tbuckley/cabot-search huggingface dataset:
Abstract 4141414: Glycoprotein 130 Antagonism Counteracts Autophagy-Mediated Mitochondrial Metabolic Derangements and Improves Right Ventricle Function in Pulmonary Artery Banded Pigs
Authors: Jenna Mendelson, Jacob Sternbach, Ryan Moon, Lynn Hartweck, Felipe Kazmirczak, Kurt Prins
Journal: Circulation (2024)

Background: Right ventricular dysfunction (RVD) is a risk factor for death in PAH, but RV-specific therapies are lacking. We showed inhibition of glycoprotein 130 (GP130) signaling with the small molecule SC144 improved RV function in rodent RVD. However, SC144’s efficacy in a translational large animal model of RVD is untested. Methods: Ten 4-week-old castrated male pigs underwent pulmonary artery banding (PAB). After 3 weeks, PAB pigs were randomized into 2 groups (daily injections of SC144 [2 mg/kg, PAB-SC144, n =5] or vehicle [PAB-VEH, n =5] for 3 weeks). Five pigs of a similar age served as controls. Cardiac MRI quantified RV function, mass, and volume. Mitochondrial morphology was examined from electron micrographs of RV free wall cardiomyocytes. Wheat Germ Agglutinin stained RV cross sections were used to calculate cardiomyocyte remodeling. Lipidomics and metabolomics quantified lipid species and metabolites in whole RV tissue. Quantitative proteomics evaluated RV mitochondrial enrichments. Results: SC144 significantly improved RV ejection fraction (CONTROL: 60±4%, PAB-VEH: 23±11%, PAB-SC144: 38±6%) despite identical RV afterload. SC144 normalized RV cardiomyocyte size (CONTROL: 131±54 µm 2 , PAB-VEH 200±70 µm 2 , PAB-SC144: 129±62 µm 2 ), mitochondrial dimensions, and cristae morphology. Integrated lipidomics, metabolomics, and proteomics revealed changes in lipid metabolism in PAB pigs, which was counteracted by SC144. In particular, the accumulation of acylcarnitines, the mitochondrial form of fatty acids, and the downregulation of fatty acid oxidation proteins was mitigated by SC144. The improvements in mitochondrial structure, protein regulation, and metabolic activity were likely due to the restoration of autophagy as SC144 mitigated the reduction in numerous autophagy proteins. Conclusion: SC144 improves RV function in porcine RV failure, likely by maintaining autophagy, which ultimately preserves mitochondrial fatty acid oxidation.
Abstract 4141534: Burden of coronary artery disease predicts mortality in ischaemic stroke patients: The Norwegian Stroke in the Young Study
Authors: Khuluud Abdi Jibril, Beenish Nawaz, Ulrike Waje-Andreassen, Halvor Naess, Annette Fromm, Abukar Ali, Terje Hjalmar Larsen, Øyvind Bleie, Kier Jan Kuiper, Sahrai Saeed
Journal: Circulation (2024)

Background and purpose: Earlier European studies in young stroke patients have identified coronary artery disease (CAD) as a contributor to mortality. In the present Norwegian Stroke in the Young Study (NOR-SYS) sub-study we aim to investigate the true prevalence of CAD and the impact on mortality and event-free survival in young and middle-aged stroke survivors. Methods: Between September 2010 and December 2015, a total of 385 patients (15-60 years) with ischemic stroke were included. Clinical characteristics, echocardiographic and coronary imaging (angiography or cardiac CT) data, and arterial stiffness indices (pulse wave velocity, carotid intima media thickness and femoral plaque) were analysed. No CAD was defined as no history of CAD and no femoral artery plaque on vascular ultrasound (US) or negative coronary imaging. Coronary imaging was done if history of CAD or femoral plaque on US. Results: Mean (±SD) age was 49.6 (±9.7) year, 68.1% males. The overall prevalence of CAD was 25.2% (n=97) (non-obstructive 9.6% [n=37] and obstructive 15.6% [n=60]). In a subsample of patients (n=58) without a previous history of CAD or symptoms, who underwent cardiac CT as part of screening following femoral plaque on US, 46% (n=27) had non-obstructive CAD and 28% (n=16) had obstructive CAD. When further classified 17.2% had one-vessel disease, 3.4% two-vessel disease and 6.9% three-vessel disease. During a mean (±SD) follow-up of 9.8 (±2.5) years, 35 patients (9.1%) died (3.1% one-year mortality) and 83 (21.6%) reached a composite endpoint of new stroke, myocardial infarction or death, while 63 (16.4%) reached a composite endpoint of new stroke or death. In a Kaplan-Meier curve event-free survival was significantly lower in patients with CAD versus no-CAD (Figure). This was confirmed by multivariate cox regression models, in which CAD was an independent predictor of all-cause mortality (HR 2.25; 95% CI 1.07-4.47, p= 0.033) and composite endpoint of death or recurrent ischemic stroke (HR 3.26; 95% CI 1-47-7.23, p=0.004) adjusted for potential confounders. Conclusions: In the present study of young and middle-aged ischemic stroke survivors, a quarter of patients had CAD. In patients without previous history of CAD or symptoms who underwent cardiac CT on the basis of femoral plaque on US, nearly a half had non-obstructive and one-third obstructive CAD. CAD, and in particular obstructive CAD, was a major independent predictor of mortality and recurrent stroke.
Abstract 4141328: Exercise right heart catheterization combined with echocardiography in evaluation of subclinical pulmonary hypertension and heart failure with preserved left ventricular ejection fraction
Authors: Vishaka Chetram, Vikramjit Khangoora, Xiaoxiao Qian, Brett Hunter, Oksana Shlobin, Qiong Zhao
Journal: Circulation (2024)

