Risultati per: Caratterizzazione dell'asma in base all'età di insorgenza: uno studio di coorte multi-database

Circulation, Volume 150, Issue Suppl_1, Page A4138722-A4138722, November 12, 2024. Introduction:Multidisciplinary team (MDT) discussions are integral to Transcatheter Aortic Valve Implantation (TAVI) decision making. Large language model (LLM) ubiquity and low-code no-code platforms have enabled clinician lead solution development. Specialised chatbots or ‘agents’ have evolved into multi-agent systems that can personify human collaboration. We assess the performance of an artificial intelligence (AI) multi-agent TAVI MDT.Methods:Four de-identified TAVI cases from two metropolitan Australian hospitals were assessed by a mock human TAVI MDT (h-MDT) and an AI multi-agent TAVI MDT (ai-MDT). The ai-MDT was created with Agentflow within Flowise AITM and had a hierarchical multi-agent architecture suited to complex reasoning required for TAVI MDT simulation (figure). LLM limitations necessitated the ai-MDT rely on imaging reports rather than clinical images. The h-MDT and ai-MDT consisted of similar team members. Outputs from the h-MDT and ai-MDT was adjudicated by a panel of four blinded TAVI doctors that determined if output was human vs AI and assigned a SMIC score (4-12, 4=good, 12=poor) that assessed structure, missing information, incorrect information and clinical utility. Time durations for h-MDT and ai-MDT were recorded.Results:Adjudicators differentiated human vs. AI output 100% of the time and ai-MDT output had better SMIC scores than h-MDT (U-stat 213, p=0.0011). ai-MDT outperformed h-MDT in the domains of structure, missing information and clinical utility but was not statistically different in the incorrect information domain (U-stat 132, p=0.88). The average time for each case in h-MDT was 15 minutes and 45 seconds compared to 97 seconds for ai-MDT.Conclusion:This demonstrates the potential of using LLM based multi-agent systems as a clinical adjunct in highly specialized multidisciplinary clinical meetings. AI responses were superior for structure, clinical utility and missing information and non-inferior for incorrect information compared to humans, which highlights that hallucinations remain an issue with generative AI. Time was saved but image interpretation still requires human input, for now. Cognitive AI continues to require human supervision for implementation.

Circulation, Volume 150, Issue Suppl_1, Page A4140245-A4140245, November 12, 2024. INTRODUCTION:Atrial fibrillation (AF), often diagnosed in the Emergency Department (ED), increases the risk of stroke by 64% but can be mitigated by guideline-directed oral anticoagulant (OAC) treatment.RESEARCH QUESTION:Does clinician education of an AF clinical decision support (CDS) tool increase OAC prescription rates for patients with new-onset AF or paroxysmal AF (pAF)?GOALS:To increase guideline recommended care practice of OAC prescribing for appropriate candidates in the ED.Methods:This multi-center, multi-phase, stepped-wedge cluster-randomized clinical trial includes a retrospective phase (Phase 0) and implementation of an external browser link to the CDS in the EHR (Phase 1) which included patient-specific stroke and bleeding risk stratification scores with recommendation for OAC based on professional society guidelines, along with targeted provider education on how to use the resource. Data was collected from ED visits of patients aged > 18 with a primary AF/pAF diagnosis from Jan 1, 2020–May 25, 2024. The three sites, one academic and two community hospitals, implemented Phase 1 in January ‘22, April ‘22, and April ‘23. Eligibility for OAC treatment was based on clinical judgment weighing the benefit of stroke prevention against the risk of bleeding. A logistic GEE model assessed the intervention’s impact on OAC prescribing and treated ED providers as a random effect to account for clustering. The model included the CDS intervention and covariates for site, cardiology consultation, guideline citation, and patient factors such as sex, race, ethnicity, and age.Results:Of 4397 patients analyzed, 655 met inclusion criteria, among which 296 (45.19%, median age 68) were prescribed OAC, 175 in Phase 0, and 121 in Phase 1. The odds ratio estimates and their corresponding 95% confidence intervals are as follows: CDS intervention 1.75 [1.20, 2.54], sex female vs male 2.31 [1.57, 3.38], age 0.27 [0.12, 0.61], site 0.55 [0.29, 1.04] and 0.45 [0.25, 0.83] for each community site vs academic, cardiology consultation 4.56 [2.80, 7.42], and guideline citation 2.23 [1.44, 3.43]. Race and ethnicity did not show significant associations.CONCLUSION(S):We demonstrated that clinician education and limited CDS tool integration into the EHR are linked to an almost two-fold increase in OAC prescribing for suitable AF/pAF patients. Future studies should evaluate the influence of further CDS integration on OAC prescribing, long-term adherence, patient outcomes.

