Circulation, Volume 150, Issue Suppl_1, Page A4146022-A4146022, November 12, 2024. Background:Rarely, SARS-CoV-2 will lead to myocarditis associated with Multisystem Inflammatory Syndrome in Children (MIS-C). It remains unclear why MIS-C only targets specific children. Coxsackieviruses (CV) are prevalent infections during childhood and, like SARS-CoV-2, can lead to viral myocarditis. To explore an association with MIS-C we investigated the sero-epidemiology of CV in admitted pediatric patients.Method:A retrospective case control study was performed by chart review of children (age ≤ 21) admitted to a tertiary care hospital with CV serological testing from January 2017 to August 2023. Clinical, laboratory and imaging findings were used to classify patients as MIS-C and CV-unlikely or CV-possible for non-MIS-C patients.Results:Out of 182 admissions (179 patients, median age 6), CVB complement fixation (CF) assay on serotypes B1-B6 and CVA immunofluorescence assay IgG on serotypes A7, A9, A16, and A24 were positive in at least one serotype in 59.2% and 80.7% of cases respectively. We observed a significant drop in CVB CF seropositivity during the peak of social distancing in 2020. The CVB titers in CV-possible cases and MIS-C were similar. The likelihood of elevated CVB CF titers was significantly higher in MIS-C than CV-unlikely group (OR: 1.92, 95% CI: 1.02-3.63,p: 0.04). CVB CF titer trended toward higher values in African Americans compared to Whites (OR: 1.57, 95% CI: 0.98-2.50,p-value:0.057). As previously shown, the frequency of MIS-C was considerably higher in African Americans than Whites (18.1%, versus 9%,p: 0.1).Conclusion:Higher likelihood of elevated CVB CF titers in patients with MIS-C and in African Americans along with a notable higher frequency of MIS-C in African Americans warrant further investigation into the role of CVB infection in MIS-C development.
Search Results for: L’eparina inibisce la proteina spike del virus SARS-Cov-2
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Abstract 4147449: Endothelial microRNAs as New Biomarkers in Patients with Diabetes and INOCA: Insights From a Multicenter Study
Circulation, Volume 150, Issue Suppl_1, Page A4147449-A4147449, November 12, 2024. Background:Diabetes mellitus (DM) and hyperglycemia are known to drive endothelial impairment and coronary microvascular dysfunction. However, currently no established biomarkers of endothelial dysfunction in patients with “Ischemia with non-obstructive coronary artery” (INOCA). We evaluated the expression of circulating microRNAs (miRs) involved in the regulation of endothelial function in individuals with confirmed INOCA, comparing patients with and without DM.Methods:We evaluated consecutive INOCA patients referred for percutaneous coronary intervention (PCI) in a multicenter study. DM was defined according to the American Diabetes Association (ADA) guidelines. INOCA was defined based on symptoms of myocardial ischemia, non-obstructive coronary artery stenosis (0.80), objective evidence of myocardial ischemia, and impaired coronary microvascular function (coronary flow reserve ≤2.0, abnormal coronary microvascular resistance indices, coronary microvascular spasm, endothelial dysfunction with ≥20% luminal constriction during acetylcholine infusion, or coronary slow flow phenomenon). Circulating miRs were isolated from plasma samples using EDTA-containing tubes and the miRNeasy Serum/Plasma kit. Quality control included using the Agilent Small RNA