tbuckley/cabot-search huggingface dataset:
Abstract 17047: Contribution of MDA-5/IL-10RA to Pulmonary Artery Homeostasis and Pulmonary Arterial Hypertension
Authors: Geoffrey Newcomb, Bryce Piper, Srimathi Bogamuwa, Elena A Goncharova, Laszlo Farkas
Journal: Circulation (2023)

Introduction: Pulmonary arterial hypertension (PAH) is a progressive and lethal disease. The current treatment options do not target pulmonary artery endothelial cell (PAEC) dysfunction. We have previously shown a role for the endosomal double stranded (ds) RNA receptor toll-like receptor 3 (TLR3) and its regulation via interleukin-10 (IL-10) in promoting PAEC dysfunction and experimental pulmonary hypertension (PH). Yet the role of the cytosolic dsRNA receptor melanoma differentiation factor 5 (MDA-5) in endothelial dysfunction is not known. Hypothesis: We hypothesized that a deficient MDA-5/IL-10 receptor A (IL-10RA) signaling axis expression exists in PAH PAECs as a potential cause of endothelial dysfunction. Goals: Our goal is to test the role of a potential new axis of MDA-5 and IL10RA in EC homeostasis and pulmonary hypertension. Methods: Western blot analysis of control and PAH PAECs and PA smooth muscle cells (SMCs) was conducted. Gene silencing was done using siRNA targeting MDA-5 and IL-10RA, followed by bulk RNA sequencing. Apoptosis was tested using Annexin V binding. IL-10 whole body knockout (IL-10 -/- ) and endothelial-specific IL-10RA haploinsufficient mice (IL-10RA fl/wt Cdh5-Cre + ) and appropriate controls were exposed to chronic hypoxia and SU5416 (Hx/Su), followed by hemodynamics. Results: Our data show a reduction of MDA-5 in PAECs, but not in PASMCs. PAH PAECs further had reduced IL-10RA expression and application of dsRNA elevated IL-10RA expression in PAH PAECs. Knockdown of MDA-5 and IL-10RA caused differential expression of 2533 and 2638 genes, respectively. Comparative analysis revealed an overlap of differentially expressed genes (DEGs) in canonical pathways including reduced nitric oxide, VEGF, Apelin and Integrin signaling. Comparison also yielded overlapping DEGs for reduced cell survival, impaired cytoskeleton organization and migration. Gene silencing of MDA-5 resulted in increased PAEC apoptosis. IL-10 -/- and IL-10RA fl/wt Cdh5-Cre + mice showed exaggerated PH. Conclusions: Our data indicate an impaired cytosolic dsRNA receptor MDA-5 and IL-10RA axis in PAH PAECs which contributes to endothelial dysfunction and PH. Experiments are underway to identify the detailed mechanisms underlying our findings.
