tbuckley/cabot-search huggingface dataset:
Abstract MP254: Decellularized Extracellular Matrix Hydrogel Lowers Fibrosis And Fibroblast Differentiation In Post-injury Mice Hearts Through Capg
Authors: Xinming Wang, Samuel Senyo
Journal: Circulation Research (2021)

Hypothesis and objective: We hypothesize that transplantation of decellularized cardiac extracellular matrix (dECM) lowers fibrosis and fibroblast differentiation. In this study we investigated collagen deposition and fibroblast differentiation in post-MI hearts and heart explants of various stiffness after dECM hydrogel treatments. The objectives are 1) determining if dECM derived from fetal and adult porcine hearts reduces fibrosis in injured hearts; and 2) identifying specific signaling pathways that regulate fibroblasts differentiation induced by extracellular proteins. Methods: Porcine dECM was injected immediately after ligating coronary artery in P1 mice. Histology was conducted on day 7 post-myocardial infarction (MI). A mice ventricle explant model was used to investigate the molecular mechanisms. Results: We observed that fetal dECM treatment lowered fibrosis and fibroblast differentiation in post-MI hearts (Fig.1). Fibroblast differentiation as indicated by α-smooth muscle actin expression in vimentin or platelet derived growth factor receptor α positive cells showed an inhibitory effect of fetal dECM on fibroblast differentiation. Using a heart explant model of modulated microenvironment stiffness, we demonstrated that increasing tissue stiffness stimulates fibroblast differentiation and collagen deposition. Fetal dECM treatment, however, inhibited fibroblast differentiation induced by increasing microenvironment stiffness. Transcriptome analysis revealed that two cytoskeleton-related genes, macrophage capping protein (CAPG) and leupaxin (LPXN), are modulated by dECM treatments. Using cytoskeleton polymerization modulators and siRNA, we demonstrated that fetal dECM lowers fibroblast differentiation through CAPG.
Abstract P405: Cardioprotective Actions Of Nitroxyl Donor Angeli's Salt Are Preserved In The Diabetic Heart And Vasculature In The Face Of Nitric Oxide Resistance
Authors: Anida Velagic, Jasmin Chendi Li, Chengxue Helena Qin, Mandy Li, Minh Deo, Sarah A Marshall, Owen L Woodman, John D Horowitz, Barbara K Kemp-Harper, Rebecca H Ritchie
Journal: Circulation Research (2021)

Introduction: The risk of fatal cardiovascular events is increased in patients with type 2 diabetes mellitus (T2DM). A major contributor to poor prognosis is impaired nitric oxide (NO•) signalling at the level of tissue responsiveness, termed NO• resistance. Nitroxyl (HNO) induces positive inotropic and lusitropic effects in healthy and failing hearts. Hypothesis: We hypothesised that in a rodent model, T2DM will promote, and HNO will circumvent, NO• resistance in the myocardium and coronary vasculature. Methods: At 8 weeks of age, male Sprague-Dawley rats commenced a high-fat diet. After two weeks, the rats received low-dose streptozotocin (two intraperitoneal injections, 35 mg/kg, over two consecutive days), and continued the diet. Twelve weeks later, hearts were Langendorff-perfused to assess responses to the NO• donor diethylamine NONOate (DEA/NO) and the HNO donor Angeli’s salt. Results: Inotropic, lusitropic and coronary vasodilator responses to DEA/NO were impaired, and responses to Angeli’s salt were preserved or enhanced, in T2DM hearts compared with non-diabetic hearts. Conclusions: This is the first evidence that inotropic and lusitropic responses are preserved, and NO• resistance in the coronary vasculature is circumvented, by the HNO donor Angeli’s salt in T2DM. These findings highlight the cardiovascular therapeutic potential of HNO donors, especially in cardiac emergencies such as acute ischaemia or heart failure. Figure 1. Dose-response curves and maximal responses to DEA/NO or Angeli's salt in diabetic or non-diabetic hearts. (A-C) LV+dP/dt, (D-F) LV-dP/dt and (G-I) coronary flow rate. Data expressed as change from baseline (denoted by Δ), mean ± SEM. Data analysed by two-way RM ANOVA with Sidak's post-hoc test. *P&lt;0.05 vs. non-diabetic. LV, left ventricular; LV+dP/dt, maximal rate of rise in LV pressure; LV-dP/dt, maximal rate of fall in LV pressure.
Abstract 12187: Arrhythmia Substrate and Approaches for First-Time and Repeat Catheter Ablation in Patients With D-transposition of the Great Arteries and Atrial Baffles
Authors: Anca Chiriac, Kamal Preet P Cheema, Davide Giardi, Samantha Espinosa, Patrick Fitzgerald, Goyal Umadat, Julio Perez-Downes, Sabrina D Phillips, Malini Madhavan, Samuel Asirvatham, Christopher J McLeod
Journal: Circulation (2021)