Introduction: Diagnosis of exercise-induced pulmonary hypertension (EIPH) or exercise-induced heart failure with preserved left ventricular ejection fraction (E-HFpEF) is challenging due to a lack of consensus. The 2022 ESC/ERS guidelines define EIPH as mean (m) PAP/CO &gt; 3 mmHg/L/min, and E-HFpEF as PCWP/CO &gt; 2 mmHg/L/min, a revision of the previous criteria of mPAP ≥ 30 mmHg and PCWP ≥ 25 mmHg. Hypothesis: We investigated the role of exercise RHC in identifying EIPH and E-HFpEF in a group of patients with dyspnea and correlated the rest echo findings with the E-RHC results. We hypothesized that the resting echo parameters can help identify patients with EIPH and E-HFpEF using 2022 ESC/ERS definitions. Methods: A cohort of patients with dyspnea and normal LVEF with E-RHC data from 2016-2019 was included. Patients were categorized into Groups (g) A-E (Fig 1-T1) according to the 2018 WSPH definition of PH. Echo, hemodynamic, and clinical data were collected. The ESC/ERS 2022 guidelines were used to identify EIPH and E-HFpEF. Echo parameters were retrospectively analyzed by logistic regression analysis. Results: 200 patients were included. The mPAP and PCWP, but not PVR, significantly increased post-exercise in all groups. Over 50% of patients in each group had evidence of at least grade I LV diastolic dysfunction on rest Echo (Fig 1). PVs/PVd was significantly lower (0.8±0.3) and E/e’ higher (15±7.9) in g-C (Post-Cap) compared to g-A (No-PH), B (Pre-Cap) and E (undifferentiated). In g-A and g-E, 46.8% and 73% demonstrated EIPH, with 87% and 100% showing a mPAP≥30 mmHg respectively. The prevalence of E-HFpEF in g-A, g-B, and g-E was 45%, 50%, and 63% respectively. Only 34%, 42%, and 56% of subjects in g-A, g-B and g-E demonstrated E-PCWP ≥ 25 mmHg. Echo parameters that predicted E-HFpEF included E and E/e’; E/e’ also predicted EIPH (Fig 1). Conclusions: In this study, Echo features of advanced LV diastolic dysfunction including decreased PVs/PVd and increased E/e’ were associated with post-capillary PH. Rest E/e’ and E (LV rapid inflow velocity) may predict E-HFpEF. Exercise RHC may have utility in the evaluation of patients with suspected subclinical PH and HFpEF, but larger prospective designs are warranted
Abstract 4141631: Abdominal Circumference and Coronary Calcium Score in a Healthy Nonobese Brazilian Cohort: ELSA-Brasil Cohort Analysis
Authors: Ronaldo Correa Fabiano, Thiago Bosco Mendes, Carlos Romero-Nunez, Giuliano Generoso, Henrique Staniak, Murilo Foppa, Raul Santos, Paulo Lotufo, Isabela Bensenor, Marcio Bittencourt
Journal: Circulation (2024)

