tbuckley/cabot-search huggingface dataset:
Abstract 4143635: Stress-related Sleep Disturbance Inflames Myocardial cGAS-STING Pathway through activating bone marrow macrophage
Authors: Xinyu Che, Yan Xia, Ao Chen, Zhangwei Chen, Juying Qian, Junbo Ge
Journal: Circulation (2024)

Background/Introduction: Delayed bedtime following stress disorder is prevalent in waves of pandemics and modern life. Considered to be a specific and important contributor to cardiovascular health, stress-related sleep disturbance has an unmet need in steady preclinical models. We previously found exciting corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVH) area of mice could induce 3-hour-long wakefulness. Methods: The chemogenetic method of designer receptors exclusively activated by designer drugs (DREADD) system was adopted to mimic stress-related sleep disturbance. We transfected PVH CRH neurons with rAAV-hSyn-DIO-hM3Dq-mCherry and rAAV-Crh-CRE. Prolonged CRH neuron activation was induced by daily intraperitoneal injection of clozapine N-oxide (CNO, 3mg/kg) at 9 am. Bulk RNA-sequencing and bioinformatics analysis were conducted for mechanistic exploration. Results: 2-week repeated chemogenetic activation of PVH CRH neurons induced a 5-fold corticosterone release, consistent with increased daily 3-hour wakefulness and corresponding decreases in both rapid eye movement (REM) as well as non-REM sleep. Over 30% of chronic CRH activation mice displayed difficulties in maintaining balance and experienced premature mortality. Mice subjected to prolonged CRH activation showed impaired left ventricular ejection fraction (67.9% versus 48.2%, p=0.0011), and immune cell infiltration demonstrated by histological staining. Intriguingly, the number of circulating monocytes increased. Then, we performed bulk RNA-sequencing of heart and bone marrow from CRH-activated and control mice. Differential gene expression and gene set enrichment analysis (GSEA) indicated marked activation of interferon-beta-related pathways in both tissues. Cytosolic DNA-sensing pathway and related key effector genes (cGAS, Cxcl10, Ccl5) were found up-regulated in the heart, while the mitochondrial oxidative phosphorylation pathway was suppressed. We further adopted the CIBERSORT tool to estimate immune infiltration in heart tissues and characterized M1 macrophage as the main pro-inflammatory cell. In our stress-related sleep disturbance mouse model, macrophages in the heart and bone marrow shared similar properties inducing interferon-stimulated genes. Conclusion(s): Taken together, we report a failing heart in a mouse model of stress-related sleep disturbance. The neuro-immune axis involvement and molecular mechanisms merit in-depth explorations.
Abstract 4143671: Transcatheter annuloplasty of tricuspid regurgitation with the K-Clip system: one-year results from the TRISTAR study.
