tbuckley/cabot-search huggingface dataset:
Abstract 4141400: Inhibition of Chylomicron Uptake Stimulates Treg Accumulation
Authors: Zihan Wei
Journal: Circulation (2024)

Introduction: Chylomicrons are major lipid fuel for cells. They contain dietary triglycerides, cholesterols, and apolipoproteins. In the intestine, apolipoprotein C-III (apoC-III) is produced during fat feeding, and secreted onto chylomicrons. ApoC-III is a key regulator of chylomicron hydrolysis and clearance through its inhibitory effects on lipoprotein lipase (LPL) and low-density lipoprotein receptor (LDLr) in multiple tissues. In humans, genetic polymorphisms in apoC-III are directly tied to plasma triglyceride levels and cardiovascular disease risk. As a result, apoC-III is a major drug target with antisense therapies already in clinical trials. Though plasma chylomicrons and the lipids they carry are well-known instigators of cardiovascular disease, they also deliver necessary lipid fuels to organs and cells that require energy. As an important regression factor in cardiovascular diseases, regulatory CD4+ Foxp3+T cells (Tregs) are a highly oxidative lymphocyte subset, and Tregs heavily rely on fatty acids to fuel their differentiation, proliferation, and anti-inflammatory functions. Hypothesis: Though Tregs rely on FA for ATP generation, few studies consider how Tregs encounter their lipid fuel and whether this process is regulated. We hypothesized that chylomicrons deliver triglyceride to Tregs, and that apoC-III would regulate this process through receptor inhibition. Methods: We used purified chylomicrons and albumin-bound fatty acid, Seahorse metabolic flux analysis of Tregs, and in vivo functional assays of inflammatory bowel disease. Finally, we asked whether these processes may be at play during atherosclerosis, where both Tregs and chylomicron lipids are critical factors. Results: Our studies reveal: CD4+Foxp3+Tregs endocytose chylomicrons lipids (both FFA and cholesterol); oxidative phosphorylation in Tregs is stimulated by lipids in apoC-III containing chylomicrons; these events can be targeted to change Treg accumulation and suppressive function in the gut and the aorta. We find that the inhibition of chylomicron uptake by Tregs also coincides with an increase in Treg accumulation at sites of inflammation, and a decrease in their expression of apoptotic markers. Conclusions: These data suggest a link between chylomicron lipid metabolism and apoptosis in anti-inflammatory Tregs. Further research will be conducted to reveal the mechanism of Treg chylomicron uptake and how regulation of this pathway alters Treg metabolism and apoptosis.
Abstract 4140889: Preclinical study of human induced pluripotent stem cell-derived endothelial cells for peripheral artery disease
Authors: Shin-Jeong Lee, Jee Eun Oh, Yonghak Kim, Dongchan Sohn, Cholomi Jung, Sangsung Kim, Jung Yoon Bae, Hyun Ok Kim, Donghoon Choi, Young-sup Yoon
Journal: Circulation (2024)

Background: Peripheral artery disease (PAD) affects approximately 230 million people globally and chronic limb-threatening ischemia (CLTI) can lead to limb amputation. Human induced pluripotent stem cell-derived endothelial cells (hiPSC-ECs) offer a promising source for PAD treatment. However, to date, regulatory criteria for the clinical application of hiPSC-ECs have not been established yet, and there have been no reports on preclinical studies involving hiPSC-ECs. This study aims to address this gap by investigating the feasibility, safety, and efficacy of clinical-grade hiPSC-ECs through a preclinical proof-of-concept analysis. Methods and Results: Clinical-grade hiPSC lines were established from the blood of three PAD patients using episomal plasmids. Their pluripotency was confirmed by assessing their expression of pluripotency markers through qRT-PCR and immunostaining, as well as their pluripotency in a teratoma assay. Furthermore, PAD-hiPSCs exhibited normal karyotypes. Subsequently, we differentiated PAD-hiPSCs into ECs, all of which displayed a cobble-stone EC morphology and expressed EC markers as confirmed by qRT-PCR and immunostaining. PAD-hiPSC-derived ECs also expressed CDH5 at a minimum of 98.4 ± 0.2% and VWF at 94.4 ± 1.3% by flow cytometry. PAD-hiPSC-ECs maintained their normal karyotypes and copy number variation across the genome, as determined by CGH array. Additionally, they exhibited endothelial characteristics such as tube formation in Matrigel and intracellular nitric oxide production. Administration of PAD-hiPSC-ECs into ischemic hindlimbs of both female and male mice led to improved blood flow recovery (~3.3 fold), reduced risk of limb loss (~8.8 ± 0.6%), and increased vascular density (~2.7 fold) compared to control groups. These engrafted hiPSC-ECs exhibited vessel-forming capacities, thereby contributing to neovascularization. More importantly, we evaluated the toxicity, biodistribution, and tumorigenic potential of these cells in immunodeficient nude mice over one year. The results demonstrated non-detection of tumorigenic cells in twelve organs and adverse events. With all the data, the use of hiPSC-ECs was approved for a clinical trial to treat PAD. Conclusions: Our preclinical proof-of-concept findings demonstrate, for the first time, the clinical compatibility of hiPSC-ECs derived from patients for autologous cell therapy for PAD. Our study further suggests regulatory guidance for the clinical development of hiPSC-ECs.
Abstract 4141401: Direct and Indirect Effects of Historic Residential Redlining on Prevalence of Cardiometabolic Diseases via Food Access
Authors: Rebekah Walker, Jennifer Campbell, Sebastian Linde, Leonard Egede
Journal: Circulation (2024)