Abstract 16656: Association of Mean Arterial Pressure Variability With Kidney Function in Living Kidney Donors
Authors: Ekamol Tantisattamo, Voramol Rochanaroon, Wanprapit Noree, Narisara Tribuddharat, Nisha Wanichwecharungruang, Narathorn Kulthamrongsri, Thanathip Suenghataiphorn, Piengpitch Naunsilp, Thitiphan Srikulmontri, Urairat Chuenchaem, Chanokporn Puchongmart, Ben Thiravetyan, Possawat Vutthikraivit, Manasawee Tanariyakul, Thiratest Leesutipornchai, Pakin Lalitnithi, Phuuwadith Wattanachayakul
Journal: Circulation (2023)

Introduction: While mean arterial pressure (MAP) is associated with poor kidney function, the association of MAP variability with kidney function in living kidney donors (LKD) is unknown. We aim to evaluate the association between MAP variability and kidney function post-donation. Hypothesis: Wide MAP variability is associated with worsening kidney function post-donation. Methods: A retrospective cohort study utilizing OPTN/SRTR included adult LKD undergoing donation between 6/1972 and 9/2022. MAP variability is assessed by the average real variability of MAP (ARV-MAP) defined byan average of absolute difference in consecutive MAP at 6, 12, and 24 months post-donation. The risk of ≥35% decrease in post-donation eGFR from pre-donation eGFR among quartiles (Q) for AVR-MAP was examined by multivariable Cox regression. Results: Of 136,984 LKD, mean±SD age was 42±12 years and 61% were female. Mean pre-donation SBP, DBP, and MAP were 122±13, 74±9, and 90±10 mmHg, respectively. Mean post-donation BP at 6, 12, and 24 months were 120±13 / 75±9, 120±13 / 75±9, and 120±12 / 75±9 mmHg, respectively and corresponding mean post-donation MAP were 89.7±9.1, 89.8±9.0, and 90.2±9.0, respectively. Median (IQR) ARV-MAP was 6 (3, 10) mmHg. Mean pre-donation eGFR was 102.1±29.1 ml/min/1.73 m 2 and eGFR at 6-, 12-, and 24-months post-donation were 60.7±42.6, 62.4±43.9, and 64.4±44.9 ml/min/1.73 m 2 , respectively. The incidence rate of the event was 8.21 per 100 person-months. Compared to Q1 of the ARV-MAP, only Q3 had a 3.8% higher risk for declined eGFR (HR Q3 (95%CI) 1.04 (1.00, 1.08)). After adjusting for age, gender, race/ethnicity, U.S. citizenship status, level of education, history of hypertension, pre-donation BMI, pre-donation MAP, eGFR, and post-donation proteinuria, Q2, Q3, and Q4 have a 6.3%, 8.3%, and 6.9% significantly greater risk of the event, respectively (HR Q2 1.06 (1.00, 1.12); HR Q3 1.08 (1.02, 1.14); HR Q4 1.07 (1.01, 1.13)). There is no effect modification of the covariates for the ARV-PP - post-donation eGFR association. Conclusions: The risk for a 35% decline in post-donation kidney function is associated with ARV-MAP. DBP and PP may involve in kidney function after unilateral nephrectomy in LKD who develop post-donation glomerular hyperfiltration.
Abstract 16819: Activation of Mitochondrial Calpain 1 Contributes to Complex I Damage During ER Stress
Authors: Qun Chen, Ling Li, Jeremy Thompson, Hu Ying, Belinda Willard, Edward J Lesnefsky
Journal: Circulation (2023)

Introduction: ER (Endoplasmic reticulum) stress is increased in failing hearts. The increased ER stress impairs complex I in cardiac mitochondria (MITO). Calpain 1 (CPN1) and calpain 2 (CPN2) are calcium-dependent cysteine proteases located in cytosol and MITO (mCPN1 and mCPN2). Activation of mCPN1 contributes to complex I damage during ischemia-reperfusion (IR) and aging. Activation of the mCPN2 causes complex I damage following IR. However. the role of mCPN1 and mCPN2 activation in ER stress-mediated complex I damage remains unclear. Hypothesis: ER stress leads to complex I damage by activating mCPN1 and mCPN2. Methods: Wild type (WT) and conditional cardiomyocyte specific calpain 4 (CPN4) knockout (KO) mice were used. CPN4 is a small regulatory subunit of CPN1 and 2, and KO of CPN4 eliminates CPN1 and CPN2 activities. Tunicamycin (TUNI, 0.4 mg/kg) was used to induce ER stress in both WT and KO mice through one time IP injection. DMSO was used as vehicle treatment. Mice were sacrificed for cardiac mitochondrial isolation after 72 hours of vehicle or TUNI treatment. Results: ER stress was increased in both WT and KO mice, as shown by increased BIP in TUNI-treated mice (Figure, Panel A). Compared to vehicle, the rate of oxidative phosphorylation (OXPHOS) was decreased in TUNI-treated WT when glutamate + malate was used as complex I substrate (Panel B). In contrast, TUNI treatment did not alter OXPHOS with complex I substrate in KO (Panel B). Direct measurement of complex I activity showed that TUNI treatment only decreased complex I in MITO from WT but not from KO (Panel C). Proteomic study showed that the contents of complex I subunits including NDUFV2 and ND5 were decreased in WT but not in KO mice (Panel D); confirmed by western blotting (data not shown). These results indicate that activation of mCPN1 and mCPN2 contributes to the degradation of complex I subunits during ER stress. Conclusion: Induction of acute ER stress using TUNI damages complex I by activating mCPN1 and mCPN2.