Authors: QINCHUN JIN, XIAOCHUN ZHANG, DAXIN ZHOU
Journal: Circulation (2024)

Background: Despite progressively high morbidity and mortality rates associated with severe tricuspid regurgitation (TR), limited treatment options are available. Aims: The single-arm, multicenter, prospective TRISTAR study(K-Clip Transcatheter Annuloplasty System in Tricuspid Regurgitation(TRISTAR) Early Feasibility Study) evaluated the 1-year outcomes of the novel transcatheter K-Clip reconstruction system in treating secondary TR. Methods: Between May 2022 and October 2022, patients with ≥severe secondary TR at 11 centers, despite medication therapy, were deemed candidates for transcatheter tricuspid repair by the local Heart Team and a multidisciplinary screening committee. Results: Ninety-six patients were enrolled(mean age 72.7±7.1 years, 60.4% female, mean TRISCORE 5.3±2.1). Technical success and procedural success were achieved in 97.9% and 93.8%. At 1 year, echocardiography showed average reductions of annular septolateral diameter by 11.3% (41.9mm vs. 37.1mm, p &lt; 0.001) with increases in stroke volume(60.8±18.5mL vs 67.6±19.8mL, p &lt; 0.001) and cardiac output(4.3±1.5 vs 5.3±2.0, p &lt; 0.001). Tricuspid regurgitation was reduced to ≤moderate in 82.5% with ≥1-grade reduction in 97.7% and ≥2-grade reduction in 66.3%. Patients experienced significant clinical improvements in New York Heart Association (NYHA) functional class I/II (32.6% to 96.5%, p &lt; 0.001). Six-minute walk test increased by 31.9m(304.3±81.2, p&lt;0.001), and overall Kansas City Cardiomyopathy Questionnaire (KCCQ) score improved by 7.6 points(66.7±16.89 vs 74.4±13.6, p&lt;0.001). No cardiovascular mortality was reported while severe bleeding was reported in 5 patients. Kaplan-Meier estimated of survival and freedom from heart failure re-hospitalization were 97.8% and 95.1%, respectively. Conclusions: One-year experience using the K-Clip tricuspid annuloplasty system demonstrated high survival rates, low complications and durable improvements in TR reduction, functional status, and quality of life for patients with severe secondary TR.&lt;div id="accel-snackbar" style="left: 50%; transform: translate(-50%, 0px); top: 50px;"&gt; &lt;/div&gt;
Abstract 4143715: An unusual cause for very early dysfunction of a bileaflet mechanical mitral valve (when push comes to shove)
Authors: Omar Khdeir, Brian Kliewer, Kofi Vandyck, Luis Velazco, Chittur Sivaram
Journal: Circulation (2024)

Description of Case: A 44-year-old man with a history of mitral valve prolapse and mitral valve repair with triangular resection and partial annuloplasty ring placement eight years prior to presenting with dyspnea and decreased exercise tolerance. His TTE showed severe mitral stenosis with thickening of the posterior mitral leaflet. A redo sternotomy with mitral valve replacement was planned. Intra-procedurally, it was noted that the previous partial annuloplasty ring was impinging on the proximal portion of the posterior leaflet resulting in restricted motion, there was also fusion of the commissures. The partial annuloplasty ring was removed, and a 25 mm On-X mechanical valve was implanted in the mitral position. At the end of surgery, after the patient was off cardiopulmonary bypass, he developed severe hypoxia, and he was started on inhaled nitric oxide. Due to the concern for poor lung compliance, his sternotomy was not closed, and packing was placed in the anterior mediastinum and covered with an antimicrobial incise drape. In the surgical ICU, he became hypotensive and required ionotropic and vasopressor support. After diuresis, the surgical team decided to bring him back to the operating room on postoperative day 3 with concerns for mechanical valve dysfunction with the possibility of redo valve replacement in addition to closure of the anterior mediastinum and sternum. Intraoperative TEE showed that the anterolateral prosthetic mitral valve disc was fixed in the open position. There was no thrombus seen on the leaflets or the valve apparatus. On removal of the anterior mediastinal packing, the valve leaflet started functioning normally. The chest was closed without the need to redo the mechanical mitral valve. Discussion: Mechanical valve dysfunction can be either endogenous or exogenous. Our case represents a unique cause of early mechanical mitral valve dysfunction related to external compression by surgical packing impinging on the anterolateral disk inferior to the left atrial appendage from the ventricular side. Intraoperative TEE with 3-D played a vital role in the recognition of this complication and the prevention of redo valve replacement.
Abstract 4143725: Down-regulation Of Cardiomyocyte Isocitrate Dehydrogenase 2 Mediates Metabolic Reprogramming, Contributing To Heart Failure By Remodeling The Lactate Microenvironment.