Kit [33] and the RNA Spike-in kit (Qiagen) with synthetic RNA spike-ins (UniSp2, UniSp4, UniSp5) and UniSp6 spike-in and cel-miR-39-3p for cDNA synthesis control. Relative gene expression was determined using the 2-ΔΔCT method, with miRs miR-125a-5p and miR-19a-5p selected for normalization using bioinformatic algorithms. Hemolysis was assessed by measuring absorbance at 414 nm and ΔCq of miR-16-5p, miR-451a, and miR-23a-3p.Results:42 patients completed the study (28 without DM, 14 with DM). We measured the expression levels of validated miRs and found that in INOCA patients with DM, there was increased expression of miRs associated with endothelial dysfunction and reduced expression of miRs protective for endothelial function. Specifically, miR-363-5p was significantly downregulated (P
Abstract 4147474: Global and regional burden of alcohol-related atrial fibrillation from 1990 to 2021: An analysis of GBD study 2021
Circulation, Volume 150, Issue Suppl_1, Page A4147474-A4147474, November 12, 2024. Background and Aims:Atrial fibrillation constitutes a major global public health issue, with its epidemiological patterns having changed significantly over the past decades. In this study, we aimed to analyze trends of mortality due to alcoholic atrial fibrillation from 1990-2021, including identifying the patterns in age-standardized death rates (ASDR), years of life lost (YLL), and disability-adjusted life years (DALY) over time, and raising awareness about the global health burden of alcoholic atrial fibrillation.Methods:Data on alcohol-related atrial fibrillation was extracted from the Global Burden of Diseases 2021 study, including ASDR, YLL, and DALY from 1990 to 2021. The dataset was globally divided and categorized by continents and World Bank income levels. Joinpoint regression analysis was performed to determine average annual percentage changes (AAPC) from 1990 to 2021.Results:Globally, the Age standardized death rates (ASDR) for alcohol-related atrial fibrillation had a constant trend from 1990-2021. The ASDR was determined to be 0.15 (95% UI 0.1-0.2) both in 1990 and 2021 (AAPC=-0.014; 95% CI -0.014 to -0.036). Although the overall trend is constant, a considerable spike in mortality rates was observed from 2000-2010 (APC=0.38). Globally, the disability-adjusted life-years (DALYs) and the age standardized years of life lost (YLL) have remained fairly constant with AAPCs of -0.052 (95% CI -0.063 to -0.036) and -0.07 (95% CI -0.098 to -0.047), respectively. In continent wise analysis, North America and Asia had intermittent spikes in ASDRs while Europe and Africa showed a constant trend throughout the analysis. From 1990 to 2021, North America had an AAPC of 1.26 (95% CI 1.23-1.29), showing a deviation from global trend with an incline. Similarly, Asia had an increasing trend with AAPC of 0.58 (95% CI 0.55-0.6). Africa also had a minutely increasing trend from 1990 to 2021 with an AAPC of 0.36 (95% CI 0.33 to 0.38). According to World Bank income levels, high-income countries had the highest death rates, followed by upper-middle income, lower-middle income and low-income countries in descending order.Conclusions:Although trends in the burden of alcohol-related atrial fibrillation have varied globally, the net change in years of life lost (YLL) and age-standardized death rates (ASDR) from 1990 to 2021 have been minimal. The data highlights the need for further research, to develop specific strategies that are targeted at specific populations.