Circulation, Volume 150, Issue Suppl_1, Page A4141571-A4141571, November 12, 2024. Background:Although ambient air pollution exposure has been linked with increased mortality in many cardiovascular or pulmonary diseases, its relationship with pulmonary arterial hypertension (PAH) is still unknown. The present study aims to investigate the association of ambient particulate matter (PM) exposure with pulmonary hemodynamics and long-term survival in patients with PAH in China.Methods:This retrospective multi-center cohort study included 1511 participants who underwent invasive right heart catheterization and were eventually diagnosed with PAH from January 2014 to December 2020. The primary outcome was transplant-free survival from the time of diagnosis. The association of PM2.5and PM10with all-cause death or lung transplantation was assessed by fitting Cox proportional risk models. Generalized linear models were used to examine the relationship between PM exposure and pulmonary hemodynamic severity at baseline. Restricted cubic splines were used to describe exposure-response curves. Mediation analysis with bootstrap method was used to explore whether potential variables mediated the associations.Results:During a median follow-up of 36.7 months, all-cause death or lung transplantation occurred in 149 patients. Per 10 µg/m3increase of PM2.5and PM10were associated with 14.5% and 7.9% increased risk of primary outcomes adjusting for potential confounding variables, respectively. PM2.5and PM10were associated with European Society of Cardiology risk stratification and with pulmonary hemodynamics at baseline, in particular pulmonary vascular resistance (PVR), mean pulmonary artery pressure (mPAP), cardiac index, and mixed venous oxygen saturation (SVO2). Effect of PM may be mediated in part by impaired glucolipid metabolism and inflammation-associated lymphocyte.Conclusions:Particulate matter exposure was associated with disease severity and pulmonary hemodynamics at baseline in patients with PAH, and higher chronic exposure to PM2.5and PM10independently predicted shorter transplant-free survival.

Circulation, Volume 150, Issue Suppl_1, Page A4140981-A4140981, November 12, 2024. Introduction/Background:Patients with hematological malignancies are at a higher risk of developing atrial fibrillation. Additionally, it can predispose to an increased risk of bleeding limiting anticoagulation for stroke prevention. LAAO has been successfully utilized among patients with atrial fibrillation and contraindication to anticoagulation.Research Question:What are the outcomes and in-hospital complications of left atrial appendage occlusion (LAAO) among patients with atrial fibrillation and hematological malignancy?Methods:The National Inpatient Sample (NIS) was analyzed from 2015-2020 to identify admissions for LAAO among patients with and without a hematological malignancy. Baseline characteristics were compared between the two groups and multivariate logistic regression was used to analyze hospitalization outcomes.Results:We identified 89,920 weighted admissions for LAAO procedures of which 1,665 patients (1.85%) had a hematological malignancy. In the adjusted analysis, the odds of MACCE (aOR 1.86, 95% CI 1.10-3.14, p 0.0205), cardiogenic shock (aOR 3.76, 95% CI 1.95-7.24, p