Authors: Juncong Li, Xiaolin Duan, Dongtu Hu, Pei Liu, Ying-wen Lin, Guoheng Zhong, Liming Wen, Shunyi Li, hao Zhang, Xiangjie Lin, Qingchun Zeng
Journal: Circulation (2024)

Backgroud: Metabolic and ventricular remodeling are early events of pressure overload that lead to heart failure. Metabolic remodeling is characterized by an imbalance between the tricarboxylic acid cycle and glycolysis.This imbalance increases glucose uptake by the heart, promotes glycolysis, and leads to its dissociation from oxidative phosphorylation, resulting in increased lactate production. Research Aim: To investigate whether there are genes that regulate the switching of energy metabolism patterns during pressure overload and act through lactate. Results: We used untargeted metabolomics to detect changes in metabolite content in transverse aortic constriction (TAC) mice and analyzed bulk RNA sequencing and single-cell sequencing data from public databases. Combined with a systematic literature review, we found that isocitrate dehydrogenase 2 (IDH2) plays an important role in switching energy metabolism modes, suggesting that IDH2 may be a potential therapeutic target.Silencing IDH2 in TAC mice using AAV resulted in an aggravated cardiac hypertrophy phenotype, accompanied by more extensive cardiac fibrosis compared to wild-type (WT) mice. On the contrary, overexpression of IDH2 by AAV attenuated cardiac hypertrophy in TAC mice. Mechanistically, IDH2 deficiency aggravates cardiomyocyte acidification, prompting cardiomyocytes to release lactate to maintain intracellular acid-base balance. Lactate, acting as a "signal molecule," is taken up by macrophages to promote H3K18 lactylation, which further enhances the expression of pro-inflammatory cytokines. In contrast, cardiac overexpression of IDH2 via AAV and administration of a lactate inhibitor alleviated cardiac hypertrophy and fibrosis.These findings suggest that lactate plays an important role in heart failure. Cardiomyocyte IDH2 can regulate the metabolic mode of cardiomyocytes and affect the lactate microenvironment, thereby altering the inflammatory state of macrophages and impacting pathological cardiac hypertrophy. Conclusion: IDH2 may be involved in the regulation of cardiac metabolism during pressure overload, leading to myocardial acidification, promoting the release of lactate and affecting the inflammatory state. This suggests the possibility of IDH2 as a potential therapeutic target and the nonmetabolic function of lactate as an intercellular signaling molecule. These findings will help to further explore the role of energy metabolic turnover in the occurrence and development of heart failure.
Abstract 4143639: Night Shift Work is Associated With Coronary Microvascular Dysfunction: Involvement of Impaired Fatty Acid Utilization Revealed by Microbial and Metabolic Profiles
Authors: Yan Xia, Xinyu Che, Ao Chen, Zhangwei Chen, Juying Qian, Junbo Ge
Journal: Circulation (2024)

Background and Aims Night shift work increases the risk of coronary artery diseases, contributing to worsened prognosis. However, the association between night shifts and coronary microvascular dysfunction (CMD) remains unclear. This study aimed to investigate whether night shift workers have a high incidence of CMD, and the potential mechanisms linking night shifts and CMD. Methods We collected cross-sectional clinical traits of traditional cardiovascular risk factors and sleep-related parameters in a security guards cohort at Fudan University. 101 subjects with no history of coronary artery disease were enrolled, of which 50 were night shift workers. Coronary flow reserve (CFR) &lt; 2.0 evaluated by single-photon emission computed tomography (SPECT) myocardial perfusion imaging was recognized as CMD. Integrated analysis of fecal 16s sequencing and serum untargeted-metabolomics was conducted for mechanistic exploration. Microbial features were centered log-ratio(CLR)-transformed for differential enrichment analysis, while metabolic traits were inverse-normal transformed. Results After adjusting for age, BMI, remnant cholesterol, TyG (triglyceride-glucose index), NT-pro BNP, and melatonin, night shift work was associated with increased occurrence of CMD (OR 5.26, 95% CI 1.41-28.71; P = 0.012). One year of prolonged night work was 29% more likely to have declined CFR, with an increasing trend between shift durations and CMD (P for trend 0.005). Instead of evident abnormalities in traditional cardiovascular risk factors, night shifts favored a microbial and metabolic profile of perturbed lipid metabolism. Specifically, reduced abundances of probiotic Lactobacillus species and an array of Bacteroides species were the main contributors to the dysbiosis of night-shift gut microbiota. Circulating metabolites of increased 2-Hydroxyhexadecanoylcarnitine and reduced LysoPC(16:0/0:0), a potential feature of impaired palmitic acid utilization, partially mediated the association between night shifts and CMD. Species- and metabolites-based classifiers of CMD status added predicting power combined with night shift durations. Conclusions The current study found working night shifts is associated with CMD independent of traditional cardiovascular risk factors. Identifying gut microbiota and circulating metabolites linked to CMD will help to recognize high-risk night shift workers. Probiotics or metabolite supplementation may be promising in conducting a healthier night shift.