Abstract 4139757: COVID-19-Related Changes in Dalily Life, Concerns, and Their Associations with Sleep Disturbances
Circulation, Volume 150, Issue Suppl_1, Page A4139757-A4139757, November 12, 2024. Background:The COVID-19 pandemic has significantly exacerbated sleep problems. Pandemic-related lockdowns and drastic changes in daily life have disrupted sleep patterns, resulting in a marked increase in sleep disturbances.Research questions:This study aims to investigate the primary factors contributing to the increase in sleep disturbances during the COVID-19 pandemic in Korea. By utilizing nationally representative data encompassing various variables, this study seeks to identify COVID-19-related factors associated with sleep disturbances during the pandemic.Method:We analyzed data from the nationally representative Korea Community Health Survey conducted in 2020, including 216,809 adults. Changes in daily life due to COVID-19 were assessed by asking participants to score their current situation compared to their pre-pandemic situation, ranging from 100 (no change) to 0 (complete cessation of daily activities). COVID-19 concerns were assessed with five questions: 1) fear of contracting the virus; 2) fear of mortality if infected; 3) fear of blame from others; 4) concerns about the health of vulnerable family members; and 5) concerns about economic impacts. Sleep disturbances were defined as sleeping 5 hours or less per night on average. Logistic regression analyses with a complex sample design were performed to examine the relationship between COVID-19-related factors and sleep disturbances, adjusting for socioeconomic and health-related variables.Results:A high level of lifestyle changes due to COVID-19 (OR = 1.15, 95% CI = 1.11–1.19) and high COVID-19 concerns (OR = 1.04, 95% CI = 1.01–1.08) were associated with an increased likelihood of sleep disturbances. Conversely, resting during COVID-19 symptoms (OR = 0.81, 95% CI = 0.76–0.87), having support during quarantine (OR = 0.93, 95% CI = 0.89–0.97), and trust in the government and neighbors (OR = 0.92, 95% CI = 0.89–0.96) were associated with a decreased likelihood of sleep disturbances.Conclusion:These findings suggest that sleep disturbances during the COVID-19 pandemic were mediated by lifestyle disruptions and high levels of concern. Social support and trust mitigated the impact of COVID-19-related risk factors. As part of preparedness, improving the environment to facilitate adequate rest during illness, ensuring strong social support, and fostering high levels of trust in the government and neighbors may be important to protect sleep health during future public health emergencies.
Abstract 4141946: Characterization of Cardiac, Autonomic, and Exercise Physiology in Patients with Long COVID
Circulation, Volume 150, Issue Suppl_1, Page A4141946-A4141946, November 12, 2024. INTRODUCTION:Mechanisms contributing to the post-acute sequelae of SARS-CoV-2 (PASC, aka Long COVID) and associated functional limitations are unclear.RESEARCH QUESTION:Determine cardiovascular, autonomic and exercise physiology among patients with Long COVID.METHODS:Twenty-one Long COVID patients (16 females, 41±12yrs) underwent cardiovascular assessment during head-up tilt at supine, 30oand 60o, a 10-minute upright standing orthostatic challenge and cardiopulmonary exercise testing (CPET). Baroreceptor sensitivity was determined with Valsalva maneuver. Heart rate (HR) and blood pressure (BP) were monitored continuously. Plasma norepinephrine (NE) was monitored during tilt.RESULTS:During tilt, HR increased with transition from supine to 30oand 60o(72±12 v. 80±14 v. 90±15bpm, P
Abstract 4139661: Usefulness of High-sensitive Troponin I and N-terminal pro-B-type Natriuretic Peptide in Coronavirus Disease 2019 Risk Stratification on and after Omicron Variant Waves: COVID-MI Registry Cohort-2 Analysis
Circulation, Volume 150, Issue Suppl_1, Page A4139661-A4139661, November 12, 2024. Introduction:Troponin-defined myocardial injury or N-terminal pro-B-type natriuretic peptide (NT-proBNP) elevation frequently coincides with coronavirus disease 2019 (COVID-19). Our prior study (COVID-MI Registry Cohort-1) confirmed that high-sensitive troponin I (HsTnI) and NT-proBNP effectively stratified mortality risk. However, variants of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) change rapidly, and it remains unclear whether these biomarkers are consistently effective in predicting prognosis of COVID-19 patients irrespective of epidemic periods.Research Questions:Can HsTnI or NT-proBNP stratify mortality risk in recent COVID-19 cohorts?Aims:To assess the potential of HsTnI and NT-proBNP levels for risk stratification in the recent COVID-19 waves.Methods:In the COVID-MI Registry Cohort-2, we enrolled 1115 consecutive COVID-19 patients admitted between October 2021 and October 2022, during the Omicron variant endemic. We collected data of HsTnI or NT-proBNP levels from hospital charts or using the samples in our hospital’s serum/plasma bank if the data were not available. The primary outcome measure was all-cause mortality.Results:On admission, more than one-third of patients were classified as having severe COVID-19. HsTnI and NT-proBNP levels were available for 427 and 414 patients, respectively. The median HsTnI and NT-proBNP levels were 16 (interquartile range [IQR]: 5-57) ng/L and 524 (IQR: 140-2056) pg/mL, respectively. We stratified the patients into three groups by HsTnI level:
Abstract 4127513: Cardiopulmonary long-term effects 6, 18 and 30 months after severe covid-19 infection
Circulation, Volume 150, Issue Suppl_1, Page A4127513-A4127513, November 12, 2024. Background:SARS-CoV-2 infection affects the cardiopulmonary system in both the acute and long-term phase. This study aimed to comprehensively assess symptoms and potential long-term impairments 6, 18 and 30 months in patients previously hospitalized for severe Covid-19 infection.Methods:This prospective registry included patients hospitalized for PCR-confirmed Covid-19 infection. Approximately 6 months post-discharge, follow-up examination included patient history, clinical examination, echocardiography, electrocardiogram, cardiac magnetic resonance imaging (cMRI), chest computed tomography (CT) scan, pulmonary function test (PFT), six-minute walk test (6MWT) and a comprehensive laboratory panel. Patients with pathologic findings during the first visit underwent a second (at 18 months) and third (at 30 months) follow-up examination. Those without pathologic findings or who refused further medical examinations were contacted via phone to inquire about symptoms.Results:Between July 2020 and April 2022, 200 patients (91% general ward, 9% intensive care unit) were recruited. Due to dropouts, the second visit was conducted in 170 patients, and the third visit in 139 (74 in person, 65 via telephone). Long Covid criteria were fulfilled by 73% at 6 months, 52% at 18 months and 49% at 30 months post-discharge, with fatigue being the most common symptom (Figure 1). Echocardiography at 6 months showed impaired left ventricular function in 15 patients, with normalization in 80% at 18 months and further 66% at 30 months (Figure 2). cMRI revealed pericardial effusions in 28 patients at 6 months, which resolved in 47% at 18 months and in further 60% at 30 months. Signs of peri- or myocarditis were present in 7 patients at 6 months and were resolved in all 4 patients who attended control studies at 18 months. Chest CT scans at 6 months identified post-infectious residues in 41 patients, with full recovery in 20% at 18 months without further normalization after 30 months.The length of in-hospital stay was identified as a significant predictor for persisting Long Covid 6 months after discharge (95% CI: 1.005 – 1.12, p=0.03).Conclusion:While the prevalence of Long Covid decreased over time, a significant symptom burden persisted at 6, 18 and even 30 months after severe Covid-19 infection. Structural and functional abnormalities were less frequent compared to reported symptoms, posing a challenge in substantiating the causes of these symptoms.
Abstract 4144823: Persistent Prothrombotic State in Post-Acute Sequelae of Mild SARS-CoV-2 Infection: Role of Extracellular Histones and Immune Complexes
Circulation, Volume 150, Issue Suppl_1, Page A4144823-A4144823, November 12, 2024. Post-Acute Sequelae of SARS-CoV-2 infection (PASC) have become a significant healthcare burden. Sustained increases in prothrombotic markers have been reported in hospitalized acute COVID-19 patients. However, whether patients with less severe acute infection also endure a persistent prothrombotic state remains uncertain. We tested for a prothrombotic state in this cohort and examined potential mediators. We enrolled 70 adult patients with prior mild acute SARS-CoV-2 infection and sustained PASC symptoms (per WHO criteria). A control healthy group matched for age and sex was also enrolled who were not previously diagnosed with COVID-19. Markers of platelet activation and platelet-neutrophil aggregates (PNA) were quantified using whole-blood flow cytometry. Markers of extracellular traps (citrullinated histones [H3Cit] and cell-free DNA [cfDNA]), anti-dsDNA IgG, and thrombin generation potential were measured in plasma. At recruitment (6 weeks to 3 years post infection), there was increased potential for thrombin generation in the plasma from PASC compared to control reflected by increased peak and velocity index (P
Abstract 4147265: Title: Immortalization of human cardiac fibroblasts using a combination of SV40 large T antigen and hTERT.