Abstract 16555: Neutrophil to Lymphocyte Ratio: A Marker of Inflammation in Pericardial Disease
Authors: Aqieda Bayat, Alveena Syed, Ambreen F Ali, vineet tornekar, Tiffany Dong, Allan L Klein
Journal: Circulation (2023)

Introduction: Neutrophil-to-lymphocyte ratio (NLR) reflects the intricate relationship between the innate and adaptive immune systems during inflammatory states. With NLR known to be a sensitive indicator of inflammation, its role as a marker in acute pericarditis is yet to be investigated. Here we describe a rare case of acute pericarditis with an elevated NLR highlighting the potential impact this marker can have within the diagnostic evaluation of pericardial disease. Clinical Case: 46-year-old male with a past medical history of long QT syndrome, crohn's disease, ankylosing spondylitis, psoriatic arthritis, and histoplasmosis who presented with a four-day history of pleuritic chest pain, fever, and chills. The patient had a recent admission two months prior for pericardial effusion s/p emergent pericardial window. Cultures then showed acute and chronic inflammatory granulation tissue and necrosis with no evidence of malignancy and negative stains for fungal organisms. He was discharged home with ibuprofen without improvement. Upon arrival, the patient was hemodynamically stable with a workup notable for leukocytosis of 13.82x 10 9 /l, elevated CRP of 22.5 mg/dL and ESR of 65 mm/hr. NLR was 7.0. Echocardiography showed preserved ejection fraction with moderate circumferential pericardial effusion (figure A). The patient was started on colchicine in addition to ibuprofen. The cardiac MRI obtained showed evidence of moderate active pericarditis (figure B, C). A decision was ultimately made to start inpatient anakinra with a plan to discharge on triple therapy with colchicine, ibuprofen, and rilonacept. Discussion: NLR has the potential to be a novel inflammatory marker in pericardial disease associated with pericardial inflammation and edema. A normal range of NLR is between 1-2, with values higher than 3.0 and below 0.7 considered pathological. Our case highlights the importance of NLR as a diagnostic and prognostic marker of pericardial disease.
Abstract 15580: Blood Transfusion in Ascending Aortic Surgery: No Inherent Cause for Concern
Authors: Asanish Kalyanasundaram, Camilo Velasquez, Mohammad Zafar, Bulat A Ziganshin, John A Elefteriades
Journal: Circulation (2023)

Introduction: There is widespread concern that blood transfusion has a strong adverse impact on early/late surgical survival, so hematocrit is often allowed to drift very low. We investigate whether this adverse impact of transfusion is seen in aortic surgery. Methods: The records of 870 patients who underwent open ascending aortic or arch surgery from 2004 to 2016 by one surgeon at a large hospital were reviewed. Of these patients, 347 (39.9%) received a blood transfusion. The mean number of intra-op units transfused was 0.89, and the mean total units transfused (intra+post-op) was 2.45. High-volume transfusion (over 5 units) was needed for only 24 (6.9%) patients. We aimed to maintain a post-operative Hct of above 28%. Mean follow-up was 6.5 years. Results: We found no significant difference in 30-day or 1-year mortality between the transfused and non-transfused groups, nor between high- and low-volume transfused patients. However, the long-term mortality beyond 1 year was higher in the transfused group than in the non-transfused group (13% vs 5.7%; p=0.0003). Notably, the transfused group was older than the non-transfused group (64.9 vs 57.7). On Kaplan-Meier analysis (Fig.1), there remained a significant adverse effect of transfusion overall (p=0.004), but this effect was eliminated if patients were propensity matched for age (p=0.18). There was no difference in high- vs low-volume K-M survival (p=0.58). Amongst those transfused, the total units transfused was not a predictor of mortality in any time-frame on multivariate regression when adjusting for pre-op Hct, blood transfusions, DHCA, type A dissection, and operation urgency (p=0.95, 0.56, and 0.45 for 30d, 1yr, and beyond 1yr respectively). Conclusions: Transfusion and transfusion volume had no significant effect on early mortality, or even on late mortality after appropriate age adjustment. Should patient condition warrant, surgeons need not be concerned that transfusion will further reduce survival.