Introduction: Atrial arrhythmias are common in patients with D-TGA and atrial switch. We sought to analyze the arrhythmia substrate and catheter ablation approaches and outcomes. Methods: We performed a retrospective review of all clinical and procedural data in patients with D-TGA followed at a large tertiary care center. Results: In a cohort of 152 patients (mean age 30±11 years), atrial tachycardia was present in 69(45%) patients. Ablations were performed in 39(26%) patients: macro-reentrant atrial flutter (N=37), atrial fibrillation (N=4), and focal automatic atrial tachycardia (N=3). Detailed electrophysiology study data was available for 34 patients. At first ablation (N=28), cavo-tricuspid isthmus dependent flutter (CTI, 23(82%)) was most common, followed by right atriotomy-related flutter (IART, 16(57%)) and focal atrial tachycardia (FAT, 1(3.5%)). Bidirectional CTI block often required ablation on both sides of the baffle to complete the isthmus line. Access to the pulmonary venous atrium was obtained in 82% of first-time ablations (via retrograde aortic access, 74%, baffle puncture, 6%, or baffle fenestration, 12%) and in 100% of redo procedures. The first ablation was acutely successful in 25 (89%) patients; the other 3 patients had either partial procedural success (1), failed ablation (1), or underwent an empirical ablation (1). Long-term arrhythmia recurrence occurred in 13(46%) after the first ablation and class III antiarrhythmic medications were utilized in 12 patients. At least one long-term recurrence occurred in 11(44%) patients. Importantly, clinical arrhythmia burden was significantly reduced post-ablation, with rare and short-limited episodes amenable to antiarrhythmic drugs or cardioversion. Repeat ablation was required in 3 cases. Long-term arrhythmia recurrence after a previously completed CTI line involved different arrhythmia mechanisms: scar-related reentry (80%) and automatic atrial tachycardia (40%). Conclusions: Atrial arrhythmia in patients with D-TGA often involves the CTI and atriotomy scars. Ablation of the CTI typically requires access to the pulmonary venous atrium to achieve bidirectional block. Despite late recurrence, the clinical arrhythmic burden is substantially improved.
The Impact of CD19 Expression Combined with Measurable Residual Disease on Post-Remission Treatment and Outcome in Adult t(8;21) Acute Myeloid Leukemia
Authors: Pengcheng Shi, Naying Liao, Ning Wu, Huan Li, Fen Huang, Na Xu, Zhiping Fan, Yu Zhang, Qifa Liu
Journal: Blood (2021)
Abstract 10362: Association of Sex and Age with Mortality in Stemi Patients Without Standard Modifiable Risk Factors: Analysis from Nationwide Readmission Database
Authors: Sun-joo Jang, Ilhwan Yeo, Parag Goyal, Jim W. Cheung, Dmitriy N. Feldman, Stephen McCullough, Udhay Krishnan, David Narotsky, Harsimran S Singh, Robert M Minutello, Geoffrey Bergman, Shing-chiu WONG, Luke K. Kim
Journal: Circulation (2021)