Circulation, Volume 150, Issue Suppl_1, Page A4147265-A4147265, November 12, 2024. Background:Fibroblasts are critical regulators of health and disease. Unfortunately, primary isolated fibroblasts retain limited proliferation potential. To enable robust biochemical experimentation in cardiac fibroblasts we immortalized human cardiac fibroblasts using lentiviral delivered SV40 large T antigen (SV40), human telomerase reverse transcriptase (hTERT), or both tools in combination.Methods:Following virus treatment with immortalization genes and hygromycin selection, we characterized subsequent immortalized cell lines for proliferative capacity and ability to become activated in response to TGF-β1 treatment. Expression of Periostin (POSTN), alpha smooth muscle actin (αSMA) and Sertad4 was measured via qPCR after 48hrs of vehicle or TGF-β1 (10ng/ml) treatment. Western Blot analysis was performed to detect the phosphorylation of SMAD2, AKT and P38 in response to TGF-β1 and cell doubling time was calculated at each passage through passage 20.Results:Fibroblasts immortalized with SV40 did not proliferate past passage 18 while those immortalized with hTERT quiesced at passage 19. Only the combination treatment resulted in fibroblasts that proliferated through passage 20 (last measured doubling time of 3.25 days – shortest doubling time of 1.23 days at passage 11). Early passage fibroblasts (passage 7) from each immortalization strategy showed increased mRNA expression of Sertad4, POSTN and αSMA following TFG-β1 treatment. However, only the combination strategy resulted increased Sertad4 and POSTN expression in higher passage cells upon stimulation. All immortalization strategies resulted in decreased αSMA expression upon TGF-β1 treatment in fibroblasts beyond passage 10. All cell lines tested retained the ability to increase AKT and SMAD2 phosphorylation in response TGF-β1 treatment.Conclusions:These results indicate that fibroblast immortalization through a combined SV40 large T antigen and hTERT expression approach is superior to individual manipulation. The combination strategy resulted in increased proliferative capacity and more robust TGF-β responsiveness. These cells may be a useful tool for investigating molecular mechanisms of fibroblast activation when the inability to expand primary cultures would be limiting
Abstract 4118018: Increased Risk of Post-Transplant Malignancy After Isolated Heart Transplant in Adult Patients with Congenital Heart Disease
Circulation, Volume 150, Issue Suppl_1, Page A4118018-A4118018, November 12, 2024. Introduction:Patients with congenital heart disease (CHD) are at increased risk of cancer. In patients with CHD and advanced heart failure, isolated heart transplantation (HT) can be considered. In the overall HT population, immunosuppression after HT increases the risk of post-transplant malignancy (PTM). However, cancer outcomes among adult HT patients with CHD have not been investigated.Methods:Patients aged ≥ 18 years who received HT between January 1, 2010 and December 31, 2021 were identified using the United Network for Organ Sharing (UNOS) registry. Patients with CHD were compared to those without. Outcomes were PTM and hematologic malignancy (either leukemia, lymphoma or post-transplant lymphoproliferative disorder). Multivariable Fine-Gray competing-risk regression adjusting for age, sex, race, prior cardiac surgery, smoking, diabetes, induction immunosuppression, recipient and donor cytomegalovirus and Ebstein-Bar virus status was used to estimate subhazard ratio (SHR).Results:Of the total of 29,717 patients with HT were included, 1,017 (3.4%) had CHD. Patients with CHD were younger, more likely to be female, and more likely to have had prior cardiac surgery. After multivariable competing-risk regression, CHD was associated with higher risk of PTM (aSHR 1.44, 95% CI 1.15 – 1.80) and hematologic malignancy (aSHR 2.09, 95% CI 1.28 – 3.42). Among patients < 45 years old, CHD had an unadjusted SHR of 1.55 (95% CI 1.11 – 2.16) of PTM, Figure.Conclusions:Among adult patients with HT, CHD was associated with increased risk of PTM and hematologic malignancy. Further investigation is warranted to identify risk factors and screening strategies for malignancy in this patient population.