Background: Given the importance of access to healthy food for adults at risk of cardiometabolic diseases, this study focused on investigating food access as a possible pathway between structural racism and prevalence of disease. Methods: Census tract level data were combined to create a final analytic dataset of 11,457 census tracts across 201 counties, within 38 states. Structural racism was defined as historic residential redlining using Home Owners’ Loan Corporation (HOLC) residential security maps from the Mapping Inequality project (score between 1=best to 4=redlined). Food access was defined using the modified retail food environment index (mRFEI) calculated as the number of healthy food retailers divided by the number of healthy and less healthy food retailers per census tract. Prevalence of disease in each census tract was based on CDC PLACES data and included prevalence of diabetes (DM), high blood pressure (HBP), coronary heart disease (CHD), and obesity. Direct and indirect relationships between redlining and each cardiometabolic disease via food access was investigated using structural equation modeling run in Stata v17, controlling for population of each census tract. Results: Mean prevalence of DM was 11.8%, HBP 31.9%, CHD 6.0%, and obesity 31.8%. Redlining (0.22, p&lt;0.001) and lower food access (-0.11, p&lt;0.001) were directly associated with higher prevalence of DM. Redlining (0.10, p&lt;0.001) and lower food access (-0.10, p&lt;0.001) were directly associated with higher prevalence of HBP. Redlining (0.12, p&lt;0.001) and lower food access (-0.04, p&lt;0.001) were directly associated with higher prevalence of CHD. Redlining (0.18, p&lt;0.001) and lower food access (-0.12, p&lt;0.001) were directly associated with higher prevalence of obesity. Redlining was also significantly indirectly associated with DM, HBP, CHD, and obesity via food access (-0.10, p&lt;0.001). Conclusions: Structural racism measured using historical redlining is associated with higher diabetes, high blood pressure, coronary heart disease, and obesity prevalence via decreased food access. Based on these results, interventions to improve access to healthy food options at the community level may help address the impact of structural racism on the health of individuals, particularly those at risk for cardiometabolic diseases living in historically redlined neighborhoods.
Abstract 4141367: Telemonitoring as a Strategy to Reduce Mortality and Hospitalizations in Heart Failure: A Systematic Review
Authors: Umang Gupta, Venkata Sai Abhilash Meda, Ashok Adhikari, Chandana Tadigotla, Ashwith Reddy Gaddam, Yogeshkumar Vaghamashi, Binay Panjiyar
Journal: Circulation (2024)