Circulation, Volume 150, Issue Suppl_1, Page A4147046-A4147046, November 12, 2024. Background:Stroke is one of the leading causes of death for older individuals with hypertension. This research investigates the variations in stroke mortality rates and trends among 65-year-old hypertension patients in the US from 2000 to 2020.Methods:The CDC WONDER database’s mortality data from 2000 to 2020 was used for a retrospective analysis. Average Annual Percentage Change (AAPC) and Annual Percent Change (APC) were used to evaluate trends and produce age-adjusted mortality rates (AAMRs) per 100,000 people. Data was stratified by year, sex, race/ethnicity, and geographical regions.Results:Between 2000 and 2020, 598,341 deaths among individuals 65 years of age or older in the United States were related to stroke due to hypertension. Most occurred in nursing homes/long-term care facilities (36.7%). The overall AAMR for stroke in hypertension-related deaths dropped from 86.6 in 2000 to 51.8 in 2020, with an AAPC of -2.86 (95% CI: -3.18 to -2.61, p < 0.000001). Between 2000 and 2012, the AAMR had a considerable reduction (APC: -2.30, p < 0.000001). Subsequently, from 2012 to 2018, there was a more dramatic decrease (APC: -6.85, p < 0.000001) than a notable rise (APC: 6.45, p = 0.024) from 2018 to 2020. Older women had higher AAMRs than older men (women: 66.5; men: 60.1). Both sexes experienced decreases, with the decline more prominent in women (women: AAPC: -3.20, p < 0.000001; men: AAPC: -2.22, p < 0.000001). There were notable racial differences: Black people had the highest AAMRs (31.0), followed by White people (21.8), American Indians and Alaska Natives (18.6), Asians and Pacific Islanders (12.9), and Hispanics (12.5). All racial groups experienced decreases in AAMRs, most pronounced in Asians (AAPC: -4.62, p < 0.000001). Geographically, Massachusetts had the lowest (36.3), and Mississippi had the highest (117.7) AAMRs. The Western region had the highest average AAMR (71.8), while nonmetropolitan areas exhibited higher AAMRs than metropolitan areas (nonmetropolitan: 25.9; metropolitan: 20.7).Conclusion:The study uncovers significant variations in mortality rates among elderly individuals in the US due to stroke and hypertension. The recent uptick emphasizes the necessity for targeted efforts to tackle these disparities and improve the health outcomes of affected communities.

Circulation, Volume 150, Issue Suppl_1, Page A4134396-A4134396, November 12, 2024. Backgrounds:Ischemic heart disease (IHD) remains a leading cause of mortality globally and has a high prevalence in the United States, necessitating an understanding of long-term trends to inform interventions. This study examines IHD-related mortality trends among US adults from 1999 to 2020, considering demographic and geographic disparities.Aim:This study aimed to evaluate patterns and geographical variations in mortality associated with IHD among adults in the United States.Methods:Death certificates from the CDC WONDER database spanning from 1999 to 2020 were analyzed to investigate mortality related to IHD among adults aged 35 years and above. Age-adjusted mortality rates (AAMRs) per 100,000 persons and annual percent change (APC) were calculated, stratified by year, sex, race/ethnicity, and geographic region.Results:Ischemic Heart Disease (IHD) caused 12,756,359 deaths among U.S. adults aged 35 and above from 1999 to 2020. Annual trends in age-adjusted mortality rates (AAMRs) showed a decline from 48.7 in 1999 to 28.9 in 2020, with notable fluctuations. Men consistently had higher AAMRs than women. NH Black or African American individuals exhibited the highest AAMRs. Geographically, significant disparities existed among states and regions, with the Northeast having the highest mortality. Nonmetropolitan areas consistently had higher AAMRs compared to metropolitan areas, showing varying trends over the study period.Conclusion:Fluctuations in mortality trends among IHD patients were observed over the study duration, revealing significant disparities across demographic and geographic parameters. Targeted interventions are imperative to alleviate the burden of IHD and mitigate mortality rates in the United States.

Circulation, Volume 150, Issue Suppl_1, Page A4147077-A4147077, November 12, 2024. Background:Tricuspid regurgitation (TR) worsens heart failure symptoms and perpetuates right ventricular failure (RVF). Given the limited efficacy of medicines and high risk of surgical mortality, percutaneous therapeutic options are gaining importance. The TRILUMINATE study reported an 86% reduction in TR severity and 4% mortality rate using Triclip G4 tricuspid transcatheter edge-to-edge repair (T-TEER) system with improvement in health status. Triclip subsequently gained FDA approval for TR on April 2, 2024.Objective:To evaluate reported device and patient related adverse events during early experience with Triclip system for T-TEER.Methods:The events reported for Triclip since it gained FDA approval were extracted from the FDA MAUDE database. Previously published reports, duplicates and events before FDA approval were excluded. Grades of TR at baseline and after T-TEER associated with single leaflet device attachment (SLDA) were compared using Wilcoxon rank sum test.Results:After excluding 14 reports, 45 were included, dating from 04/02/24 to 05/31/24. Of these, 31 (67.4%) featured patient complications, with SLDA being the most frequent (n=24, 53%).(Figure-1) Cause of SLDA was reported in 8 reports.(Figure-2) SLDA led to regression of TR to pre-procedure levels in 10 patients and Polymorphic VT in one patient. Other patient issues included damage to leaflets (n=7, 15.6%) which necessitated surgery in one case and prompted consideration of the same in another. There were 4 reports of clip entrapment in the chordae. Device-related issues included 3 cases of leaks in the steerable guide catheter affecting its ability to hold the column, knotting on the lock line, difficulties with positioning the second clip above the valve, clip reopening beyond the expected 5°, clip opening while locked but staying closed post-deployment, delays in clip delivery, and challengers in guiding catheter positioning. No acute deaths were reported in the MAUDE database within 2 months of device approval.Conclusion:Our research findings summarize the reported adverse events during the early period following FDA approval of Triclip G4 T-TEER system. This provides valuable insights into common failure modes and complications, offering guidance on their optimal utilization. Multiple adverse events can be noted soon after approval of the Triclip, underscoring the importance of good initial training and proctoring.