Abstract 4143841: Cardiomyocyte-specific PLCe1 knock-down attenuates Angiotensin II-induced cardiac hypertrophy.
Circulation, Volume 150, Issue Suppl_1, Page A4143841-A4143841, November 12, 2024. Background:Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disease. We have recently identified Phospholipase C epsilon 1 (PLCe1) to be upregulated in cardiomyocytes (CMs) from HCM patients. PLCe1 has been reported to play a critical role in developing cardiac hypertrophy and PLCe1 heart-specific genetic ablation in mice prevents hypertrophic growth following transaortic constriction.Aim:To further assess the therapeutic potential of PLCe1 modulation, we assessed whether PLCe1 knockdown can rescue agonist-induced cardiac hypertrophy both in vitro and in vivo.Methods:Cardiomyocyte hypertrophy was induced by endothelin 1 (ET1) stimulation in iPSC-derived CMs and primary neonatal mouse ventricular myocytes (NMVMs) followed by PLCe1 knockdown using siRNAs. For in vivo assessment, cardiac hypertrophy was induced in C57BL/6J wild type mice by implanting angiotensin II (Ang II) osmotic minipumps for 4 weeks. Adeno-associated virus serotype 9 carrying GFP-tagged shRNAs against PLCe1 (AAV9-shPLCe1) or GFP alone (AAV9-GFP; control) were delivered retro-orbitally on the day of the surgeries and 1 week after Ang II infusion. M-mode echocardiography was performed at baseline and weekly for 4 weeks.Results:PLCe1 silencing in either human iPSC-CMs or NMVMs treated with ET1 resulted in 25% reduction in cell size, 46% reduction in total protein synthesis, and 72% and 81% reduced expression of the hypertrophic markers NPPA and NPPB, respectively. To evaluate whether PLCe1 therapy can promote left ventricle hypertrophy regression, mice were infused with Ang II and subsequent delivery of AAV9-shPLCe1. Approximately 65% of the CMs were transduced within 3 days after AAV9-shPLCe1 delivery while the maximal transduction levels of 74% were observed after 1 week. We observed significant attenuation of the cardiac hypertrophic response represented by decreased wall thickness and preserved cardiac structure and function 1 week after PLCe1 modulation. Ongoing analysis of the later time points will allow us to better evaluate the salutary effects of PLCe1 therapy.Conclusion:Cardiomyocyte-specific PLCe1 knockdown attenuates Ang II-induced cardiac hypertrophy, highlighting PLCe1 as a potential target for HCM.
Abstract 4146939: Impact of Diagnosis Timing (Early vs Late) on Atrial Fibrillation Progression in Patient with New Onset Atrial Fibrillation During COVID Illness
Circulation, Volume 150, Issue Suppl_1, Page A4146939-A4146939, November 12, 2024. Background:New onset AF during acute illness has a high rate of AF recurrence within 5-yr. However, little is known about AF progression in patients with new onset AF during COVID illness. It is also unknown whether the time of COVID diagnosis (early vs late) impacts AF progression. More specifically, did the potentially different immune and inflammatory responses during early vs late COVID produce structural and electrical cardiac remodeling that would increase the likelihood of AF progression.Objective:We sought to compare AF progression in patients with new onset AF during early vs late COVID and hypothesized that early COVID was associated with increased AF progression compared to late COVID.Methods:From Apr 2020 to Feb 2024, patients receiving a SARS-2-CoV test without a history of AF with new onset AF and at least 3-mo of follow up were included (N=11,767). Patients were subdivided based on pos vs neg SARS-2-CoV test and time of diagnosis. Early COVID diagnosis (n=3052) included Apr 2020-Aug 2021 and late COVID (n=8715) included Sep 2021-Feb 2024. AF progression endpoints at 3-, 6- and 12-mo included AF hospitalization, AF emergency department (ED) visit, cardioversion and AF ablation.Results:Patients with late COVID were more likely females with hypertension, coronary artery disease and hyperlipidemia compared to early COVID patients. At 3- and 6-mo follow-up there was no difference in AF progression between the early and late COVID groups for any endpoint. In contrast, at 12-mo follow up there was in increase in late diagnosis group AF ED visits (11% vs 7.6%,p