Introduction: Obesity increases coronary artery disease (CAD) risk and is highly associated with diabetes. Although body mass index (BMI) is more frequently used as an objective assessment of obesity, abdominal circumference (AC) is often overlooked as a risk factor, especially in nonobese individuals. We examined the association between AC and coronary artery calcium score (CAC), a marker of subclinical CAD. Methods: We analyzed data from 2184 asymptomatic nonobese individuals (BMI 18 - 30 kg/m 2 ) without prior cardiovascular disease (CVD) from the ELSA-Brasil cohort. The association of standardized AC and CAC incidence was examined by multivariable logistic regression models. Models were adjusted for age, sex, race, premature family history of CVD, tobacco use, physical activity, hypertension, triglycerides, LDL, statin use, diabetes, and interaction between diabetes and AC. CAC incidence was defined by initial CAC = 0 and repeated CAC &gt; 0 and were performed between 2010-2018. Results: The mean age was 48±8, 60% were female, and 67.2% were white. CAC incidence was 15% (327/2184) and the mean CAC interval in years was 5.2±1. AC was significantly associated with CAC incidence across all models (Model 1 OR = 1.53, 95% CI: 1.24-1.89, p&lt;0.001; Model 2 OR = 1.49, 95% CI: 1.20-1.85, p&lt;0.001; Model 3 OR = 1.46, 95% CI: 1.16-1.83, p=0.001). Diabetes mellitus status did not significantly alter the risk estimates. Conclusions: Abdominal circumference is an independent risk factor for the incidence of subclinical CAD assessed by CAC in nonobese asymptomatic individuals without prior CVD, after adjusting for classical risk factors. This finding suggests that AC may serve as a subtle clinical marker of residual risk factors, potentially indicating the importance of visceral fat in this population.
Abstract 4141244: RNA interference versus antibody-based PCSK9 inhibition for the prevention of cardiovascular disease: A drug-target Mendelian randomization study
Authors: Eloi Gagnon, Dipender Gill, Jerome Bourgault, Emilie Gobeil, Patricia Mitchell, Arnaud Girard, Audrey Paulin, Christian Couture, Yohan Bosse, Sebastien Theriault, Patrick Mathieu, Marie-Claude Vohl, Andre Tchernof, Kausik Ray, John Kastelein, Benoit Arsenault
Journal: Circulation (2024)

Background and Aims: RNA interference therapy targeting the proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) gene lower low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB) levels and is approved worldwide. As opposed to monoclonal antibodies neutralizing PCSK9 in the circulation, their effect on atherosclerotic cardiovascular disease (ASCVD) outcomes is unknown. We used drug-target Mendelian randomization (MR) to assess the potential impact of RNA interference therapies targeting PCSK9 on cardiometabolic traits and outcomes. Methods: We performed RNA-sequencing of 246 liver samples and genome-wide genotyping was performed to identify single-nucleotide polymorphisms (SNPs) associated with liver expression of PCSK9 . Genome-wide association study (GWAS) summary statistics of plasma protein levels of PCSK9 from the deCODE study (n=35,559) were used to instrument inhibition of circulating PCSK9 levels. A three-sample MR approach was undertaken using SNPs that influence liver PCSK9 gene expression levels (mimicking PCSK9 RNA interference) or plasma PCSK9 protein levels (mimicking PCSK9 neutralizing antibodies) as study exposures. Genetic instruments were standardized for their effect on apoB levels. Main outcomes measures included GWAS summary statistics on coronary artery disease (CAD), ischemic stroke (IS) and type 2 diabetes (T2D). Results: Each SD decrease in apoB was linked with a 55% and 56% reduction in CAD risk, respectively for genetically predicted reductions in plasma PCSK9 levels (OR [odds ratio]=0.45 [95% CI], 0.36-0.56, p=1.7e-13) and liver PCSK9 gene expression levels (OR=0.44 [95% CI], 0.22-0.88, p=0.02). Genetically predicted reductions in plasma PCSK9 levels and liver PCSK9 gene expression levels were associated with slightly lower IS risk (OR=0.82 [95% CI], 0.68-0.98, p=0.03 and OR=0.73 [95% CI], 0.51-1.04, p=0.08, respectively). Genetically predicted reductions in plasma PCSK9 levels and liver PCSK9 gene expression levels were not associated with T2D risk (OR=1.08 [95% CI], 0.92-1.28, p=0.34 and OR=1.26 [95% CI], 0.93-1.71, p=0.14, respectively). The effect of PCSK9 inhibition on CAD was entirely mediated by reductions in apoB levels. Conclusions: Genetically predicted reductions in plasma PCSK9 levels and liver PCSK9 gene expression levels were associated with lower ASCVD risk, suggesting that LDL-C/apoB reductions may provide cardiovascular benefits, regardless of how PCSK9 function is inhibited.
Abstract 4141689: Sex-based Differences of Inpatient Mortality Following Coronary Artery Bypass Grafting: Insight From Large National Database
Authors: Zaid Abood, Eric Weiss, Yuting Chiang, Andrew Lin, Balamrit Sokhal, Kirsten Tunink, Mohamed Hommeida, Tanvir Bajwa, Suhail Allaqaband, M. Fuad Jan
Journal: Circulation (2024)

