tbuckley/cabot-search huggingface dataset:
Abstract 13228: Finerenone Inhibits the Progression of Cardiac Hypertrophy in the HFpEF Mouse Model
Authors: kei morikawa, Yuichiro Arima, Kenichi Tsujita
Journal: Circulation (2023)

Background: The efficacy of mineralocorticoid receptor antagonists (MRA) for heart failure with preserved ejection fraction (HFpEF) has not been established, but there are some reports of MRA being effective for early HFpEF.Furthermore, the FIGARO-DKD trial has demonstrated that finerenone, a nonsteroidal MRA, improves cardiovascular outcomes in patients with type 2 diabetes mellitus.The pathogenesis of HFpEF has yet to be fully elucidated, and further investigation is required to validate the mechanistic role of MRAs based on the distinct pathogenesis of HFpEF. Methods: As an HFpEF mouse model, we used the 15 weeks combined stress model of obesity and hypertension. (Schiattarella et al., Nature 2019). High fat diet ingestion and 0.5 g / L of Nω-nitro-L-arginine methyl ester drinking were loaded. As a drug administration experiment, with combined stress for 10 weeks, placebo or 10 mg/kg/day finerenone was administered for the last two weeks. After loading, body weight, blood pressure, heart weight, myocardial cross-sectional area, and mitochondrial protein acetylation were evaluated. Results: Histological analysis revealed the enlargement of cardiomyocyte cross-sectional areas in the combined stress group. In addition, we found mitochondrial protein acetylation level, adjusted by ubiquinol-cytochrome c reductase, rieske iron-sulfur polypeptide 1 (UQCRFS1) was also enhanced in the combined stress model. Subsequently, finerenone administration did not show remarkable reduction of blood pressure compared to the placebo group. However, echocardiography showed that the finerenone group reduced left ventricular diastolic septal wall thickness. And histological analysis revealed reduction of cardiomyocyte CSAs in the finerenone group. Mitochondrial protein hyperacetylation tended to be reduced with the finerenone group, but the difference was not significant. Conclusion: In the HFpEF murine model, finerenone improved cardiac hypertrophy independent of blood pressure. In addition, mitochondrial protein hyperacetylation, which involves mitochondrial dysfunction, was also alleviated by finerenone administration. Our findings indicate that the cardioprotective effects of finerenone may also affect mitochondrial function.
Abstract 16832: Biomarker Enhanced Risk Prediction of Incident Heart Failure in Low-Risk Patients: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Zainali Chunawala, Sadiya S Khan, Arman Qamar, Sameer Arora, Marat Fudim, Muthiah Vaduganathan, Robert J Mentz, Deepak Bhatt, Justin L Grodin, Ambarish Pandey, Melissa C Caughey
Journal: Circulation (2023)

Background: Primary prevention strategies to reduce heart failure (HF) burden are urgently warranted. The Pooled Cohort equations to Prevent HF (PCP-HF) risk score is a validated risk tool that integrates readily available parameters obtained in primary care setting to estimate the 10-year risk for incident HF. Although PCP-HF performs well for high-risk individuals, the model’s predictive utility for low-risk individuals may potentially be enhanced by integration of biomarkers. Methods: In this study, the PCP-HF risk score was derived from data collected at visit 5 (2011-2013) of the ARIC cohort study and its 5-year predictive accuracy was investigated using surveillance data up to 2019. Participants with &lt;10% PCP-HF risk probability of incident HF were classified as low-risk. Incremental improvement in predicting incident HF by including laboratory and imaging-based biomarkers in the low-risk population was analyzed by logistic regression, by calculating the area under the curve (AUC) from receiver operating characteristics. Results: Of 4980 study participants with 5 years of follow up, 47% had a low PCP-HF risk score (mean age 73 years, 71% women, 32% Black). Of these, 3% developed HF within 5 years. Compared to those with a high PCP-HF risk score, individuals with low PCP-HF risk score were younger, more often female and Black; had lower left ventricular (LV) mass index and left atrial volume index, higher magnitude of LV global longitudinal strain, and lower levels of NT-proBNP and hs-TnT. On further analysis, the model incorporating laboratory and imaging-based biomarkers exhibited greater predictive accuracy for incident HF compared to the original PCP-HF risk score in this low-risk population (AUC: 0.85 vs 0.62). Conclusion: The integration of laboratory and imaging-based biomarkers with the PCP-HF risk score enhances the predictive accuracy of risk modeling for incident HF, especially in individuals identified as low-risk by the 10-year risk prediction tool.
Abstract 14677: Surgical Thymectomy for Autoimmune Encephalitis With CRMP-5 and AMPAR Antibodies Induced by SARS-CoV-2 Infection
Authors: Cristian Puerta, Moises Hernandez, Yu Zhang, Mark Onaitis, Joshua Boys, Patricia Thistlethwaite
Journal: Circulation (2023)

