tbuckley/cabot-search huggingface dataset:
Abstract 4142317: β-hydroxybutyrate attenuates abdominal aortic aneurysm formation via BHB-mediated epigenetic modification of CTPS1 expression
Authors: LIXIN FANG, Yuanwei Chen, Fan Yang, Jianfang Luo
Journal: Circulation (2024)

Background: Ketone body β-hydroxybutyrate (BHB), a lipid metabolic intermediate, is known as protective functions in cardiovascular diseases. We had reported that BHB attenuated chronic kidney disease through anti-inflammation. Abdominal aortic aneurysm (AAA) is a devastating cardiovascular disease without effective medication treatment. It is unclear whether BHB attenuates AAA formation and the potential molecular mechanism. Methods: Exogenous supplementation of BHB, and systemic HMGCS2(the key enzyme for the synthesis of BHB) knockout mice were employed to observe the effect of BHB on AAA with angiotensin II (Ang II)-induced in ApoE knockout/CaPO4-induced in C57BL/6J mice. Ultrasonography, histology and immunohistochemistry, Gelatine zymography were used to evaluate the formation of AAA. Bioinformatics analysis, small interfering RNA, pathway inhibitor, DNA pulldown and CUT&amp;RUN were used to explore the potential mechanisms. Results: Clinically, we found that AAA patients showed low expression of BHB in serum and in aortic tissue compared with healthy human subject. Exogenous supplementation of BHB exhibited a reduced maximal diameter of AAA, alleviated vascular elastin degradation, and decreased the gathering of extracellular matrix proteins (MMPs) in Ang II-induced ApoE knockout mice and CaPO4-induced C57BL/6J mice through decreasing the expression of inflammasome and MMPs in both macrophage and vascular smooth muscle cells (VSMCs). Conversely, HMGCS2 knockout mice significantly increased maximal diameter and deteriorated elastic fiber degradation of abdominal aorta. Furthermore, BHB attenuated Ang II+LPS-stimulated inflammasome and LPS-stimulated MMPs expression through PI3/AKT dependent mechanism, while the suppressive effects of BHB were reversed by LY294002 (PI3-kinase inhibitor). The top 10 most differentially upregulated mRNAs were identified by transcriptomics on the aorta, of these, Cytidine triphosphate synthase 1(CTPS1) was closely related to PI3K/AKT signaling pathway. We found that BHB significantly increased the expression of CTPS1, which CTPS1 siRNA could diminished the inhibition of BHB on inflammasome and MMPs in vivo and in vitro. Finally, we found that BHB regulated CTPS1 expression by enhancing local β-hydroxybutyrylation of H3K9 at the promoter of CTPS1 gene. Conclusion: BHB attenuated AAA formation via BHB-mediated epigenetic modification of CTPS1 expression which activated PI3K/AKT signaling pathway in macrophages and VSMCs.
Abstract 4142564: A Body Shape Index at Age 25-64 Predicts Mortality and CHD Hospitalization
Authors: Itamar Shafran, Nir Krakauer, Jesse Krakauer, Gali Cohen, Yariv Gerber
Journal: Circulation (2024)

Introduction: Obesity is a known risk factor for cardiovascular disease (CVD) morbidity and mortality. A body shape index (ABSI) is a waist circumference (WC) measure of abdominal obesity independent of body mass index (BMI) that has been shown to predict mortality and numerous clinical outcomes. Aims: To study the predictive value of ABSI in conjunction with BMI for all-cause mortality and coronary heart disease (CHD) hospitalization among adult participants. Methods: Participants (n=2,225) were drawn from the First Israeli National Health and Nutrition Survey (1999-2001), constituting adults aged 25-64. Baseline anthropometrics, including weight, height, and WC, were measured and expressed as their allometric indices: BMI (weight/height 2 ) and ABSI [WC/(BMI 2/3 *height 1/2 )]. Follow-up lasted through 2021 for mortality and 2022 for hospitalizations. Cox regressions assessed the adjusted risk of all-cause mortality and CHD hospitalization. Results: The baseline mean [SD] age was 43 [11] years, and 50% were women. The correlation between BMI and WC was 0.78, and 0.02 for BMI and ABSI. Over a median follow-up of 21 years, 247 (11.1%) deaths occurred. The multivariable-adjusted hazard ratios (HRs) for mortality per 1 SD increase in BMI and ABSI were 1.11 (95% CI: 0.97; 1.27) and 1.55 (95% CI: 1.33; 1.79), respectively (Table). ABSI exhibited a significant association with mortality risk across all standard BMI categories; adjusted for demographics and classic CVD risk factors, the HRs (95% CIs) per 1 SD increase in ABSI were 1.38 (1.01; 1.88) for individuals with a BMI of 18.5-24.9, 1.70 (1.34; 2.16) for BMI 25.0-29.9, and 1.46 (1.13; 1.87) for BMI ≥30.0. Among CVD-free participants at baseline (n=2,146), 267 (12.4%) were hospitalized for CHD during follow-up. The latter had higher ABSI (0.082 vs. 0.078, P&lt;.001) and BMI (28.1 vs. 26.7, P&lt;.001) than individuals who remained free of CHD. An increase in the adjusted HR was seen for both ABSI [1.34 (95% CI: 1.15; 1.55)] and BMI [1.16 (95% CI: 1.01; 1.33)] (Table). Conclusion: In a 20-year prospective study of a middle-aged cohort, baseline ABSI was a stronger predictor of mortality than BMI and predicted CHD hospitalization independently of BMI.
Abstract 4142590: Machine Learning Approaches for Predicting Cardiac Rehab Utilization in Patients with Cardiovascular Diseases
Authors: Xiarepati Tieliwaerdi, Kathryn Manalo, Aaisha Shah, Muhammad Ibraiz Bilal, Andrew Oehler
Journal: Circulation (2024)