Background: Female patients referred for coronary artery bypass grafting (CABG) are generally older and have more comorbidities than their male counterparts. Although higher perioperative mortality among female patients has been reported, there is a lack of large-scale, real-life data on this outcome and its trend. Aim: To study the mortality rate among female patients undergoing CABG from 2015-2020 and compare it with that of their male counterparts. Methods: The National Inpatient Sample from January 2015 to December 2020 was utilized to identify the study population using the International Classification of Diseases, Ninth and Tenth Revisions, Clinical Modification. The primary outcome was the overall in-hospital mortality of CABG based on sex, and the secondary outcome was the mortality trend between the groups. Results: We evaluated 929,759 patients who underwent CABG, of whom 230,000 (24.3%) were female. The female patient group was slightly older than the male patient group (66.4 vs 65.4 years, P&lt;.001) and had a lower proportion of Caucasians (73.7% vs 79.4%, P&lt;.001). Overall mortality among the female patients was nearly double that of their male counterparts (2.5% vs 1.4%, P&lt;.001). Over the study period, the adjusted mortality rate declined in both sexes but remained higher in the female group (Fig. 1A). Among female patients, the mortality rate decreased from 2.5% in 2015 to 1.6% in 2019 (P&lt;.001), then increased to 2.0% in 2020 (P=.050). The mortality rate among male patients consistently declined, from 1.9% in 2015 to 1.2% in 2020 (P&lt;.001). Conclusion: This analysis reveals that female patients undergoing CABG have higher mortality rates than their male counterparts despite overall declines in mortality rates over the study period. The persistent disparity and the observed increase in mortality in female patients in 2020 highlight the need for further research to identify and address the precipitating factors of this outcome.
Abstract 4141701: Legacy Effects of Supervised Exercise Training on Body Composition and Cardiorespiratory Fitness in STRRIDE-Prediabetes
Authors: Leanna Ross, Alyssa Sudnick, Katherine Collins, Julie Counts, Kim Huffman, William Kraus
Journal: Circulation (2024)

Background: While exercise training elicits substantial health benefits, too few individuals adopt exercise as a health maintenance strategy. Thus, determining if a relatively modest duration of exercise training can lead to sustained benefits years later (legacy effects) is clinically important. The STRRIDE I Reunion revealed legacy effects for cardiorespiratory fitness (CRF) and cardiometabolic risk factors 10 years after exercise intervention. In an older cohort at greater risk of disease development, the STRRIDE-PD Reunion study aims to determine whether prior exercise training–with or without weight loss–elicits legacy health effects. Hypotheses: Those who completed vigorous intensity training will have maintained CRF to the greatest extent, while those who completed a high amount of training will have maintained body composition to the greatest extent. Methods: In STRRIDE-PD, sedentary adults (45-75 y) with prediabetes and overweight/obesity were randomized to one of four 6-month aerobic training groups: 1) low amount/moderate intensity (LM); 2) high amount/moderate intensity (HM); 3) high amount/vigorous intensity (HV); or 4) LM plus diet/weight loss (LMD). Waist circumference (WC), body composition via BODPOD, and CRF (relative peak VO 2 ) were measured at baseline, post-intervention, and Reunion (10 y). Change scores were calculated as Reunion value minus baseline. Two-tailed t -tests determined within-group significance (p&lt;0.05). ANCOVA with baseline values assessed among-group effects. Results: Seventy-three participants (71.3±7.2 y; 64% women; 78% White) returned for the STRRIDE-PD Reunion study. Compared to baseline, all groups either maintained (HM and LMD) or significantly reduced (HV and LM) WC and total body mass. LM, LMD, and HV experienced significant reductions in fat free mass. All groups showed a significant decrease in CRF, ranging from ~10% (LM, LMD, and HV) to 16% (HM). Magnitudes of change were not different among groups. Conclusion: All groups exhibited legacy effects for WC, fat mass, and body mass. Although LM and HV significantly reduced WC and body mass compared to baseline, these changes were coupled with fat free mass reductions. Contrary to STRRIDE I, vigorous intensity participants did not maintain CRF to a greater extent than moderate intensity. These STRRIDE-PD specific findings may indicate aging-related skeletal muscle loss and an accelerated CRF decline for older individuals at increased risk for cardiometabolic disease.
Abstract 4141282: Cystamine/Pentagalloylglucose-based versatile modification strategy of decellularized porcine pericardium for transcatheter tissue engineered heart valves
Authors: Yuqi Liu, Yin Xu, Pengning Fan, Li Xu, Xingyu Qian, Yidan Zheng, Ming Chen, Fei Li, Weihua Qiao, Nianguo Dong
Journal: Circulation (2024)