Introduction: SARS-CoV-2 has been linked to development of autoimmune diseases. We describe a case of a patient with untreated thymoma who developed 2 cross-reactive autoantibodies between thymus and brain: collapsing response mediator protein-5 (CRMP-5) and alpha-amino-3-hydroxyl-5-methyl-4-isoxazole propionic acid receptor (AMPAR), triggered by SARS-CoV-2, inducing encephalitis and coma. Emergency thymectomy reduced anti-CRMP-5 and anti-AMPAR antibodies and restored patient neurologic function within 3 months. Description of Case: A 31-year-old male with a known history of thymoma with myasthenia gravis presented with a 1-day history of memory loss, hallucinations, ataxia, involuntary movements, and tachypnea. Rapid nasal swab COVID-19 test was positive. Over several hours, the patient became unresponsive, requiring urgent intubation for airway protection. Brain computed tomography and magnetic resonance imaging with gadolinium showed no abnormalities. Cerebrospinal fluid (CSF) analysis revealed leukocytosis with lymphocytic predominance. Four days later, CSF and serum were tested for and demonstrated high levels of CRMP-5 and AMPAR antibodies, consistent with autoimmune encephalitis. Complete robotic thymectomy was performed. Pathologic analysis revealed type B2 thymoma with negative resection margins. Three months after surgical intervention, antibody titers normalized, the patient regained consciousness, and had no neurologic deficits. Discussion: Surgical thymectomy effectively treats autoimmune encephalitis in patients with thymoma and positive CRMP-5 and AMPAR antibodies in the setting of SARS-CoV-2 infection. This rare condition is typically seen in patients with thymoma or small cell lung cancer who experience acute viral infection. Although autoantibodies to CRMP-5 and AMPAR are known to be induced by viral infection, this is the first time it has been reported for SARS-CoV-2. Timely surgical intervention is necessary to reverse obtundation and acute encephalitis by removing the cross reactive epitopes in the thymus gland. Future studies are needed to explore the molecular mechanism of SARS-CoV-2 induced immune dysfunction and autoimmunity involving cross-reactive epitopes in this deadly syndrome.
Abstract 17132: IRE1α Protects Against Cardiac Fibrosis via Regulating Selective Transcript Degradation
Authors: Sarah N Parker, Ernie H Sandoval, Chris C Glembotski, Erik Blackwood
Journal: Circulation (2023)

Background: Upon cardiac injury, cardiac fibroblasts become activated and differentiate intomyofibroblasts to maintain cardiac structure and function through secretion of stabilizingextracellular matrix (ECM) components. However, if this persists, it leads to stiffening of themyocardium and heart failure. The unfolded protein response (UPR) responds to an increaseddemand for folding of nascent secreted ECM proteins trafficked through the endoplasmicreticulum such as collagen. IRE1α, the most evolutionarily conserved arm of the UPR, actsadaptively both by enhancing protein folding of secreted proteins and reducing prolongedincreases in protein synthesis as occurs during pathologic cardiac fibrosis. Hypothesis: IRE1α protects against cardiac fibrosis via inhibiting pathologic sustained fibroblastactivation. Methods: Primary cardiac fibroblasts (CFBs) were cultured with transforming growth factor beta(TGF-β) to promote activation, in vitro . Small molecule targeting approaches were utilized tospecifically inhibit or activate IRE1α. IRE1α-floxed mice were injected with AAV9 to knockoutIRE1α specifically in myofibroblasts (IRE1mfbKO) and were subjected to transverse aorticconstriction (TAC) as a model of heart failure to stimulate fibroblast activation, in vivo . Results: While small molecule activation of IRE1α significantly blunted CFB activation inresponse to TGF-β, specific inhibition of IRE1α’s endonuclease domain enhanced CFBresponsiveness to TGF-β. Importantly, this effect occurred independent of IRE1α’s canonicalmechanism of activating the transcription factor, XBP1, implicating regulated IRE1α-dependentdecay (RIDD) as a novel anti-fibrotic protective mechanism. Transcriptomics of CFBs identifieda novel “RIDD-ome” of pro-fibrotic mRNA targets of IRE1α-mediated degradation. Finally, inresponse to TAC, IRE1mfbKO mice exhibited an exacerbated decrease in cardiac function andmarked increase interstitial fibrosis. Conclusions: IRE1α protects against pathologic differentiation of CFBs in response to TGF-β or TACvia regulating the degradation of a novel subset of pro-fibrotic transcripts. Thus, small moleculetargeting of IRE1α represents a novel approach to mitigating cardiac fibrosis.
Abstract 18133: Inducible, Endothelial Cell-Specific Knockout of <i>Heg1</i> Exacerbates Atherosclerosis Development in Mice
Authors: Ian Tamargo, Kyung In Baek, Dong-Won Kang, Yerin Kim, Shoutaro Tsuji, Hanjoong Jo
Journal: Circulation (2023)

