeartKey software maintained high accuracy in detecting QRS beats and analysing heart rate.

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 A4147894-A4147894, November 12, 2024. Background:Patients undergoing epicardial access for ventricular tachycardia (VT) have a higher rate of complications and VT recurrence post-procedure. Data regarding electrophysiological factors driving the outcomes are scant.Objective:To compare the factors and outcomes associated with epicardial vs endocardial VT ablation.Methods:A single-center, retrospective study of patients undergoing catheter ablation for scar-related VT was conducted. Data collected included demographics, comorbidities, medications, relevant laboratory abnormalities, electrocardiograms, echocardiograms, detailed procedural characteristics, and outcomes.Results:Our cohort of 554 patients had 89 (16.1%) epicardial and 465 (83.9%) endocardial VT ablations. Patients undergoing epicardial ablation had a greater frequency of NICM, and more patients had undergone sympathetic modulation for VT (p < 0.05) but had lesser frequency of valve surgery, and CABG. Epicardial ablation was associated with greater use of both short-term (6 months) anti-arrhythmic drugs (AAD) (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 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