Abstract 4138507: Uncovering Risk Factors for Myocarditis and Cardiac Arrhythmia in Youth Post-SARS-CoV-2 Infection: Insights from the N3C Database and Advanced Machine Learning
Circulation, Volume 150, Issue Suppl_1, Page A4138507-A4138507, November 12, 2024. Background:SARS-CoV2 infection has been associated with cardiovascular consequences, including myocarditis and cardiac arrhythmias. Myocarditis secondary to SARS-CoV2 infection and cardiac arrhythmias may often go unrecognized and can present with late and nonspecific symptoms. Predicting those at risk allows for prompt treatment and prevention of their potentially life-threatening consequences.Methods:The National COVID Cohort Collaborative (N3C) database was used to identify patients aged 0-30 years with COVID-19 index date between 1/1/2020 and 3/31/2022, whose sites provided data for at least six months beyond the index date. Outcomes included myocarditis and new arrythmias within 6 months of the index visit. Patients with known cardiac comorbidities were excluded. Predictors included gender, race, COVID severity as an ordinal scale, vaccination status, clinical comorbidities, and Area Deprivation Index (ADI). The data were stratified by age groups (0-4, 5-17, 18-30). Random forest models were used for data analysis and SHapley Additive exPlanations (SHAP) method was applied to optimize results. These analyses were conducted using the NCATS N3C Data Enclave.Results:Of the 1,487,741 patients in our study population, 4,105 (0.28%) had the measured outcomes; 404 had myocarditis only, 3,634 had arrhythmia only and 67 had both. Severity of COVID (SHAP 0.2344 for 0-4 years, 0.2114 for 5-17, 0.1370 for 18-30) was identified as the most important risk factor for de-novo myocarditis and arrhythmias overall. Increase in ADI (indicating lower socioeconomic status) was the second most important risk factor for the 0-4 and 5-17 age groups (SHAP: 0.0370, 0.0223). Among the 18-30 age group, race (SHAP 0.0321) and gender (SHAP 0.0289) were the second and third most important risk factors, with White and Black patients more likely to develop an event and Hispanic patients less likely. Women were less likely to develop a cardiac outcome than men.Conclusion:The severity of COVID was identified as the most important risk factor for the occurrence of myocarditis or cardiac arrhythmia within 6 months of infection. ADI, race, and gender were also identified as important, though less influential, risk factors.
Abstract 4144997: Pro-B-Type Natriuretic Peptide Kinetics across Pre-, Index, and Post-Acute COVID-19 in Hospitalized Acute on Chronic Heart Failure Patients: A Learning Health System Science Initiative
Circulation, Volume 150, Issue Suppl_1, Page A4144997-A4144997, November 12, 2024. Introduction:Myocardial injury in patients hospitalized with acute on chronic heart failure concurrent with index SARS-CoV-2 (CoV-2) infection is well described, though studies incorporating pre- and post-acute COVID-19 (PAC) are lacking. We address this gap by estimating intensity of acutely decompensated heart failure (ADHF) using time-series pro-BNP levels across hospitalizations pre- vs. respectively index and initial readmission (PAC1).Hypothesis:Case time series analysis will reveal association (p
Abstract 4142346: EPAC2-expressing neurons within the stellate ganglia are responsible for cardiac sympathetic innervation