Background/purposes: Cardiac rehabilitation (CR) is shown to reduce cardiovascular mortality and hospital re-admissions in patients with cardiovascular diseases. Despite its benefits, CR faces challenges with low participation rates: only 25% of eligible patients attend at least one session, and only 27% of those who participated complete the recommended 36 sessions. This study aims to predict non-attenders and incomplete-attenders in CR using machine learning (ML) algorithms to guide early interventions for improving adherence. Methods: This was a retrospective study of patients referred to CR at a single outpatient center from 2020-2023. The dataset was split into training and testing sets at a 7:3 ratio. Patient demographics, travel distance, medical comorbidities, referral indications and insurance type were used for prediction. We employed multiple ML algorithms including XGBoost, AdaBoost, random forest (RF), decision tree(DT). Those models were compared to traditional prediction models such as logistic regression (LR). Model performance was assessed using area under the curve(AUC) of the receiver operating characteristic (ROC) curve and mean absolute error (MAE) to measure the difference between predicted and actual completion sections. Results: Among 762 patients referred to CR, 16.1% (n=123) were non-attenders, 60.1% (n=458) were full attenders, and 23.8% (n=181) were incomplete attenders (Figure 1). The XGBoost model showed the best performance with an AUC of 0.72 (Figure 2), indicating a 72% chance of correctly predicting patients who are full attenders and those who are incomplete attenders or non-attenders. This was followed by RF, AdaBoost and DT models. LR had the poorest performance. The MAE was 8.2, indicating a significant error between predicted and actual sessions attended. Conclusion: ML models outperform LR in predicting patients with a low CR participation rate but are not precise in predicting the exact number of attended sessions.
Abstract 4142247: Granzyme B PET Imaging for Non-Invasive Early Diagnosis of Acute Heart Allograft Rejection
Authors: Zhuxin Wei
Journal: Circulation (2024)

Background: Cardiac transplantation remains the single most effective treatment for end-stage heart failure. Despite the routine use of anti-rejection drugs in clinical practice, approximately 40% of cardiac transplant patients still experience unavoidable rejection. Timely diagnosis of early acute rejection (AR) is essential to prevent further tissue damage. Transplant rejection and graft damage is primarily mediated by recipient cytotoxic CD8 + T cells, which attack allografts by releasing perforin and granzyme B (GzmB). Aim: This study aimed to evaluate whether GzmB-targeted positron emission tomography (PET) imaging agent ( 68 Ga-grazytracer) can characterize T lymphocyte infiltration in AR. Method: Mice were subjected to GzmB-targeted PET/CT on POD 3, 5, and 7. Autoradiography, Masson staining, immunohistochemistry, and flow cytometry were performed to verify the inflammatory infiltration and graft damage . Allograft-bearing mice were intraperitoneally administered with tacrolimus (2 mg kg −1 ) daily from operative day to post-operative day (POD) 7. Result: The uptake of 68 Ga-grazytracer was observed increased with the extension of rejection time(SUVmax:0.54 ± 0.07 vs. 0.19 ± 0.05 at POD 7 days, P&lt;0.001). To assess 68 Ga-grazytracer sensitivity and specificity between isograft and allograft groups, POD 7 PET/CT imaging were analyzed for their catalytic activities by receiver-operating-characteristic(ROC)analysis (AUC=0.95, 95% CI = 0.8143–1). HE staining of the myocardium indicated massive inflammatory cell infiltration and disruption of the myocardial integrity in the allograft myocardium. Immunohistochemistry and flow cytometry showed significantly high expression of GzmB and CD8, in line with the PET/CT imaging results. Autoradiography revealed 68 Ga-grazytracer accumulation in the transplanted heart. The 68 Ga-grazytracer uptake of treated mice was significantly reduced compared with that in the allograft group (SUVmax: 0.262±0.05% vs. 0.54±0.07 at POD 7 days; P&lt;0.001). Daily treatment with tacrolimus improved heart allograft outcome and graft survival curves revealed complete rejections of the allograft within POD 15±3 days. Conclusion: This study demonstrated the potential of 68 Ga-grazytracer imaging to delineate early non-invasive diagnosis of heart allograft rejection. This study provides an entirely imaging-based method for monitoring allograft status. In the future, the development of imaging of GzmB may be more readily translated into clinical applications.
Abstract 4142501: Bystander Abdominal Thrusts and Back Blows were Associated with Favorable Neurological Outcomes in Patients with Foreign Body Airway Obstruction
Authors: Yutaka Igarashi, Tatsuya Norii, Shoji Yokobori
Journal: Circulation (2024)