Circulation, Volume 150, Issue Suppl_1, Page A4144108-A4144108, November 12, 2024. Background:The CHA2DS2-VASc risk score is a clinical tool for stroke prediction. It is mainly used in patients with atrial fibrillation (AF) but is also applied to the non-AF population. We previously reported that artificial intelligence (AI)-enabled left atrial (LA) volumetry from coronary artery calcium (CAC) scans (AI-CAC) predicts AF as early as one year and outperformed CHARGE-AF and NT-proBNP. In this report, we compare AI-CAC LA volumetry to the CHA2DS2-VASc risk score and evaluate the incremental value of incorporating AI-CAC LA volume to CHA2DS2-VASc for incident stroke prediction in the non-AF population.Methods:We applied the AutoChamberTMLA volumetry component of AI-CAC to CAC scans of 5830 people without AF (52.2% women, age 61.7±10.2 years) enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA) baseline (2000-2002). We used the 15-year outcomes data for incident stroke (ischemic and hemorrhagic) and assessed discrimination using the time-dependent area under the curve (AUC) between AI-CAC LA volume vs. CHA2DS2-VASc risk score. Notably, the CHA2DS2-VASc score in this non-AF population ranges from 0 to 5, whereas in the AF population it typically ranges from 0 to 9 points.Results:252 cases of stroke accrued over 15 years. The median and mean ± SD of CHA2DS2-VASc score at baseline were 1.0 and 1.58 ± 1.15, respectively. The cumulative incidence of stroke for the 95thpercentile of AI-CAC LA volume (n=291) vs. CHA2DS2-VASc 4 or 5 points (n=364) was 13.0% and 13.7%, respectively. AI-CAC LA volume significantly improved the AUC of CHA2DS2-VASc for stroke prediction at 2-year follow-up (0.76 for CHA2DS2-VASc vs. 0.81 for CHA2DS2-VASc plus LA volume, p=0.03), 5-year follow-up (0.73 vs. 0.77, p=0.01), 10-year follow-up (0.70 vs. 0.75, p

Circulation, Volume 150, Issue Suppl_1, Page A4139407-A4139407, November 12, 2024. Background:Higher aortic valve calcium (AVC) burden is associated with an increased risk of cardiovascular disease (CVD) and non-CVD. Despite shared risk factors between AVC and chronic kidney disease (CKD), the association of AVC with incident albuminuria is unknown.Methods:We examined 5,464 MESA participants who had AVC quantified by cardiac CT at Visit 1 (2000-02), an eGFR of ≥60 mL/min/1.73 m2, a normal spot urine albumin to creatinine ratio (ACR) ( 0. During a median follow up of 14.2 years, 921 (17%) developed albuminuria. There was a significantly increased rate of incident albuminuria with higher AVC values (p < 0.001) (Figure). In multivariable adjusted models, a higher risk of incident albuminuria was observed when AVC was examined as a continuous variable (per log-unit [AVC+1]) HR 1.05;p= 0.03 and for participants with AVC ≥100 HR 1.43; (p= 0.02) compared to AVC=0, but not for participants with AVC 1-99 (HR 1.13;p= 0.29). A significant progression in log transformed ACR was observed for AVC as a continuous variable (β 0.03;p< 0.001) along with participants who had AVC 1-99 (β 0.13;p< 0.001), and AVC ≥100 (β 0.16;p= 0.001), compared to AVC=0. The associations between continuous AVC and incident albuminuria remained after further adjusting for CAC score (p= 0.04), Lp(a) (p= 0.03), and the APOE-ε4 genotype (p= 0.04). The signal was consistent for ACR progression after further adjusting for CAC score (p< 0.01), Lp (a) (p< 0.01), and the APOE-ε4 genotype (p< 0.01).Conclusions:In a multi-ethnic cohort of participants free of CVD and CKD at baseline, AVC was independently associated with a higher risk of incident albuminuria and progression of ACR.