Introduction: The proportion of STEMI patients without standard modifiable cardiovascular risk factors (SMuRFs: hypertension, diabetes mellitus, hypercholesterolemia and smoking) has increased over time. However, outcomes of STEMI patients without SMuRFs are not well known. Hypothesis: To test the hypothesis that age and sex would have a significant impact on mortality after STEMI in the absence of SMURFs. Methods: Patients who underwent primary PCI after STEMI were identified from the Nationwide Readmission Database. Clinical characteristics, in-hospital and 30-day mortality in STEMI patients with or without SMuRFs were compared in men and women stratified into 5 age groups (&lt;50, 50 to 59, 60 to 69, 70 to 79 and ≥80 years of age). Results: Between January 2010 and November 2014, 54,665 (11.3%) of 482,947 patients, who underwent primary PCI for STEMI, did not have pre-existing SMuRFs. Absence of SMuRFs was more common in men than women (11.4% vs 9.8%, p&lt;0.001) across all age groups, and patients without SMuRFs had higher in-hospital mortality rates than those with SMuRFs . Among those without SMuRFs, in-hospital mortality rate was significantly higher in women than men (13.5% vs 9.3%, p&lt;0.001) accross all age groups and was increased with advanced age groups. In addition, absence of SMuRFs was associated with higher 30-day mortality rates than those with SMuRFs (0.5% vs 0.3%, p&lt;0.001). Among patients without SMuRFs, women had higher 30-day mortality than men (0.7% vs 0.5%, p&lt;0.001). The increased risk of in-hospital (Odds Ratio [OR] 2.02, 95% CI 1.87 to 2.20) and 30-day mortality (OR 1.40, 95% CI 1.11 to 1.78) in patients without SMuRFs remained significant after multivariate adjustment. Conclusions: Patients presenting with STEMI without SMuRFs have a significantly higher risk of in-hospital mortality and 30-day mortality compared with those with SMuRFs. Women and older age group without SMuRFs experienced more frequent in-hospital mortality and 30-day mortality.
Abstract 10305: Cardiac Remodeling and Disease Progression in Patients with Repaired Coarctation of Aorta and Aortic Stenosis
Authors: Likhita Shaik, Janaki Devara, Renuka Reddy Katta, Momina Iftikhar, Ahmed Goda, Alexander C Egbe, Heidi M Connolly
Journal: Circulation (2021)

Introduction: Valvuloarterial impedance (Zva) is used for assessment of left ventricular (LV) global pressure load in patients with aortic stenosis (AS) and impaired arterial compliance. Since patients with coarctation of aorta (COA) have impaired arterial compliance, we hypothesized that COA patients with ≥moderate AS (AS-COA group) will have higher Zva, symptomatic progression, and cardiovascular events, as compared to non-COA patients with similar AS severity (AS group). Methods: 1:1 propensity matching of 71 AS-COA and 71 AS patients based on age, sex, body mass index, and aortic valve mean gradient. Results: The AS-COA group had higher Zva (4.2±0.6 vs 3.5±0.4 mmHg/ml*m 2 , p&lt;0.001), more advanced cardiac remodeling, and higher 5-year incidence of symptomatic progression (85% vs 51%, p&lt;0.001). Pre-operative Zva was independently associated with cardiac remodeling (r=0.66, p&lt;0.001) and symptomatic progression (HR 1.08, 1.05-1.12, per mmHg/ml*m 2 increase in Zva). Of 172 patients, 117 underwent aortic valve replacement (AVR). The AS-COA group had higher residual Zva(3.3±0.5 vs 2.4±0.4 mmHg/ml*m 2 , p&lt;0.001), less robust LV mass index (LVMI) regression at 1-year post-AVR, and higher 5-year incidence of cardiovascular events. Post-operative Zva was independently associated with LVMI regression (r=-0.46, p&lt;0.001) and cardiovascular events (HR 1.06, 1.02-1.10, per mmHg/ml*m 2 increase in Zva). Conclusions: Adults with repaired COA repair and moderate-severe AS had higher LV global pressure load, cardiac remodeling, symptomatic progression, and cardiovascular events as compared to non-COA patients with similar severity of AS. Zva can identify patients at risk for adverse outcomes, and perhaps should be used for risk stratification with regards to timing of AVR.
Abstract 14099: Using a Respiratory Resistance Device as a Therapeutic Modality in Patients With a History of Heart Failure, Preliminary Report
Authors: Jordan Parks, Jesse Schwartz, Meredith Shea, Bruce Johnson, Regis Fernandes, Courtney Wheatley-Guy
Journal: Circulation (2021)