Abstract 13612: Association Between B-Type Natriuretic Peptide and Inferior Vena Cava Diameter as a Measure of Hypovolemia in Cancer Patients
Authors: Raed Qarajeh, Amy Tu Trinh Le, Bart Wilder, Akash Sharma, Lolita Golemi, Tochukwu Okwuosa
Journal: Circulation (2023)

Introduction: Hypovolemia is frequently seen in cancer patients due to catabolism, cachexia, and decreased oral intake. However, volume status assessment in this population is often difficult due to competing comorbid conditions such as edema. Elevated B-type natriuretic peptide (BNP) is an established biomarker of myocardial wall stress in patients with hypervolemia. We sought to determine if very low BNP could be an objective marker of hypovolemia in cancer patients Hypothesis: In cancer patients undergoing treatment, is low BNP level (&lt;10 pg/mL) associated with small inferior vena cava (IVC) diameter (&lt; 1.4 cm) - an established marker of hypovolemia on transthoracic echocardiography (TTE)?We hypothesize that BNP &lt;10 pg/mL is associated with small IVC as a marker of hypovolemia in cancer patients. Methods: We conducted a retrospective study (N=91) with solid malignancies, undergoing chemo- and/or radiation therapy (RT), divided into 3 groups based on BNP values in pg/mL: low (BNP &lt;10), normal (BNP 10-100) and high (BNP&gt;100). Retrospective data were obtained between 2016-2023 from Rush University Medical Center Cardio-Oncology Registry. IVC measurements by 2 medial trainees (Cohen’s intraclass correlation coefficient = 0.87, p &lt; 0.01) were acquired from formal TTEs obtained within 1 week of BNP measurements. Linear regression was used to calculate the adjusted means (for age, sex, BMI, blood pressure, creatinine, RT, TSH) of the 2 measured IVC diameters per datapoint. Mean difference in IVC diameters was compared between the 3 BNP groups. Results: The population mean age was 59.99 ± 12.19, 67% women. Adjusted mean IVC measurements were 1.89cm, 1.55cm, and 1.26cm for the high, normal, and low BNP groups respectively. The mean difference in IVC diameters between high and low BNP groups was 0.628 ±0.164 cm (p&lt;0.01). Conclusions: In cancer patients undergoing treatment, very low BNP (&lt;10pg/mL) was associated with small IVC as a marker of hypovolemia. In this group of patients, BNP measured with routine lab data is a readily available tool to identify individuals with hypovolemia where other measures of volume status such as physical exams might be uncertain.