Abstract 4143525: Real-World Data On Cardiovascular Outcomes In Colchicine Use After Acute Myocardial Infarction
Authors: Sittinun Thangjui, Kerollos Abdelsayed, Michele Fouad, Basma Amer, Basel Abdelazeem, Mohamed Ellabban, Khaled Elfert, sudarshan balla
Journal: Circulation (2024)

Background: After acute myocardial infarction (AMI), physicians typically address traditional coronary artery disease risk factors such as LDL-C, smoking, hypertension, and diabetes. However, residual inflammatory risk may be overlooked. Low-dose colchicine has been shown to reduce stroke and recurrent angina requiring revascularization in clinical trials, but real-world data is limited. This study aims to evaluate the use of colchicine post-AMI and its impact on cardiovascular outcomes. Methods: We utilized the TriNetX database (January 2006 to January 2023) to include all new AMI patients aged ≥18 years who underwent revascularization, comparing those started on colchicine post-AMI to those who were not. Baseline characteristics were assessed. At a 5-year follow-up, outcomes such as death, cardiac arrest, recurrent AMI or revascularization, heart failure (HF), stroke, new-onset atrial fibrillation (AF), and diarrhea were evaluated. Results: Out of 151,182 patients, 3,099 (2%) were started on colchicine after the index AMI. The mean ages were 64.7±12.1 years for the non-colchicine group and 65.6±11.8 years for the colchicine group. At 5 years, the colchicine group had a lower incidence of composite cardiovascular outcomes (56.3% vs. 82.6%, p &lt; 0.01). Specifically, recurrent AMI/revascularization (12.4% vs. 71.2%, p &lt;0.01), cardiac arrest (2.7% vs. 5.3%, p&lt;0.01), and stroke (5.8% vs. 7.3%, p&lt;0.01) were lower in the colchicine group. However, new-onset AF was higher in the colchicine group (26.8% vs. 21.8%, p&lt;0.01). No significant differences were observed in death (14.3% vs. 15.1%, p=0.25), HF (38.1% vs. 37.7%, p=0.62), and diarrhea (8.5% vs. 8.2%, p=0.62). Propensity matching showed better cardiovascular outcomes for the colchicine group across all subgroups. Conclusion: Colchicine use post-AMI is associated with improved cardiovascular outcomes in a real-world setting, although its utilization remains low.