Transcatheter valve replacement has become the preferred treatment for high-risk elderly patients considering the advantages of less invasive surgical trauma and faster postoperative recovery. Transcatheter heart valves (THVs) primarily made of glutaraldehyde-crosslinked pericardial materials pose a risk of thrombosis and calcification, and are subjected to additional stress during catheter delivery, which leads to poor durability. Herein, we constructed a novel transcatheter tissue engineered heart valve for in situ regeneration through functional modification of cystamine (CySA) and pentagalloylglucose (PGG) on decellularized porcine pericardium (DPP), referred to as CySA/PGG-PP. A dynamically reversible fiber network structure was formed by the modification of CySA and PGG, resulting in excellent resistance to enzymatic degradation and crimping stability of CySA/PGG-PP. The distinctive capability of CySA to catalyze the production of endogenous nitric oxide (NO) provided CySA/PGG-PP with a long-term NO release system that inhibited platelet adhesion and activation to improve hemocompatibility. Proteomics analysis revealed that the improvement of hemocompatibility might be mediated by protein phosphorylation and arachidonic acid metabolism-related pathways. Furthermore, we found that CySA/PGG-PP exhibited significant recellularization and tissue remodeling in a rat abdominal aortic implantation model, accompanied by a mild inflammatory response and no calcification. The positive results in vivo might be regulated by genes associated with cell adhesion and differentiation, extracellular matrix organization, and TGF-β signaling pathway, as revealed by RNA sequencing. Consequently, the instructive transcatheter tissue-engineered valve overcomes the limitations of existing THVs with the aim of significantly improving valve durability for clinical therapy.
Abstract 4140978: DOT1L mediates diabetic vascular remodeling by promoting insulin-induced phenotypic conversion of VSMCs through the NOTCH1-related pathway
Authors: Jian Yang, Jing Zhang, Di Wu
Journal: Circulation (2024)

Introduction: The transformation of vascular smooth muscle cells (VSMCs) from contractile to synthetic is an important step in diabetic vascular remodeling. DOT1L, the only lysine methyltransferase at the H3K79me locus, has not been fully elucidated in diabetic vascular remodeling, and DOT1L-based methods may be critical in discovering phenotypic transformation of VSMCs to improve clinical outcomes in patients with diabetic cardiovascular disease. Hypothesis: Whether DOT1L promotes the phenotypic transformation of VSMCs and further affects diabetic vascular remodeling. Methods: Primary VSMCs were extracted from the thoracic aorta of healthy, SPF-free male rats. DOT1L was up-regulated or down-regulated in vitro by lentivirus infection with VSMCs, followed by an insulin stimulation. VSMCs phenotype was assessed by EdU, flow cytometry, scratch assay, Transwell chamber assay, western blot; In addition, the mechanism of DOT1L on insulin-induced phenotypic transformation of VSMCs was explored. SD rats were fed with high glucose and high fat for 4 weeks, and were given a single intraperitoneal injection of low-dose (30 mg) STZ to establish a diabetes model. After 2 weeks of continuous high-glucose and high-fat feeding, a carotid balloon injury model was established, and then lentivirus was injected into the injured artery segment to overexpress or knock down DOT1L in vivo, and the role and mechanism of diabetic VSMCs phenotype were evaluated by immunohistochemistry and western blot. Results: After 24 hours of stimulation with 100 nmol/L insulin, the expressions of VSMCs synthesized phenotype OPN, proliferative phenotype PCNA, migration phenotype MMP2 and MMP9 increased, the expression of α-SMA decreased, and proliferation and migration occurred. Down-regulation of DOT1L can inhibit the conversion of insulin-induced VSMCs from contractile to synthetic and improve diabetic vascular remodeling. Mechanistically, overexpression of DOT1L promotes the activation of JAG1/NOTCH1 signaling pathway, promotes the expression of synthetic phenotypic proteins, and inhibits the expression of contractile phenotypic proteins, which ultimately promotes the transformation of VSMCs from contractile to synthetic in diabetic environment. Conclusions: Down-regulation of DOT1L can inhibit the activation of JAG1/NOTCH1 signaling pathway, thereby inhibiting the phenotypic transformation of VSMCs and improving diabetic vascular remodeling.