Circulation, Volume 150, Issue Suppl_1, Page A4142346-A4142346, November 12, 2024. Background:Neurons located in the stellate ganglia (SG) are responsible for providing sympathetic nerve supply to the heart. This innervation plays a role in cardiac sympathetic overactivity, which can lead to malignant ventricular arrhythmias and chronic cardiac remodeling during disease processes. However, the specifics of how SG contributes to cardiac innervation are still not well understood.Methods:We used retrograde neuroanatomical tracing and immunofluorescence assays to confirm the presence of cardiac-innervating neurons, specifically the exchange protein directly activated by cAMP 2 positive (EPAC2+) neurons in the SG. Subsequently, single nucleus RNA sequencing was performed to determine the transcriptional profiles of SG cells, including EPAC2+ neurons. Additionally, we evaluated the physiological function of EPAC2+ neurons in healthy dogs and in an acute myocardial infarction (MI) model induced by occlusion of the left anterior descending artery. To explore the pathological role of EPAC2+ neurons in cardiac remodeling, we used a chronic MI model with neuron-specific adeno-associated virus (AAV).Results:We identified EPAC2+ neurons within the SG that specifically innervate the heart. These EPAC2+ neurons exhibited a unique transcriptional profile compared to EPAC- neurons, with a notable enrichment in genes involved in the calcium signaling pathway, including calcium channels and adenylyl cyclases 8 and 9 (AC8 and AC9). Functionally, activation of EPAC2 in the SG led to increased sympathetic activity. Inhibition of EPAC2 specifically reduced SG nerve activity and prevented ventricular arrhythmias following acute myocardial infarction. Moreover, targeted knockdown of EPAC2 in neurons diminished SG hyperactivity, enhanced cardiac function, reduced sympathetic nerve sprouting at the infarct border zones, and decreased ventricular remodeling after MI, while reversing the phosphorylation of MEK1/2 and ERK1/2.Conclusions:The results indicate that EPAC2+ neurons in the SG play a crucial role in heart innervation. This research enhances our understanding of cardiac sympathetic innervation and could lead to new therapeutic approaches.
Abstract 4142506: Comparative Proteomic Analysis of Myocarditis: COVID-19 mRNA Vaccination vs. Pre-Pandemic Viral Etiologies
Circulation, Volume 150, Issue Suppl_1, Page A4142506-A4142506, November 12, 2024. Introduction:Myocarditis has been reported after mRNA-based COVID-19 vaccination, but the immune mechanisms remain unclear. This study aimed to identify the proteome-based immunopathogenesis of post-vaccination myocarditis compared to viral myocarditis in the pre-COVID-19 era.Methods:Proteomic analysis of right ventricle (RV) biopsy specimens was performed in myocarditis patients (pre-pandemic viral myocarditis: n=3, post-vaccination myocarditis: n=3) and controls (normal endomyocardial biopsy specimens of heart transplant recipients, n=4) using mass spectrometry. Differentially expressed proteins were analyzed with CIBERSORTx, Gene Ontology (GO) analysis, and Ingenuity Pathway Analysis (IPA). To examine the relationship between the SARS-CoV-2 spike protein and post-vaccination myocarditis, immunohistochemistry (IHC), mass spectrometry analysis of spike protein, and activation-induced marker (AIM) assay in T cells from RV samples were conducted.Results:In the proteomic analysis, 6,861 proteins were identified. Post-vaccination myocarditis showed increased extracellular matrix formation and cardiac fibrosis. Both pre-pandemic and post-vaccination myocarditis had elevated pro-inflammatory cytokine activities. However, post-vaccination myocarditis exhibited higher expression of interferon-alpha (IFNα) and pattern recognition receptor activation, including TLR3 and TLR7. Pre-pandemic myocarditis showed higher activation of the complement system, neutrophils, and NK cells, whereas post-vaccination myocarditis showed increased Th2 cell activation and classical macrophage activation. Spike protein and related T-cell activation were not detected.Conclusion:The immune activation in myocarditis after COVID-19 mRNA vaccination may be triggered by the mRNA in the vaccine via an IFNα-driven immune response, leading to autoimmune-like features. Further studies are necessary to validate whether these proteins correlate with clinical characteristics.