Abstract 15227: Venous Thromboembolism and Effects of Statin and Hormone Therapy: A Case-Control Study of 250,000 Women Aged 50-64
Authors: John W Davis, susan C weller, Laura Porterfield, Lu Chen, Gregg Wilkinson
Journal: Circulation (2023)

Background: Post-menopausal hormone therapy (HT) may elevate the risk of venous thromboembolism (VTE), while statin therapy may lower risk. Purpose. To estimate VTE risk from HT exposure with/without statin therapy in women 50-64 years of age. Methods: This was a case-control study in a large database of commercially insured subjects. We matched cases of VTE diagnoses (1:10) to controls without VTE on age, +/- 2 years. Conditional logistic regression estimated odds ratios (ORs) for recent HT exposure (any estrogen and/or progestogen within 60 days) and current statin therapy ( &gt; 90 days continuous exposure) controlling for VTE risk factors, comorbidities, and coronary artery disease. We assessed risk by current exposure to a statin of any intensity (Model 1) and then by increasing intensity (Model 2). Results: In a comparison of cases (n=20,359) and matched controls (n=203,590), 9% (n=19,558) had recent HT exposure and 16% (n=36,238) had current/continuous statin exposure. After adjustment for all covariates, the OR for any recent HT exposure (regardless of statin exposure) was 1.51 (95% CI: 1.43, 1.60) compared to no HT exposure. The OR for current statin therapy (regardless of HT exposure) was 0.88 (95% CI: 0.84, 0.93). For those with HT exposure without statin therapy the OR was 1.53 (95% CI: 1.44, 1.63), for those with HT exposure with statin therapy the OR was 1.25 (95% CI: 1.10, 1.43), and for those exposed to statin therapy without HT exposure the OR was 0.89 (95% CI: 0.85, 0.94), compared those not exposed to either statin or HT. HT with statin therapy had a 18% significantly lower odds ratio than HT without statin therapy (OR=0.82, 95% CI: 0.71, 0.94). Exposure to high intensity statin therapy trended towards greater risk reduction for VTE compared to low/moderate exposure. Conclusion: Statin therapy may reduce VTE risk associated with HT.
Abstract 15008: Novel Sheathless Guiding Catheter Equipped With Peel-Off External Dilator for Percutaneous Coronary Intervention With Distal Radial Approach - A Multicenter Study
Authors: Takeshi Yamada, Takuya Izumikawa, Akihiko Takahashi, Norimasa Taniguchi, Shunsuke Nakajima, Tetsuya Hata
Journal: Circulation (2023)

Objectives: Hyperion Sheathless guiding catheter (Asahi Intecc) is a novel guiding system for percutaneous coronary intervention (PCI) which is equipped with peel-off type outer dilator to facilitate smooth insertion of catheter tip. The aim of this study was to access feasibility and efficacy of this system for the patients who underwent PCI through distal radial artery. Methods: A total of 179 patients underwent PCI using a 6-Fr Hyperion sheathless guiding catheter in 2 hospitals. Of those, 168 patients including 27 patients with ST elevation myocardial infarction were treated with distal radial approach. Procedural success, bleeding complication and radial occlusion examined using Doppler ultrasound at discharge was accessed. Results: Mean age of the patients was 72.1 +/- 11.3 years and 114 patients were male. Procedural success was 100 % with no patient requiring conversion to conventional radial access. Doppler ultrasound examination of the distal radial artery at 1-day follow-up was available in all patients, with 2 patients (1.2%) was found to have radial artery occlusion. One patient presented forearm hematoma equivalent to EASY hematoma classification I and 4 patients showed dorsum hematoma. Conclusions: The current study illustrated that the use of the Hyperion Sheathless guiding catheter for distal radial PCI was feasible and associated with a low rate of procedure-related complications even in the patients with ST-elevation myocardial infarction.