Circulation, Volume 150, Issue Suppl_1, Page A4148110-A4148110, November 12, 2024. Background:Critical Limb Ischaemia (CLI) is a concerning medical emergency condition with notable mortality among older adults. This study highlights the trends and demographic disparities in mortality rates due to CLI in patients aged 55 and older in the United States from 1999 to 2020.Aim:This study aimed to evaluate patterns and geographical variations in mortality associated with CLI among adults in the United States.Methods:Death certificates from CDC WONDER database from1999 to 2020 were analyzed to investigate mortality related to CLI among adults. Age-adjusted mortality rates (AAMRs) per 100,000 persons were calculated, stratified by year, sex, race/ethnicity, and geographical regions.Results:CLI caused a concerning 620,205 deaths among US adults aged 55+ between 1999 and 2020, primarily in hospitals (42%). The overall AAMR for CLI-related deaths showed decline from 51.6 in 1999 to 40.1 in 2020, with an AAPC of -1.51 (95% CI: -1.75 to -1.25, p < 0.000001). The AAMR experienced a steeper decrease from 1999 to 2011 (APC: -3.31, p < 0.000001), followed by a slight increase from 2011 to 2020 (APC: 0.94, p = 0.031174). Men had higher AAMRs than women, though both sexes experienced reductions (men: 48.3; women: 32.6). The AAMR for men decreased from 64.9 in 1999 to 42.8 in 2011, increasing to 50.1 by 2020. For women, the AAMR decreased from 42.9 in 1999 to 28.3 in 2014, followed by a slight increase to 32.3 by 2020. Racial/ethnic disparities were apparent, with Black individuals having the highest AAMRs (58.7), followed by Whites (39.0), American Indians/Alaska Natives (38.0), Hispanics (28.5), and Asians/Pacific Islanders (13.8). All racial groups experienced decreases in AAMRs. Geographically, AAMRs varied from 20.4 in Utah to 53.2 in Ohio. The highest mortality noted in the Midwestern region (AAMR: 43). Nonmetropolitan areas unveiled higher AAMRs than metropolitan areas (nonmetropolitan: 43.5; metropolitan: 38.2). Both regions showed a decrease in AAMRs from 1999 to 2020 (metropolitan AAPC: -1.36, p < 0.000001; nonmetropolitan AAPC: -0.81, p = 0.001399).Conclusion:Our analysis highlights significant demographic and geographic differences in older adult mortality due to CLI in the U.S. Continued decreases over time but recent upturn in mortality rates emphasizes need for focused interventions to close these gaps and to improve population health outcomes for affected populations.

Circulation, Volume 150, Issue Suppl_1, Page A4146535-A4146535, November 12, 2024. Introduction:Cardiovascular(CV) disease is one of the leading cause of death in females in USA out of which 44% suffer. According to the latest CDC guidelines, 13.4 % are suffering from the infertility.It includes the most common conditions including endometriosis, poly cystic ovarian syndrome. Studies shows a mutlitude of factors including genetic abnormalities, hormonal imbalances like chronic anovulation or increased androgens predispose the women to subsequent health conditions.Literature review suggests that long term cv risks are less understood in the infertile women.Aim:The aim of the study is to identify the CV outcomes including coronary heart disease(CAD) , acute coronary syndrome(ACS), and heart failure in women with underlying infertility condition.Methods:The NIS 2020 was queried for the female adult population (age >18 years) with a primary or secondary diagnosis of infertility. Prevalence of CV risk factors were compared between females with and without infertility problem. The association of cardiac diagnoses including CAD, ACS and was analysed. Multivariate regression analysis was performed taking all-cause mortality as a primary outcome.Results:A total of 3870 adult patients with a primary or secondary diagnosis of infertility were identified and the mean age was 36 years.In adult population without infertility condition, patients with an underlying infertility were found to have an increased association with DM (48.16%vs 23.11%; P