Abstract 4143746: Single Center Rates and Trends in Diagnosis of Necrotizing Enterocolitis in Pediatric Shunt-Dependent Congenital Heart Disease
Authors: Jarae Payne, Keith Baxelbaum, Robert Olsen, Deepthi Gunturi, Svetlana Ostapenko, Melanie Savoca, Erin Sullivan, J Gaynor, Benjamin Kozyak, Monique Gardner
Journal: Circulation (2024)

Background: Necrotizing enterocolitis (NEC) is a rare comorbidity in infants with heart disease, specifically those with shunt-dependent congenital heart disease (SDCHD). We aimed to describe NEC incidence and cofactors in our center’s SDCHD population and diagnostic practice changes. Methods: A retrospective case-control study in patients who underwent first staged palliation for SDCHD between 1/1/2013 and 6/30/2022. Palliation procedures included stage one Norwood with a BTTS or RV to PA conduit, hybrid, BTTS only or PDA stent. Demographics, clinical factors, and diagnostics including abdominal ultrasound (AUS) were abstracted for subjects for 21 days after palliation. NEC was defined with Bell’s criteria from databases and AUS was assessed by chart review. Hierarchical logistic regression models assessed surgical era rates into three cohorts 2013-2016, 2017-2019, and 2020-2022. Groups were compared with Chi-square, Fisher’s exact test, Wilcoxon rank-sum tests, and trends over time with logistical regression. Results: Of 531 patients included, 77 (14.5%) had NEC. There was no association of NEC diagnosis with sex, race, and ethnicity, presence of genetic syndromes or extracardiac abnormalities. The primary and majority SDCHD diagnosis was hypoplastic left heart syndrome and variants (61%). On univariate analysis, risks significantly associated with NEC include younger gestational age, delayed sternal closure, catheter reintervention, ECMO, cardiac arrest, seizures, &gt;/= moderate ventricular dysfunction, increased pre- and post-procedural VIS scores, and postoperative anemia. Logistic regression found a significant increase in NEC by year, with a 23% increase in odds for each increasing year across the time range (OR 1.23, 95% CI 1.12-1.36, p&lt;0.001) and odds of AUS use significantly increased by year (OR 1.14, 95% CI 1.05-1.24, p=0.003). When controlling for gestational age, procedure type, presence of a genetic syndrome and chromosomal abnormality the odds of having a NEC diagnosis increased by 1.24 on average with each change in era. Conclusions: Rates of NEC diagnoses at our institution have increased over time with ultrasound as a diagnostic indicator. Clinical risks factors suggesting higher acuity of illness were associated with higher rates of NEC. Further studies are needed to assess AUS sensitivity and its contribution to NEC rates, as well as a multicenter analysis to collate risk factors for this fragile patient population.
Abstract 4143776: Growth Differentiation Factor 15 is a Novel Cardiac Hormone that Causes Cachexia in Heart Failure
Authors: Maya Trujillo, Ria Gupta, Da Young Lee, Zhe Jiao, Samuel Berhanu, Andrew Antolic, M. Neale Weitzmann, Michael Burke
Journal: Circulation (2024)

Background: Cachexia is a common complication of heart failure (HF) and is associated with high mortality. Growth differentiation factor 15 (GDF15) regulates food intake and can cause cancer cachexia. GDF15 is a sensitive biomarker in humans, though its biologic function in HF is unknown. Objective: We sought to define the role of GDF15 in HF. Methods: We utilized a genetic mouse model of dilated cardiomyopathy (DCM) caused by a mutation in the phospholamban gene (PLN R9C ). PLN R9C mice have dysregulated cardiac calcium handling (a common feature of nearly all forms of HF) and develop progressive DCM that leads to HF and premature death. Expression analyses were performed on tissue and isolated myocardial cells via flow cytometry and single nucleus RNA-sequencing (snRNA-seq) in PLN R9C and age-matched wild type (WT) mice. A double transgenic mouse was created by crossing PLN R9C with a constitutive Gdf15 knock-out (KO). Cardiac function and fibrosis were assessed using echocardiography and histochemistry, respectively. We measured food intake in individually housed mice, and tissue composition was quantified by weight at necropsy, dual-energy X-ray absorptiometry (DXA) and histochemistry. Survival was assessed by Kaplan-Meier. Results: GDF15 mRNA (43-fold; p&lt;0.01) and protein (54-fold; p&lt;0.01) were increased in LV tissue, and circulating GDF15 was elevated (8.3-fold; p=0.03) in PLN R9C mice. In other organs, Gdf15 expression was minimal and did not increase with DCM. Single nucleus sequencing revealed that Gdf15 was specifically increased in cardiomyocytes with progression to DCM. The GDF15-specific receptor GDNF-family receptor a-like (GFRAL) was selectively expressed in the hindbrain of these mice. PLN R9C mice consumed less food and developed cachexia (reduced fat and lean mass at necropsy, reduced fat mass by DXA and reduced skeletal muscle cross-sectional area; p&lt;0.01 for all vs. WT), findings that were reversed in PLN R9C - Gdf15 KO mice. Gdf15 KO had no effect on cardiac structure or function by echocardiography and PLN R9C / Gdf15 KO mice displayed only a small reduction in cardiac fibrosis relative to PLN R9C mice (-3%; p&lt;0.01). Despite this, Gdf15 KO prolonged survival in PLN R9C (29±3 vs. 25±3 weeks; p&lt;0.01). Conclusions: Selective upregulation of GDF15 in failing cardiomyocytes triggers cardiac cachexia and worsens survival by an extra-cardiac mechanism. We therefore propose that GDF15 is a novel cardiac hormone produced in HF.