Abstract 17202: Cross-Species Evaluation of Cellular TNF Receptor-Associated Factor (TRAF) Expression, Regulation and Function in Murine and Human Atherosclerosis
Authors: Mark Colin Gissler, Hauke Horstmann, Dirk Westermann, Dennis Wolf
Journal: Circulation (2023)

Background: TNF receptor-associated factors (TRAFs) potently modulate immune cell function and activity in a variety of inflammatory diseases. However, due to the limited availability of viable animal models, the roles of TRAF3, TRAF4 and TRAF7 in atherosclerosis remain unknown to date. Here, we present a stepwise multiparametric approach to delineate cellular expression, regulation and implications on cardiovascular outcomes of TRAFs in murine and human atherosclerosis. Methods: To induce atherosclerotic lesion formation, LDLR-/- mice were fed a high cholesterol diet for 20 weeks and expression of TRAF1-7 was determined in whole tissue lysates of the murine aorta as well as on sorted leukocytes. We then performed scRNAseq and bioinformatical integration of leukocytes from human and mouse atherosclerotic plaques to analyze and compare single cell TRAF expression in both species. Finally, potential significance of cellular TRAF3, 4 and 7 expression in human atherosclerosis was assessed in three independent clinical study cohorts. Results: Aortic TRAF3 and TRAF4 expression was 2-fold higher in atherosclerotic mice compared to controls, whereas TRAF7 expression was significantly lower. Between species, humans exhibited higher cellular TRAF3 expression than mice. Further, TRAF7 blood expression was lower in patients with an unstable CAD angiogram than in patients with stable CAD while expression of TRAF3 in human atherosclerotic plaques was significantly higher in unstable compared to stable lesions. Finally, TRAF3 expression on circulating CD16+ monocytes determined by scRNAseq of PBMCs was substantially higher in atherosclerotic patients that died from a cardiovascular cause during 20 years of follow-up compared to survivors from the same study collective, indicating that cellular TRAF expression may predict cardiovascular long-term outcomes. Conclusion: Here, we present the first cross-species assessment of cellular TRAF3, 4 and 7 expression in murine and human atherosclerosis by utilizing a multiparametric approach to circumvent the lack of viable knockout models. Finally, we provide first evidence that cellular TRAF expression assessed by scRNAseq may add to the clinicians armamentarium for MACE prediction in the future.
Abstract 15410: Obstacles to Implementation in a Heart Failure Nurse Practitioner and Pharmacist Lead Guideline Directed Medical Therapy Program
Authors: Omaima Ali, Gladys Baksh, Michele Haydo, Heather Reesor, Carlos Contreras, Samaa Ahmed, Allen R Kunselman, Andrew Foy
Journal: Circulation (2023)

Background: The aim of this study was to describe differences in baseline characteristics of patients who did or did not complete a HF-GDMT optimization program at our institution and who reached vs did not reach target doses of therapies. Methods: We instituted a structured program in September 2020 led by a heart failure nurse practitioner and clinical pharmacist to optimize GDMT in a safe and expedited manner that involved telephone visits and labs every 2 weeks. Since this is an exploratory analysis differences between groups were reported with p values &lt;0.10. Results: A total of 247 patients were enrolled. The average age of the cohort was 62.3 (13.9), 31% were women, 53% had new onset within 6 months of enrollment, and 66% were nonischemic. Overall, 198 (80%) patients completed the program and 49 (20%) did not. Non-completers were more likely to have transportation limitations (25% vs 5%; p&lt;0.001 ), to be on Medicare or Medicaid (76% vs 54%; p=0.009 ), to be referred to a prescription assistance program (33% vs 21%; p=0.084 ), and were less likely to have commercial insurance (18% vs 39%; p=0.008 ). Among patients who completed the program only 48 (24.3%) reached the recommended doses of all medicines and 150 (75.7%) did not. Patients who reached the recommended doses were younger (mean age 57.5 vs 64.4; p= 0.002), and were more likely to have nonischemic vs ischemic cardiomyopathy (29% vs 16%; p=0.078) and chronic vs new onset disease (31% vs 18%; p=0.046). Patients under 50 were far more likely to reach target doses compared to those &gt;80 (46% vs 4%). Conclusions: Important differences in patients who did or did not complete the program and who reached or did not reach target doses were identified. These differences help identify implementation challenges in real-world settings.