Circulation, Volume 150, Issue Suppl_1, Page A4141689-A4141689, November 12, 2024. Background:Female patients referred for coronary artery bypass grafting (CABG) are generally older and have more comorbidities than their male counterparts. Although higher perioperative mortality among female patients has been reported, there is a lack of large-scale, real-life data on this outcome and its trend.Aim:To study the mortality rate among female patients undergoing CABG from 2015-2020 and compare it with that of their male counterparts.Methods:The National Inpatient Sample from January 2015 to December 2020 was utilized to identify the study population using the International Classification of Diseases, Ninth and Tenth Revisions, Clinical Modification. The primary outcome was the overall in-hospital mortality of CABG based on sex, and the secondary outcome was the mortality trend between the groups.Results:We evaluated 929,759 patients who underwent CABG, of whom 230,000 (24.3%) were female. The female patient group was slightly older than the male patient group (66.4 vs 65.4 years, P

Circulation, Volume 150, Issue Suppl_1, Page A4141628-A4141628, November 12, 2024. Introduction:Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of mortality worldwide. Lipid-lowering therapies (LLTs) are a key element to reduce the risk of recurrence of ASCVD events. However, despite concordant guidelines, LLTs are often underused in real-life setting.Research questions:The aim of this study is to describe the use of LLTs and its impact on morbi-mortality in the year following a first ASCVD event.Methods:This retrospective study used the national health data system (SNDS), collecting health insurance claims and hospital discharge data from 99% of the French population. Incident cases in 2021 were identified, corresponding to all adults with a first ASCVD event, based on ICD-10 hospital coding. ASCVD includes coronary artery disease [myocardial infarction, unstable angina or coronary revascularization], cerebrovascular events [ischemic stroke, carotid revascularization] and peripheral artery disease (PAD) requiring artery revascularization. In patients discharged alive from the index event, longitudinal analyses were performed at 1-year from discharge to describe LLT use, occurrence of major ASCVD events and all-cause mortality.Results:In 2021, 195,211 newly diagnosed ASCVD cases were identified among 43,1M adults (mean age: 70.3 (±13.7) yo; 62% of male). The first ASCVD event was myocardial infarction (N=51,614) or ischemic stroke (N=52,865) in 53.5% of incident cases. The remaining 46.5% corresponded mostly to coronary revascularization procedures (N=83,910), followed by PAD (N=26,925). In-hospital mortality was 5.5% (N=10,673). In patients analyzed at 1 year (N=180,875), 16.9% did not receive any LLT. This value rose to 26.7% among patients who had no received LLT prior to the ASCVD event. After a myocardial infarction, patients were more likely to receive LLT (91.9%) compared to after an ischemic stroke (72.9%) or revascularization for PAD (68.0%). Finally, 1-year all-cause mortality was higher in non-LLT compared to LLT patients (20.9% vs 4.0%). Additional data on the recurrence of ASCVD events as a function of LLT use are currently being analyzed and will be presented at the congress.Conclusion:Contrary to recommendations, the underuse of LLTs after a first ASCVD event remains very high, particularly after a stroke. This is associated with a significantly higher mortality at 1 year, justifying the need to reinforce implementation of the guidelines in real life for a better management of residual lipid risk.

Circulation, Volume 150, Issue Suppl_1, Page A4139238-A4139238, November 12, 2024. Intro:Myocarditis is an inflammatory cardiac condition that may progress to dilated (DCM) or arrhythmic (ACM) cardiomyopathy. Prior cohort studies indicate genetic factors significantly influence myocarditis susceptibility and outcomes; yet, this has not been studied at a population level, which holds potential for clinical risk prediction.Objective:To investigate DCM and ACM gene variant burden and clinical consequences by a multi-population approach encompassing diverse genetic ancestries.Methods:Individuals with exome sequencing (ES) in UKBB and AoU were included, and poor-quality samples excluded. Individuals with myocarditis were identified by ICD code and compared with myocarditis-neg population. Cardiomyopathy (CM) genes in ClinGen DCM- and ARVC-associated genes with at least moderate evidence of disease causality were included and filtered by our previously published variant pipeline and ClinVar 2* criteria for pathogenic/likely pathogenic (P/LP). Cardiac phenotype and CM variant burden were analyzed by chi-squared analysis.Results:200,580 individuals in UKBB and 230,013 in AoU had ES. 137 in UKBB and 284 in AoU had myocarditis. Myocarditis cohorts in both populations had increased phenotypic burden of CM, ventricular arrhythmia, and HF vs myocarditis-neg. Myocarditis-pos showed increased CM (16.8% vs 0.2%); VA (10.9% vs 0.9%) and HF (32.8% vs 3.1%) in UKBB (p