Background: Foreign body airway obstruction (FBAO) represents a major public health challenge in developed countries with aging populations. We previously reported that bystander FBAO interventions were associated with about a two-fold increase in favorable neurological outcomes; however, the impact of each different type of intervention on patient outcomes remains unknown. Hypothesis: We hypothesize that abdominal thrusts and back blows are associated with favorable neurological outcomes in patients with FBAO compared to no bystander intervention. Methods: The MOCHI (Multi-center Observational CHoking Investigation) registry is a prospective, multi-center study conducted in Japan, focusing on patients with FBAO in emergency departments. From April 2020 to March 2023, 25 hospitals, including eight university hospitals, participated. For this analysis, we included only adult patients who were over 18 years. Data were collected electronically, documenting demographics, FBAO specifics, bystander characteristics, intervention types, and 30-day outcomes. Primary outcomes were favorable neurological outcome defined as Cerebral Performance Category 1 or 2 and survival outcome at 30 days. Inverse probability of treatment weighting (IPTW) and logistic regression were used to adjust for potential confounders. Results: Among 407 patients, 24, 76, and 175 received abdominal thrusts, back blows, and no bystander interventions, respectively, while the rest received other interventions. Median age was 81, with equal male-to-female ratio. FBAO incidents mainly occurred at home (57%). Patients with abdominal thrusts or back blows had higher rates of favorable neurological outcome than those without bystander interventions (37% vs. 15%, p = 0.01 for abdominal thrusts; 32% vs. 15%, p = 0.004 for back blows). IPTW analysis showed that abdominal thrusts and back blows groups had higher rates of favorable neurological outcome compared to the no-bystander intervention group (38% vs. 15%, p = 0.038 for abdominal thrusts; 31% vs. 16%, p = 0.013 for back blows). Cox proportional models showed that the back blow was independently associated with survival (adjusted Hazard Ratio [HR] 0.52, 95% CI, 0.35–0.78); however, abdominal thrusts was not independently associated with survival (adjusted HR 0.73, 95% CI, 0.40–1.35). Conclusion: Bystander abdominal thrusts and back blows were associated with favorable neurological outcomes in FBAO compared with no bystander intervention.
Abstract 4142484: Mechanism of miR-203a-3p regulating the proliferation and migration of PASMCs through PIK3CA/PI3K/Akt pathway in PAH
Authors: Tengteng Zhu
Journal: Circulation (2024)