Abstract 4143692: Racial Disparities in Age-adjusted Sudden Cardiac Death Rates in the United States: Insights from CDC-WONDER Database, 1999-2020
Authors: Hitesh Bhatia, Adishwar Rao, Muhammad Khan, Akriti Agrawal, Siddharth Agrawal, . Parul, Asna Aafreen, Shraddha Bhattarai, Saurabh Sharma
Journal: Circulation (2024)

Hypothesis: Small prospective and dataset-based studies predicted the rates of sudden cardiac death (SCD) are higher in the African American (AA) population as compared to White Americans (WA). However, there is a lack of long-term data over two decades looking for racial differences in SCD. Aim: Our study aims to analyze and quantify the racial differences in age-adjusted mortality rates(AAMR) related to SCDs between AA and WA to further explore potential contributing factors, such as socioeconomic status, sex, and varied comorbidity burdens, to these differences. Methods: We analyzed the Centers for Disease Control and Prevention (CDC) Wide-ranging Online Data for Epidemiologic Research (WONDER) database, containing death certificate records for various causes of mortality in the US from 1999 to 2020. We searched the CDC WONDER database for patients, 18-45 years old whose cause of death was SCD corresponding to ICD-10 code; I46.1. We searched for AAMR and stratified patients based on race and gender on a total population of 48668 (41975 WA; 6693 AA). Temporal trends were analyzed by fitting log-linear regression models using the Joinpoint Regression Program. Results: We calculated annual percent change (APC) with 95% confidence intervals (CIs) in AAMR for the line segments linking joint points. The AAMR for SCDs in AA males ranged from 2.1% in 2000 to 0.9% in 2020 with an APC of 0.68 between 1999 and 2009, -26.72 between 2009 and 2012, and 4.34 between 2012 and 2020 suggest that the rate peaked between 2008 and 2010, followed by a significant decline in the following years. WA males had consistently lower rates compared to AA males. The AAMR for WA males peaked at 1.5% in 2000 followed by a stepwise decline until it reached a rate less than 0.9% in 2020, with APCs -1.32 between 1999 and 2009, -19.58 between 2009 and 2012. [Figure A]. AA females had APCs of 2.01, -31.88, and 1.73 while WA females had APCs of -2.32, -21.38, and 0.43 between 1999 and 2009, 2009 and 2012, and 2012 and 2020, respectively [Figure B]. Rates in AA females had a similar progression to that in AA males [Figure C]. Conclusion: Racial disparities in SCDs related AAMR in the US suggest the role of a complex interplay between healthcare delivery, underlying pathological processes, and race. AA demonstrated higher age-adjusted SCD rates than WA. These findings should be used to guide policymaking and address areas of unmet need in providing racially equitable healthcare for all patients.