Introduction: Stable blood flow patterns in straight, non-branching regions of the vasculature protect against atherosclerosis by inducing expression of atheroprotective proteins in endothelial cells. Heart of glass homolog 1 (HEG1), a recently-identified, stable flow-induced endothelial protein, is a single-pass transmembrane glycoprotein that has been shown to be essential for vascular development and integrity. Hypothesis: Due to its demonstrated importance in vascular biology, and its induction by stable flow, HEG1 was hypothesized to mediate atheroprotective endothelial responses to stable flow and protect against atherosclerotic plaque formation. Methods: To test the effect of HEG1 expression on atherosclerosis development, inducible endothelial cell-specific HEG1 knockout mice (HEG1 iECKO ) were generated, and exposed to hypercholesterolemia- and flow-induced models of atherosclerosis. Atherosclerotic plaque development, as well as vascular functional and mechanistic responses were compared between HEG1 iECKO and littermate control mice. Results: HEG1 expression was found to be necessary for endothelial Krüppel-like factor 2 and 4 (KLF2/4) expression, two critical transcription factors that control the majority of flow-sensitive endothelial gene transcription. HEG1 iECKO mice were found to have more extensive and advanced atherosclerotic plaques as compared to littermate controls. Conclusions: Together, these data indicate that HEG1 is an atheroprotective protein that mediates beneficial effects of stable flow on vascular endothelial cells, likely via control of KLF2/4 expression, and that HEG1 may be a promising new drug target for the treatment of atherosclerosis.
Abstract 14774: Differences in the In-Patient Mortality in Marantic Endocarditis Per Etiology: Systematic Review of Case Reports
Authors: Majd Al Deen Alhuarrat, Vibhor Garg, Pawel Borkowski, Natalia Nazarenko, Mohammad Rasoul Alhuarrat, Ayman Abushairah, Batool Al Zyoud, Exarchos-Marios Bitsis, Diego Barzallo Zeas, Rebecca Alemu, Amrin Kharawala, Sanjana Nagraj, Claudine Abdou, Aurelia Minuti, Robert Faillace, Leonidas Palaiodimos
Journal: Circulation (2023)

Introduction: Non-bacterial thrombotic endocarditis (NBTE; also known as marantic endocarditis) is a unique entity characterized by sterile fibrin deposits on valves caused by hypercoagulability and endocardial injury. Literature is limited regarding the distinction between its causes based on in-hospital mortality. Hypothesis: Would a significant difference in in-patient mortality be present in NBTE admissions depending on etiology? Methods: A review of the literature using the PubMed, Embase, Cochrane, and Web of Science databases was conducted to obtain case reports and series reporting NBTE from inception to September 2022. Crude and univariate analyses were performed. Results: 396 case reports and 20 case series were identified, of which 450 patients were extracted. Females represented 64% of our sample (median age: 46, interquartile range [IQR]: 32 - 60) while 36% were males (median age: 50, IQR: 36 - 64). Overall all-cause in-hospital mortality was 36%. NBTE was associated with cancer in 202 (47%), autoimmune disease in 191 (45%), and other causes in 34 (8%) cases. Older population and cancer etiology were associated with higher mortality (OR: 1.77, CI 95%: 1.19 - 2.62 &amp; OR: 8.29, CI 95%: 4.97 - 13.83, respectively). A significant decrease in mortality is noted in the more recent years compared to the 20 th century (OR: 0.10, 95% CI: 0.06 - 0.18). Conclusions: Although an improvement in all-cause in-hospital mortality for admission related to NBTE has been noticed in recent years, cancer as an etiology and old age are two risk factors associated with higher mortality.
Abstract 12872: Epigenetic Regulation of Vascular Smooth Muscle Cell Phenotypic Switch and Neointimal Formation by PRMT5
Authors: Ni Zhu, Zhifu Guo, Jianxin Sun
Journal: Circulation (2023)