Circulation, Volume 150, Issue Suppl_1, Page A4141762-A4141762, November 12, 2024. Introduction:Chronic heart failure (HF) is linked to elevated serum TNF-α levels and affects multiple signaling pathways in non-cardiomyocytes, such as immune cells, intestinal epithelial cells, lymphatic endothelial cells, vascular cells, and their interactions. The combined dysbiosis of host transcriptomics and gut microbiota concerning altered TNF-α signaling in older adults with HF remains unknown.Methods:We recruited 10 older adults with heart failure (HF) (6 females) and 16 healthy controls (HCs) (10 females) from the Northeastern U.S. Non-fasting peripheral blood and stool samples were collected. Serum TNF-α was assayed using Enzyme-linked Immunosorbent Assay (ELISA) kits. Differentially expressed genes (DEGs) between HF and HCs were investigated using the R package “DESeq2” after aligning the raw blood RNA sequence data to the reference database and undergoing quality control. The QIAGEN Ingenuity Pathway Analysis (IPA) was used to analyze the canonical pathways associated with the DEGs. The 16S rRNA V4 gene regions of stool samples were sequenced and processed using the Mothur 1.42.3 pipeline. The Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) was used to predict the metagenomic functions of different gut microbiota compositions.Results:The mean ages of the HF and HC subjects were 73.50 (SD = 8.33) and 63.19 (SD = 7.75), respectively. HF subjects had significantly higher serum TNF-α levels than HCs (p < 0.05). Among the DEGs, HF subjects had 18 downregulated genes (e.g.,AK5,FAM167A,RGCC, andSARDH) and 3 upregulated genes (SMPD3,TMIGD3, andFRRS1) compared with HCs. TNF signaling (p < 0.01) was one of the significantly different canonical pathways in the DEGs between HF and HCs. HF subjects had significantly enrichedMogibacteriumand diminishedSutterellathan HCs (p < 0.05) and lower P53 signaling pathway activity than HCs (p < 0.05) among the predicted functions in stool samples.Conclusions:By analyzing serum TNF-α, whole transcriptomics, and gut microbiota, we identified higher serum TNF-α, differentially expressed genes (DEGs) and their canonical pathways, and distinct compositions and predicted functions of gut microbiota in older adults with HF compared to healthy controls. These findings suggest that TNF-α signaling may be a potential target for developing precise HF interventions and highlight the need for further large-scale multi-omics analysis in understanding and treating HF.

Circulation, Volume 150, Issue Suppl_1, Page A4143199-A4143199, November 12, 2024. Introduction:Exercise is critical to cardiovascular health. However, the underlying molecular mechanisms are not well described. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) seeks to create a detailed molecular map of the response to exercise. Described here is the first human cohort of MoTrPAC, enrolled prior to the COVID-19 shutdown (N=175).Methods:Healthy, sedentary adults were randomized to an 8-exercise circuit of resistance exercise (RE, N=73), a 40 minute submaximal endurance exercise bout (EE, N=65), or to non-exercising control (N=37). Blood, muscle, and adipose tissue were sampled at 4-7 time points relative to exercise, depending on tissue/modality. Samples were deep phenotyped across multiple omic domains including chromatin accessibility, transcriptomics, proteomics, phosphoproteomics, and metabolomics.Results:The cohort was 72% female, with a mean±sd age of 41±15 years and BMI of 27.1±4.0 kg/m2. Exercise affected over 34,000 molecular features in ≥1 tissue/time point including a high proportion of transcriptomic and phosphoproteomic features (Figure A). Molecular signatures were compared between EE and RE: enrichment analysis of muscle phosphoproteomics showed a greater activation of MAP kinases in RE compared to EE at all time points. To identify plausible exerkines (secreted molecules signaling an acute exercise bout), differentially abundant features in any sampled tissue cells were compared to temporally-matched cognate protein levels in plasma, yielding 110 features. A known exerkine, CX3CL1 (fractalkine) was identified, in addition to novel candidates, such as cellular communication network factor 1 (CCN1), a secreted extracellular matrix protein linked to plasma triglyceride levels, which showed increased abundance early post exercise (Figure B). Network analysis across tissues and omes identified novel transcription factor “hubs” as candidate master regulators of exercise response.Conclusions:These first MoTrPAC data represent an unparalleled multi-tissue, multi-omic, multi-time point, multi-modality map of acute exercise, enhancing our understanding of the molecular transducers that may link exercise and cardiovascular health.