Background: Pulmonary arterial hypertension (PAH) is characterized by an elevation in pulmonary vascular resistance and arterial pressure, culminating in right ventricular failure and mortality. Excessive proliferation and accumulation of pulmonary artery smooth muscle cells (PASMCs), driven by aberrant gene expression, stand as hallmark pathologies of PAH. Among the regulatory elements implicated in this process, microRNAs (miRNAs) such as miR-203a-3p are crucial, influencing cellular proliferation and migration. Nevertheless, the precise role and mechanisms through which miR-203a-3p modulates PAH pathophysiology remain poorly defined. Objective: This study seeks to elucidate the expression patterns and functional roles of miR-203a-3p in idiopathic pulmonary arterial hypertension (IPAH) and in rodent models of PAH, with an emphasis on understanding the underlying molecular mechanisms. Methods: Expression levels of miR-203a-3p were quantified in plasma from IPAH patients and healthy controls via RT-qPCR at the Second Xiangya Hospital. Rodent models of PAH were generated using either Monocrotaline (MCT) or Su5416 in conjunction with chronic hypoxia. MiR-203a-3p expression in plasma and lung tissue was evaluated at predetermined intervals. Additionally, the effects of miR-203a-3p overexpression on primary PASMC functions were assessed, and therapeutic potential was explored through administration of an adeno-associated virus vector encoding miR-203a-3p prior to model induction. Results: Significantly reduced levels of miR-203a-3p were observed in both IPAH patients and PAH-model rats compared to healthy controls, correlating inversely with indicators of disease progression. Overexpression of miR-203a-3p inhibited PASMC proliferation and migration and attenuated disease phenotypes in experimental models. Molecular analysis revealed that miR-203a-3p directly targets PIK3CA, influencing the PI3K/Akt signaling pathway, a critical mediator of PASMC function. Conclusion: The downregulation of miR-203a-3p in IPAH and its regulatory impact on PASMC behavior via the PIK3CA/PI3K/Akt pathway highlight its potential utility as a biomarker and therapeutic target in PAH. These findings provide a foundation for further investigations into the therapeutic benefits of miR-203a-3p in the clinical management of PAH, supporting its development as a novel therapeutic strategy.
Abstract 4142305: Demand Ischemia Predicts Worse Cardiovascular Outcomes in Patients With Nonocclusive Coronary Disease Admitted for Nonsevere Sepsis
Authors: Boluwaduro Adeyemi, Ahmad Harb, Oluwafunmbi Fatunmbi, Mariam Khabsa, Folake Ishola, Chidubem Ezenna, Gabriel Alugba, Raj Desai
Journal: Circulation (2024)

Background: Demand ischemia is typically ascribed little importance but likely indicates an elevated cardiovascular risk that is more significant than current convention dictates, despite the absence of plaque rupture. Hypothesis: Demand ischemia likely predicts worse 3-month cardiovascular outcomes in patients with nonocclusive CAD admitted for nonsevere sepsis. Methods: We conducted a retrospective cohort study using data from the National Readmissions Database 2017 to 2020 to evaluate whether demand ischemia predicts increased risk of 3-month readmission with adverse cardiovascular outcomes in patients with nonocclusive CAD admitted for nonsevere sepsis. The outcomes of interest were 3-month readmissions with acute heart failure, ventricular tachyarrhythmia, cardiogenic shock, STEMI, acute respiratory failure, AKI and vasopressor use. Multivariate analysis was employed to derive adjusted odds ratios (OR) after accounting for age, Charlson comorbidity index, household income, hospital location and size, hypertension, diabetes mellitus, hyperlipidemia, CHF, atrial fibrillation/flutter, CKD, tobacco use, anemia, malnutrition, obesity, OSA and OHS. Results: Among patients with nonocclusive CAD admitted for nonsevere sepsis, 717,110 did not have demand ischemia, compared to 25,728 patients who did. In patients with demand ischemia, our results showed significantly increased risk of 3-month readmission with acute heart failure (OR 2.10, P &lt; 0.0005, CI 2.00 – 2.19), ventricular tachyarrhythmia (OR 2.51, P &lt; 0.0500, CI 1.19 – 5.34), cardiogenic shock (OR 1.66, P &lt; 0.0005, CI 1.45 - 1.90), acute respiratory failure (OR 1.97, P &lt; 0.0005, CI 1.89 – 2.05), AKI (OR 1.48, P &lt; 0.0005, CI 1.42 – 1.54) and vasopressor use (OR 1.52, P &lt; 0.0005, CI 1.31 – 1.78) There were no cases of 3-month readmissions with STEMI, possibly due to coding. Conclusion: Our results indicate that despite being considered a relatively benign diagnosis, demand ischemia is likely actually a marker for meaningfully elevated cardiovascular risk. Further studies will be needed to support this idea and to identify interventions that mitigate the risk.
Abstract 4142228: The Association Between Sodium-glucose Cotransporter-2 Inhibitors and Major Adverse Cardiac Events in Tafamidis-treated Transthyretin Amyloid Cardiomyopathy: A Real-World Analysis
Authors: Kuan Yu Chi, Pawel Borkowski, Anita Osabutey, Dimitrios Varrias, Junmin Song, Cho Han Chiang, Yu-Cheng Chang, Pei Lun Lee, Yu Chang, Shivank Madan, Snehal Patel
Journal: Circulation (2024)