Rationale: Phenotypic transition of vascular smooth muscle cells (VSMCs) from a contractile to a synthetic state is involved in the development of cardiovascular diseases, including atherosclerosis, hypertension, and post-angioplasty restenosis. Arginine methylation catalyzed by protein arginine methyltransferases (PRMTs) has been implicated in multiple cellular processes, however, its role in VSMC biology remains undetermined. Objective: To determine the role of PRMTs in VSMC phenotypic switch and vascular remodeling after injury. Methods and Results: Our results show that PRMT5 is the most abundantly expressed PRMT in human aortic SMCs, and its expression is upregulated in platelet-derived growth factor (PDGF)-stimulated VSMCs, human atherosclerotic lesions, and rat carotid arteries after injury, as determined by western blot and immunohistochemical staining. PRMT5 overexpression inhibits the expression of SMC marker genes, and promotes VSMC proliferation and migration, while silencing PRMT5 exerts the opposite effects. Mechanistically, we found that PRMT5 overexpression led to histone di-methylation of H3R8 and H4R3, which in turn attenuates acetylation of H3K9 and H4, thus limiting recruitment of the SRF/myocardin complexes to the CArG boxes of SMC marker genes. Furthermore, both SMC-specific deletion of PRMT5 in mice and local delivery of lentivirus expressing shPRMT5 to rat carotid arteries significantly attenuated neointimal formation after injury. Likewise, pharmacological inhibition of PRMT5 by EPZ015666 markedly inhibited carotid artery ligation-induced neointimal formation in mice. Conclusions: Our results identify PRMT5 as a novel regulator in VSMC phenotypic switch and suggest that inhibition of PRMT5 may represent an effective therapeutic strategy for proliferative vascular diseases.
Abstract 16731: Post-GWAS Functional Analysis of CBLN2 Locus Reveals the Role of CUX1 in the Inflammatory Pathogenesis of Pulmonary Arterial Hypertension
Authors: Wei Sun, Wadih El Khoury, Danli Jiang, Ying Tang, Ting Wu, Yingze Zhang, Gang Li, Stephen Y Chan
Journal: Circulation (2023)

Introduction: Pulmonary arterial hypertension (PAH) is a complex and deadly pulmonary vascular disease highly relevant to genetic susceptibility and acquired inflammatory triggers. Chr18q22.3 near cerebellin 2 precursor (CBLN2) gene is the first genetic locus identified by Genome-wide Association Study (GWAS) that is significantly associated with PAH risk in the European population. This locus includes closely linked non-coding intergenic single nucleotide polymorphisms (SNPs) downstream of CBLN2. Although CBLN2 is upregulated in PAH and causes pulmonary vascular dysfunction, it remains unknown how these non-coding SNPs remotely affect CBLN2 and in turn, alter the genetic susceptibility of PAH. Methods and Results: We combined Hi-C chromatin interaction analysis, electrophoretic mobility shift assay, and SNP genotype-PAH correlation analysis with the All of Us database (N=20,343). In doing so, we identified rs11151770(A/G) as a PAH-associated functional SNP (fSNP), among 19 haplotype SNPs in linkage disequilibrium with the associated CBLN2 locus. The genomic region containing rs11151770(A/G) exhibited long-range chromatin interaction with the CBLN2 promotor. Proteomic analysis revealed that nuclear transcription factor Cut-like Homeobox 1 (CUX1) binds specifically to the risk allele A of rs11151770 but not to the non-risk allele G, regulating the expression of CBLN2 as an activator in pulmonary arterial endothelial cells. CUX1-CBLN2 was upregulated by acquired inflammatory PAH triggers IL-1β and IL-6. SNP genotyping in PAH patients (N=159) and non-PAH controls (N=87) showed a 2.2-fold enrichment of the risk allele A only in patients with PAH associated with connective tissue disorders (N=77, p=0.036). These findings supported a pathogenic mechanism of an inflammation-sensitive pathway (CUX1-CBLN2) controlled by an fSNP (risk allele A) underlying the reported genetic association of the CBLN2 locus with PAH risk. Conclusion: Our post-GWAS functional genomics analysis defined a pathogenic CUX1-mediated, fSNP rs11151770(A/G)-controlled, and inflammation-responsive pathway that provides a mechanistic explanation for the GWAS-identified association between genetic variants in CBLN2 locus and PAH susceptibility.
Abstract 15702: Leveraging Advanced AI Algorithms for Predicting Outcomes in Non-Acute Coronary Syndrome Chest Pain Patients
Authors: Renata Valeri de Freitas, Thiago Sousa, Mariana Fuziy Nogueira De Marchi, Vinicius Ruiz Uemoto, Renato Hortegal, Louis N Nakayama Ohe, Hugo Ribeiro Ramadan, Rogerio Leite, Lucas Damiani, Roberto Botelho, Fausto Feres, Kleber G Franchini
Journal: Circulation (2023)