Introduction: Heart failure (HF) is associated with limited blood flow reserve due to reduced cardiac output (Q). HF is also associated with generalized respiratory muscle weakness, despite patients being exposed to an increased work and cost of breathing due primarily to increased flow resistive work from an altered breathing pattern. We hypothesized that the use of a respiratory training device during aerobic exercise training would positively impact patients with HF by training the inspiratory muscles and modifying their respiratory response to exercise. Methods: 15 subjects completed all study visits (age 67.5±10.0 yr, Ht 179.3±6.1cm, BMI 28.8±5.7 m/cm 2 ). Patients diagnosed with HF and currently enrolled in cardiac rehabilitation (CR) completed the Minnesota living with heart failure questionnaire (MLHFQ), pulmonary function testing, and measures during exercise that included Q (soluble gas method), ventilation (V E ) and respiratory gas exchange. Measures were made at baseline and after completion of CR. Participants were randomized to no respiratory resistance (NR) or mild-moderate inspiratory resistance (MR, 15 to 20 cmH 2 O) provided by a respiratory resistance mask (Training Mask Co., Cadillac, MI) worn during aerobic portions of CR. Results: Participants completed on average 23.9 ± 2.5 CR sessions with 10 subjects in the MR group and 5 in the NR group. The MR group had a decrease on the MLHFQ score of 19.9±26.9 and the NR group had a decrease of 6.0±23.4 (p=0.330). At a matched workload of 30 Watts (W), V E declined by 4.0±7.0 L/min and increased by 2.2±13.1 L/min for subjects in the MR and NR groups, respectively (p=0.06). Respiratory rate (RR) decreased in MR by 1.2± 4.9 and decreased in NR by 0.67± 5.9 (p&gt;0.05). Heart rate at 30W decreased with time in both the MR and NR groups 10.4±12.4 and 3.9±8.9 respectively (p=0.036, no difference between groups). Stroke volume at 30W tended to increase for both MR and NR (p&gt;0.05, no difference between groups). Conclusion: The addition of moderate inspiratory resistance to the aerobic training during CR was well tolerated by HF patients and preliminarily suggests trends toward improved ventilatory responses when assessed during submaximal exercise.
Abstract 13315: Feasibility and Effectiveness of Using a Modified Microvascular Plug to Reduce Pulmonary Blood Flow for Various Congenital Heart Diseases
Authors: Ashley Kiene, Evan Harvey, Jason Johnson, Benjamin Waller, Chris Knott-Craig, Shyam Sathanandam
Journal: Circulation (2021)

Background: Neonates with certain congenital heart diseases (CHD) experience pulmonary overcirculation requiring a sternotomy for either pulmonary artery banding or neonatal corrective surgery. We present an alternative, percutaneous technique of utilizing custom fenestrated microvascular plug (MVP) as pulmonary flow reducers (PFR) for five different CHDs complicated by pulmonary overcirculation in the newborn. Methods: Fourteen PFRs were implanted percutaneously via a femoral venous only approach under fluoroscopic and echocardiographic guidance in nine neonates for five different CHDs. The success rates, complications, effectiveness and follow-up details are described. Results: All 14 PFRs were successfully implanted in the desired locations in with no procedural failures or complications. Bilateral PFRs were implanted within the branch pulmonary arteries in two patients to balance pulmonary and systemic circulations in single ventricle physiology and in three patients to reduce left-to-right shunt physiology. Single PFRs were placed within the patent ductus arteriosus (PDA) in one patient with a PDA stent who developed pulmonary overcirculation and three patients with large PDAs and pulmonary hypertension. Effectiveness was assessed either by a 10% drop in systemic oxygen saturation, &gt; 35 mmHg Doppler gradient, or weaning off diuretics depending on the indication. On latest follow-up, there were no PFR related mortality or re-interventions. Conclusion: It is feasible to modify and implant the MVP to function as an effective PFR for various congenital heart lesions in neonates. Outcomes following explanation such as, pulmonary artery growth, re-interventions rates are unknown. Once the learning experiences are overcome, longer term comparison studies are necessary to demonstrate benefits over existing therapies.
TAMI-20. GLIOMA CELLS REPROGRAM SERINE-DEPENDENT ONE-CARBON METABOLISM TO SURVIVE GLUTAMINE STARVATION
Authors: Kazuhiro Tanaka, Hiroaki Nagashima, Yuichi Fujita, Mitsuru Hashiguchi, Takashi Sasayama
Journal: Neuro-Oncology (2021)

Abstract Cancer cells optimize nutrient utilization to supply energetic and biosynthetic pathways. This metabolic process also includes redox maintenance and epigenetic regulation through nucleic acid and protein methylation, which enhance tumorigenicity and clinical resistance. However, less is known about how cancer cells exhibit metabolic flexibility to sustain cell growth and survival from nutrient starvation. Here, we find that serine and glycine levels were higher in low-nutrient regions of tumors in glioblastoma multiforme (GBM) patients than they were in other regions. Metabolic and functional studies in GBM cells demonstrated that serine availability and one-carbon metabolism support glioma cell survival following glutamine deprivation. Serine synthesis was mediated through autophagy rather than glycolysis. Gene expression analysis identified upregulation of methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) to regulate one-carbon metabolism in GBM patient-derived sphere cells as well as in GBM cells. In clinical samples, MTHFD2 expression was highest in the nutrient-poor areas around “pseudopalisading necrosis.” Genetic suppression of MTHFD2 and autophagy inhibition caused tumor cell death and growth inhibition of glioma cells upon glutamine deprivation. These results may have important implications for serine-dependent one-carbon metabolism for glioma cells to survive glutamine starvation and suggest a new therapeutic strategy for patients with malignant glioma.
Abstract P460: Role Of Hopx In Antiretroviral Drugs Induced Cardiac Hypertrophy And Epigenetic Modification
Authors: Shiridhar Kashyap, Olena Kondrachuk, Manish K Gupta
Journal: Circulation Research (2021)