Background: Heart failure (HF) is a chronic condition with high morbidity and mortality rates, and is known to pose a significant burden on the healthcare system. Telemonitoring, an innovative approach using remote monitoring of patients' health data, has emerged as a potential solution to enhance HF management and improve patient outcomes. Research Question: This systematic review investigates whether telemonitoring interventions improve heart failure outcomes compared to standard care. Aim: We aim to synthesize the current evidence on the impact of telemonitoring on all-cause mortality, cardiovascular mortality, heart failure-related hospitalization, and health-related quality of life in patients with heart failure. Methods: We conducted a thorough search of electronic databases, including PubMed, Cochrane Library, Google Scholar, and PLOS Medicine, to identify relevant randomized controlled trials (RCTs) and systematic reviews/meta-analyses (SRs/MAs) evaluating telemonitoring interventions in heart failure. Studies were selected based on pre-defined criteria. A review of the literature and risk of bias assessment was performed independently by four reviewers. Results: Out of 16,778 articles reviewed, eight were chosen for this study, comprising 3 SRs/MAs and 5 RCTs. The findings suggest that using telemonitoring interventions, such as structured telephone support, mobile health interventions, and medication support, significantly reduces deaths and hospitalizations in heart failure patients compared to standard care. Longer telemonitoring duration (≥12 months) significantly lowered hospitalization rates. Conclusions: This systematic review suggests that telemonitoring may be associated with improved heart failure outcomes, including reduced mortality and hospitalization rates. However, further research is needed to explore telemonitoring interventions' long-term effects and cost-effectiveness in heart failure management.
Abstract 4141048: Inflammatory biomarkers predict long-term all-cause mortality in males but not in females.
Authors: Dennis Nilsen, Reidun Aarsetoey, Volker Poenitz, Thor Ueland, Annika Michelsen, Pal Aukrust, Trygve Brugger-Andersen, Harry Staines, Heidi Grundt
Journal: Circulation (2024)

Background: α1-antichymotrypsin (SERPINA3), high sensitivity C-reactive proten (hsCRP) and Pentraxin 3 (PTX3) are acute phase proteins triggered by inflammation. Hepatocytes are a primary source of SERPINA3 and CRP, while PTX3 is produced by a variety of tissues including endothelial cells. These inflammatory markers are upregulated after an acute myocardial infarction (AMI). Comparisons of their long-term prognostic value in acute coronary syndrome (ACS) patients by gender are scarce. We aimed to assess their long-term prognostic utility in females and males, respectively, hospitalized for chest pain of suspected coronary origin. Methods: A total of 871 consecutive patients (39.0% females) with a median age of 72.6 years (females 77.3, males 69.1) were admitted in the study. Of these, 386 were diagnosed with an acute MI based on Troponin-T (TnT) levels &gt;50 ng/L. Stepwise Cox regression models, applying normalized continuous log e /SD values, were fitted for the biomarkers with total mortality within 7 years as the dependent variable. Results: At 7-year follow-up, 332 patients had died; 44.1 % females vs. 34.1 % males (χ 2 (1) = 9.368; p = 0.0022). Blood samples were available for analysis of SERPINA3, hsCRT and PTX3 in 847, 868 and 795 patients, respectively. There was no significant differences between the means of the sexes for SERPINA3 (p = 0.20), hsCRT (p = 0.84) and PTX3 (p = 0.068), respectively. None of the biomarkers predicted long-term outcome in females after multivariable adjustment (p=0.92, p=0.40 and p=0.57, respectively), but were good predictors in males [SERPINA3: HR 1.34 (95%CI 1.16-1.56), p=0.00001. hsCRP: HR 1.19 (95%CI 1.02-1.38), p=0.027. PTX3: HR 1.22 (95%CI 1.04-1.44), p=0.018]. Furthermore, the p-values for interaction would suggest a gender difference in the prognostic weighting, favoring SERPINA3 (p=0.015) and to a lesser degree hsCRP (p=0.074) and PTX3 (p=0.14). Conclusion: SERPINA3, hsCRT and PTX3 are good predictors of long-term all-cause mortality in males admitted with chest pain of suspected coronary origin, but were not shown to predict outcome among females of that population. The prognostic utility of the studied inflammatory biomarkers may essentially be related to males.
Abstract 4141624: The inadequacy of Physician’s Knowledge of Iron Deficiency Anemia in Heart Failure
Authors: Olva Bess, George Tung, Alejandro Toral Lama
Journal: Circulation (2024)