Background: In patients with transthyretin amyloid cardiomyopathy (ATTR-CM), residual mortality remains high despite the use of tafamidis. Research Question: What is the impact of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on tafamidis-treated ATTR-CM? Aims: We aimed to examine if SGLT2i were associated with additional benefits in this population. Methods: We conducted a retrospective, propensity score-matched cohort study using aggregate data from the TriNetX Global Collaborative Network database. We included adult patients with ATTR-CM, through the identification of tafamidis prescription, between May 1 st , 2019 and Nov 1 st , 2023. SGLT2i users were defined as having SGLT2i prescriptions on the day of tafamidis initiation. SGLT2i nonusers had no records of SGLT2i during the same period. Index date was set as the date of tafamidis initiation. The primary endpoint was major adverse cardiac events (MACE), defined as a composite of any death, hospitalization for heart failure (HF), or cardiac arrest/ventricular tachycardia/fibrillation. Secondary endpoints were individual MACE. We set pneumonia and gastrointestinal bleeding as falsification endpoints. Differences in baseline characteristics between SGLT2i users and non-users were compared using standardized mean differences (SMDs) after propensity score matching. The outcomes were compared within 2 years of index date between SGLT2i users and non-users. Results: Of 4,995 tafamidis-treated ATTR-CM, 468 SGLT2i users were matched with 468 nonusers (mean age: 76.5 vs 76.3; females: 21.0% vs 18.5%; mean ejection fraction: 47.9% vs 47.8%). Important covariates were also balanced between two arms. The use of SGLT2i was associated with a significantly lower risk of MACE (HR, 0.72; 95% CI, 0.57 to 0.92), primarily driven by reductions in hospitalization for HF (HR, 0.69; 95% CI, 0.51 to 0.93) and all-cause mortality (HR, 0.70; 95% CI, 0.50 to 0.98) (Figure). There was no difference in prespecified falsification endpoints between two arms (Figure). Conclusions: In this retrospective database analysis, SGLT2i use in patients with tafamidis-treated ATTR-CM was associated with a significant reduction in MACE. This association warrants further investigation in prospective trials.
Abstract 4142444: The Effect of Left Atrial Filling Pressure on Exercise Arterial Oxygenation in HFpEF: Does the V-wave matter?
Authors: Le Huang, James Macnamara, Tiffany Brazile, Bryce Balmain, Andrew Tomlinson, Christopher Hearon, Tony Babb, Benjamin Levine, Satyam Sarma
Journal: Circulation (2024)

Background: Left atrial (LA) myopathy is common in patients with heart failure with preserved ejection fraction (HFpEF) and is characterized by decreased LA compliance, pulmonary vascular dysfunction, and decreased survival. However, the mechanistic relationship between these variables are unclear. It has been thought pulmonary capillary wedge pressure (PCWP), particularly the v-wave which is directly transmitted backwards into the pulmonary circulation, contributes to worsened pulmonary vascular function through disruption of lung diffusion of oxygen. Though efforts to reduce PCWP, such as with interatrial shunt devices, have not improved outcomes. We hypothesized that HFpEF patients with greater v-wave amplitudes would have worse pulmonary gas exchange assessed by lower arterial partial pressure of oxygen (PaO2) but that reductions in the v-wave amplitude would not improve arterial gas exchange. Methods: Patients with HFpEF underwent upright invasive hemodynamic exercise testing with right heart and radial arterial catheterizations. PCWP tracings and arterial blood gases were obtained during rest and submaximal 20W exercise without (control: con) and with nitroglycerin (NTG) on a semi-recumbent cycle. V-wave peaks were measured manually by two observers (blinded). Results: In 40 patients with HFpEF, mean v-wave amplitudes at rest were 9.9 ± 4.4 mmHg (con) and 9.4 ± 4.0 mmHg (NTG; p=0.33) and during 20W exercise were 27 ± 15 mmHg (con) and 22 ± 9.9 mmHg (NTG; p=0.018). PaO2 at rest was 86 ± 12 mmHg (con) and 82 ± 10 mmHg (NTG) and during 20W exercise was 85 ± 13 mmHg for both control and NTG. PaO2 was negatively correlated with v-wave amplitude across all conditions (figure) but increases in v-wave amplitude from rest to 20W exercise did not correlate with changes in PaO2 under either condition (control: p = 0.49, R^2 = 0.013; NTG: p = 0.55, R^2 = 0.0093). Similarly, reductions in v-wave with NTG did not improve PaO2 at rest or with 20W exercise. Conclusions: While higher v-wave amplitudes correlated with a lower PaO2, changes in v-wave amplitude, whether via increases through exercise or decreases with NTG, had no effect on arterial oxygenation. These results suggest that elevated v-waves may not play a role in decreasing PaO2.