Background: Heart failure is the one of the leading causes of death in HIV patients. Application ofantiretroviral therapy (ART) raise the life expectancy of HIV patients, but survival population show higherrisk of cardiovascular disorder. The aim of this study is to understand the underlying molecular mechanismof antiretroviral drugs (ARVs) induced cardiac dysfunction in HIV patients. Method and Results: To determine the mechanism of ARVs induced cardiac dysfunction, we performeda global transcriptomic profiling in primary cardiomyocytes treated with ARVs. Differentially expressedgenes were identified by DESeq2. Functional enrichment analysis of differentially expressed genes wereperformed using clusterProfiler R and ingenuity pathway analysis. Our data show that ARVs treatmentcauses upregulation of several biological function associated with cardiotoxicity and heart failure.Interestingly, we found that ARV drugs treatment significantly upregulates the expression of a set of genesinvolved cardiac enlargement and hypertrophy in the heart. Global gene expression data were validated inthe cardiac tissue isolated from the HIV patients having history of ART treatment. Interestingly, we foundthat the homeodomain-containing only protein homeobox (HOPX) expression was significantly increasedin transcriptional and translational level in cardiomyocytes treated with ARV drugs as well as in heart tissueof ART treated HIV patients. Further, we performed adenovirus mediated gain in and siRNA mediatedknockdown approach to determine the role of HOPX in ARVs mediated cardiac hypertrophy and epigeneticmodifications. Mechanistically, we found that HOPX expression level plays a key role in ARV drugsmediated increased cardiomyocytes cell size and reduced acetylation level of histone 3 at lysine 9 and lysine27. Furthermore, we found that knockdown of HOPX gene expression blunted the hypertrophy effect ofARV drugs in cardiomyocytes. It is known that HOPX reduces cellular acetylation level through interactionwith HDAC2. In our study, we found that histone deacetylase inhibitor Trichostatin A can restore cellularacetylation level in presence of ARVs. Conclusion: ART treatment causes cardiotoxicity through regulation of fatal gene expression incardiomyocytes and in adult heart. Additionally, we found that HOPX expression is critical in ARVsmediated cardiomyocytes remodeling and epigenetic modification.
Abstract 12182: Candesartan vs Lisinopril on Measures of Arterial Stiffness and Wave Reflections in Older, Hypertensive Adults
Authors: Steven Rogers, Chang Liu, Malik Obideen, Darius McDaniel, Ihab Hajjar, Arshed A Quyyumi
Journal: Circulation (2021)

Introduction: Higher arterial stiffness independently predicts risk of future cardiovascular events. Although angiotensin converting enzyme inhibitors (ACEi) and angiotensin-receptor blockers (ARBs) reduce blood pressure, their impact on vascular function may vary. Hypothesis: We hypothesized differences in the impact of ACEi compared to ARBs on arterial stiffness, wave reflections and microvascular function in hypertension among older men and women. Methods: We measured vascular function at baseline and after 1 year in 176 (87 Candesartan, 89 Lisinopril therapy) hypertensive participants with mild cognitive impairment (age 65.9 +/-7.7 years, 57% female). Pulse-wave velocity (PWV), central pulse pressure (CPP) and central augmentation index (AIx) were measured using applanation tonometry and the reactive hyperemia index using digital pulse amplitude tonometry. Results: While Candesartan and Lisinopril lowered blood pressure equally, only Lisinopril therapy resulted in a lower PWV (-0.7 ± 0.4 m/s, p=0.03) and CPP (-7 ± 4 mmHg, p=0.01) after 1 year, while Candesartan produced no significant change. There was a significant interaction by sex whereby arterial stiffness was lowered only in women with Lisinopril. Candesartan lowered AIx more than Lisinopril (-4 ± 7% vs -1.5 ± 8%, p=0.05) in both sexes. After adjustment for sex and cardiovascular risk factors, Lisinopril remained a significant predictor of lower PWV and CPP after 1 year (all p&lt;0.05). Conclusions: In a cohort of older hypertensive patients, despite equipotent anti-hypertensive effects, Lisinopril was more effective than Candesartan at lowering arterial stiffness in women. Candesartan was effective in lowering wave reflections compared to Lisinopril.