Introduction: Chest pain is often encountered in emergency rooms and the detection of acute coronary syndrome (ACS) is a major focus. However, a notable percentage of patients present with a diverse range of nonACS conditions. Accurately identifying the causes and outcomes of these cases can prevent unnecessary interventions, reduce healthcare costs, and optimize resource allocation. This study aims to explore how advanced AI algorithms can enhance risk assessment, refine classification, and predict outcomes in nonACS chest pain patients using conventional ECG analysis. Methods: We studied 3458 nonACS patients referred to the Emergency Room at Instituto Dante Pazzanese de Cardiologia with chest pain. A total of 185 features, including sex, height, ECG diagnostic statements, and measures, were used. The predicted outcome was defined as hospitalization within 14 days and/or death (1 or 0). We employed the AutoGluon framework for feature engineering and early model selection. XGBoost, a tree-based model, was chosen as the architecture. Training and k-fold stratified cross-validation were performed using an oversampled balanced dataset, and evaluation metrics such as AUROC, specificity, and sensitivity were measured using the original data. Results: In this study, 18.2% (630 patients) had a positive outcome. The sex distribution was comparable between outcome groups, with men accounting for 57-58% and women for 42-43%. Significant differences (p&lt;0.01) were observed in ECG intervals (QRS, corrected QT, RR interval, PSP) between the groups. The AI model identified important diagnostic statements, including normal ECG (19.4), atrial fibrillation (7.4), left ventricular hypertrophy (7.1), Ischemic T-wave inversion in inferior leads (6.7), T-wave changes in inferior leads (5.9), and first-degree atrioventricular block (5.8). The AI model performed exceptionally well, with a sensitivity of 97.93%, specificity of 96.08%, and an AUROC of 0.97. Conclusions: The AI model demonstrated its ability to predict outcomes in patients with acute chest pain without ACS, making it an appealing tool for effective risk stratification. The early identification provided by the AI model presents an opportunity for timely intervention to mitigate adverse outcomes.
Abstract 13686: An Implementation Science Informed, Patient Activation Intervention for Depression Treatment in Coronary Heart Disease Patients: Impact on Clinician Referral and Prescribing Behaviors
Authors: Nathalie Moise, Meredith E Dimaond, Kiara Genao, Jennifer Mizhquiri Barbecho, Chinelo Onyilofor, Nohora Ospina, Danielle Rome, Kaitlin Shaw, Samantha Simantiris, Siqin Ye
Journal: Circulation (2023)

Intro: Implementation strategies are integral to addressing gaps in AHA depression treatment guidelines in coronary heart disease (CHD) patients. Methods: From 2019 to 2023, we randomized 12 Columbia University affiliated primary care and cardiology clinics to timing of receiving a multi-level intervention. We enrolled separate pre and post EHR eligible patients/site (≥21 years old, English or Spanish speaking, CHD ICD10 and upcoming cardiologist/PCP index visit) with Patient Health Questionnaire(PHQ)9≥10 and not seeing a psychiatrist. Pre-implementation patients and their providers/sites received usual care. Post-implementation, a theory-informed intervention included problem-solving meetings for mental health social workers (MHSW), cardiologist/PCP [“provider”] education and a patient psychoeducation, activation, and treatment selection tool (with patient treatment preferences sent to MHSW/providers via EPIC). Blinded physicians extracted index visit pre vs. post provider behavior (i.e., documented CHD risk factor or mental health counseling, therapy/cardiac rehab referral, and/or antidepressant prescribing vs. none). We conducted a pre-post analysis using descriptive statistics and thematically analyzed any MHSW/provider responses to EPIC reports. Results: Of 10,625 EHR eligible CHD patients; 1759 patients were screened, 304 (16.5%) eligible and 253 (82.9%) enrolled; 52.0% were female, 56.1% Hispanic, 14.6% Black; mean age was 67.8 years old, PHQ9 13.1. Overall, all (n=71) intervention providers received EPIC messages with 67.8% of patients selecting ≥1 treatment; 29.7% of reports prompted a MHSW/provider response (themes: thinking, talking, action) ; more cardiologists acknowledged receipt/relayed plans than PCPs as did providers caring for commercially insured (vs. Medicaid) patients; 25% of providers optimized treatment pre- vs. 40% post-implementation. Conclusion: A multi-level strategy centered around patient activation may marginally improve provider guideline adherence. Key limitations are pre-post design and descriptive analyses without adjustment for temporal trends. Our ongoing study will adjust for temporality and examine impact on depressive symptoms and patient behavior.