Introduction: It is estimated that about 30% of patients with heart failure (HF) have iron deficiency anemia that can be masked as chronic normocytic anemia or functional anemia. Currently, the ACC/AHA 2022 heart failure guidelines give IV Iron replacement a Class IIa recommendation. However, many physicians who are regularly involved in the management of HF patients do not assess for or adequately treat iron deficiency anemia in these patients. This project seeks to identify the gaps in physicians’ knowledge on iron deficiency anemia and HF. Method: Over a 2-week period, a 9-item questionnaire was given to a total of 52 Internal Medicine physicians: 9 attendings, 27 residents (2nd and 3rd year) and 16 interns (1st year residents) chosen by convenience sampling. The participants at that time, were regularly involved in the care of patients with HF at a Brooklyn inter-city community Hospital. Data was collected and analyzed using IBM SPSS version 29 data analysis software. Results: All 52 participants completed the survey. When asked if all stages and classification of heart failure can be affected by iron deficiency anemia, 81.3% of interns vs 100% of both residents and attendings answered yes. However, only 18.8% of interns, 22.2% of residents and 11.1% of attendings test every patient with HFrEF &lt;40% for iron deficiency anemia. Even though over 90% of the physicians had managed patients admitted for HF within the prior 2 weeks. Remarkably, 81.3% of interns, 59.3% of residents and 44.4% of attendings were aware that anemia in HF is an independent predictor of worsening mortality and morbidity. Iron deficiency anemia in HF diagnostic criteria of Ferritin &lt; 100µg/L or ferritin between 100-299 µg/L with transferrin saturation &lt; 20%, was known by 31% of interns, 40.7% of residents and 56.6% of attendings. None of the interns while 11.1% of both residents and attendings knew the recommendation of IV ferric carboxymaltose as treatment for iron deficiency anemia in HF. Responses to Stages and classification were significant at P value of 0.028. Conclusion: Iron deficiency anemia in HF is common, however physicians, both within and post training, are unaware of the management of iron deficiency anemia according to the 2022 heart failure guidelines. the study's statistical power can be improved with increased participants. More physician education is needed on Iron Deficiency anemia and Heart Failure with aim of improving patient care.
Abstract 4140743: Impact of Frailty on In-Hospital Outcomes in Leadless Pacemaker Implantation (LPI)
Authors: Nauman Naeem, Hina Ukrani, Akshay Joshi, Roshan Karki, Mohan Rao, Moghniuddin Mohammed
Journal: Circulation (2024)

Background: Frailty is linked to adverse clinical outcomes across various patient and procedural cohorts. Leadless pacing has recently emerged as a promising therapy; however, little is known regarding its utilization and outcomes. Aim: To assess the association between frailty and hospital outcomes in patients undergoing leadless pacemaker implantation (LPI). Methods: We conducted a retrospective cohort study using the National Inpatient Sample to identify patients aged at least 18 years who underwent LPI between 2016 and 2020. Patients with a history of cardiac implantable electronic devices or procedures, including ablation, percutaneous coronary intervention, coronary artery bypass surgery, and valvular intervention, were excluded. A total of 21,210 patients were included and divided into three groups based on the Hospital Frailty Risk Score (HFRS): low risk (HFRS &lt;5, n=7540), intermediate risk (HFRS 5-15, n=12010), and high risk (HFRS &gt;15, n=1660). All analyses were performed using R, and the adjusted odds ratio (aOR) was determined using multivariate logistic regression analysis. Results: Overall, 64.4% of patients were at intermediate or high risk of frailty. The most common comorbidities in the high-risk group were diabetes (40.7%), congestive heart failure (53.3%), renal failure (55.4%), and hypertension (84.0%). Patients at intermediate or high risk of frailty had a higher risk of in-hospital mortality compared to the low-risk group (adjusted odds ratio 5.44 [95% CI, 3.20-9.25] for HFRS 5-15, and 7.07 [95% CI, 3.68-13.58] for HFRS &gt;15). The most common complications were acute kidney injury and bleeding, with aOR of 2.77 [95% CI, 2.39-3.21] in the intermediate group and 5.21 [95% CI, 3.95-6.86] in the high-risk group. The length of hospital stay (16.39 vs. 4.5 days) and discharge to a nursing facility (58.7% vs. 12%) were also higher in the high-risk group compared to the low-risk group.. Conclusion: Frailty is associated with an increased risk of mortality and complications in patients undergoing LPI and can be used for prognostication and informed decision-making with patients.
Abstract 4140763: A Case of Clozapine-Induced Myocarditis: An Under-described Side Effect
Authors: Rand Ibrahim, Kellie Clearo
Journal: Circulation (2024)

Case Descripton: A 34-year-old male with Schizophrenia was transferred from inpatient Psychiatry unit for chest tightness, fevers andtachycardia after testing positive for COVID-19. Further history revealed antipsychotics had been recently adjusted with the addition of Clozapine 1 month prior to presentation. On presentation, he was febrile (39.1°C) and tachycardic to the 146 in sinus tachycardiac on EKG and Telemetry. He was euvolemic on exam with tachycardia but no murmurs or discernable friction rub. Labs revealed no leukocytosis but an elevated C-reactive protein (CRP) 168mg/L, high-sensitivity troponin (474ng/L) and brain-natriuretic peptide (BNP, 176 pg/mL, no baseline value). Otherwise, TSH, ANA and RF were normal. Repeat Respiratory Viral Panel, respiratory biofire and blood cultures were unrevealing. Imaging (CXR and Chest CTA) were normal. TTE showed normal function and small pericardial effusion. Cardiac MRI was limited by inability to tolerate the scan but reported preserved biventricular function. The home facility was contacted and reported initial COVID testing was expired and invalid. Psychiatry was consulted for suspected clozapine-induced myocarditis and recommending holding Clozapine while resuming Risperdione. The patient reported subjective improvement in symptoms and return to baseline. Feversdefervesced and tachycardiac resolved. Discussion: Rare (0.06%-3.88% reported incidence) and not well-described, Clozapine-induced myocarditis can be a challenging entity to identify. In the literature, it is defined as having elevated CRP or detectable troponin and at least 1 sign or symptom of myocarditis, in the absence of alternative plausible etiologies. Symtoms typically onset between 1-4 weeks of medication initiation. Mortality can range between 10-30%. The acute history of symptoms, elevation in CRP and troponin shortly after medication initiation suggested a diagnosis of clozapine-induced myocarditis. The absence of reduction in systolic function and indeterminant MRI are nocompelling against clozapine-induced myocarditis in lieu of other more plausible diagnoses. Early cessation and symtpomatic managemnt is standard therapy. Conclusion: Clozapine-induced Myocarditis is an entity not well-described but carries a significant mortality risk. Perhaps cardiac-monitoring guidelines must be implemented in addition to the currently adopted montiroing for agranylocytosis with clozapine.
Abstract 4141635: Reconstructing Invasive Aortic Pressure Waveforms from Non-Invasive Brachial Measurements Using a Machine Learning Approach
Authors: Alessio Tamborini, Arian Aghilinejad, Morteza Gharib
Journal: Circulation (2024)

Background: Pulse wave analysis (PWA) of aortic pressure waveforms carries valuable information about cardiovascular health. However, due to the invasiveness of direct measurement, peripheral pressure waveforms are commonly used as surrogates. Recent findings revealed that while algorithmic methods can preserve pressure dynamics in non-invasive measurements, significant waveform morphology changes disrupt the association between peripheral and central parameters (PMID: 38591330, 2024 ). There is a need for non-invasive methods to faithfully reconstruct the central pressure waveform. Aim: Evaluate the fidelity of reconstructed aortic waveforms using a machine learning method applied to non-invasive brachial measurements. Methods: This study analyzed concurrent aortic catheterization and brachial cuff waveform measurements in suprasystolic mode in subjects referred for non-emergent left heart catheterization (N=115; mean age 66, 63% male). Our machine learning method uses a non-linear mode mapping in the frequency domain between non-invasive calibrated brachial pressure waveforms and invasive aortic ones. PWA features captured waveform magnitude and shape: systolic blood pressure (SBP), diastolic blood pressure (DBP), systolic pressure-time integral (SPTI), diastolic pressure time integral (DPTI), peak timing (T peak ), systole duration (T sys ), maximum pressure derivative ((+)dP/dt), and form factor (FF). Percentage error ((true–predicted)/true) was used to assess parameter correspondence in the testing population (N=35; cardiac cycles=994). Results: The non-linear mapping technique successfully reconstructed central pressure waveforms with good agreement between measured and estimated (MEAN=0.5 mmHg; SD=7.3 mmHg) as shown in Fig. 1A. PWA features showed low mean percentage errors for pressure (SBP=-0.7 ±5.9%; DBP=-2.9±9.4%), area (SPTI=0.2±8.7%; DPTI=-2.8±9.3%), timing (T peak =1.0±12.3%; T sys =1.2±7.1%), and shape parameters ((+)dP/dt=11.5±24.3%; FF=1.4±4.7%) shown in Fig. 1B. Conclusion: Our results demonstrate that the machine learning method applied on brachial cuff measurements captures waveform morphological changes along the arterial system allowing for a faithful representation of the central pressure waveform.