tbuckley/cabot-search huggingface dataset:
Abstract 12763: High Innate Aerobic Capacity Protects Against Angiotensin II-Induced Hypertension and Vascular Remodeling
Authors: Mark D Stevenson, Chandrika Canugovi, Aleksandr E Vendrov, Lauren G Koch, Steven Britton, Marschall Runge, Nageswara R Madamanchi
Journal: Circulation (2021)

Low aerobic capacity is associated with increased cardiovascular morbidity and mortality. A heterogeneous rat population selectively bred to segregate genes that sustain innate aerobic exercise capacity, low capacity runners (LCR) show impaired cardiac function in old age and premature death versus high capacity runners (HCR). Here we investigated whether high innate aerobic capacity offers early protection against cardiovascular disease by examining the hypertensive response of 7-month-old LCR and HCR rats to angiotensin II (Ang II, 150 μg/kg/min for 14 days). LCR and HCR rats showed no difference in basal blood pressure (105 mmHg) or vessel wall morphology, but in LCRs the mean arterial blood pressure increased to 145 mmHg versus 125 mmHg in HCRs. Congruently, LCR rats had increased aortic medial thickness and fibrosis. Aortic cytosolic and mitochondrial superoxide levels were also significantly increased in LCRs. Vascular reactivity experiments revealed impaired endothelium-dependent and -independent relaxation of mesenteric arteries of LCRs. Ang II infusion significantly increased the infiltration of macrophages into the aortic adventitia of LCRs as determined by CD68 and Mac-3 staining. Gene expression analysis by qPCR showed that markers of classically-activated macrophages CD86 and TNF-α were unchanged in rat strains but markers of alternatively-activated macrophages CD163 and Arg-1 were upregulated only in LCRs. Plasma IL-6, RANTES, CCL2 and Ang II and aortic VCAM1 levels were elevated only in LCRs whereas no difference in eNOS levels was observed between the rat strains. Aortic sections of LCRs showed increased senescence in adventitia whereas vascular smooth muscle cells (VSMC) isolated from LCR rats were more susceptible to Ang II-induced senescence. LCRs also showed increased cardiac hypertrophy and fibrosis. These data support the “outside-in” hypothesis, in which vascular inflammation initiated in adventitia progresses inwards to media and intima, causing VSMC and endothelial dysfunction, and that fibroblasts play a critical role in Ang II-induced hypertension and vascular remodeling under low innate aerobic capacity conditions, whereas high innate aerobic capacity is potentially protective against hypertension.
Abstract 10053: Outcomes of Transcatheter Aortic Valve Implantation with Baseline First Degree Heart Block (from National Inpatient Sample)
Authors: Salman Zahid, Muhammmad Khan, Waqas Ullah, Fnu Salman, Muhammad Atif Khan, AAMER UBAID, Hamza Muhammadzai, Abid Nawaz Khan Adil, Mian Tanveer Ud Din, Abdul Baqi, Devesh Rai, David L Fischman, Chadi Alraies, Mahboob Alam, bipul baibhav, Mohan Rao, Jeremiah Depta, Sudarshan balla
Journal: Circulation (2021)

Introduction: Pacemaker implantation remains a frequent complication in patients undergoing transcatheter aortic valve implantation (TAVI). Outcomes of TAVI with a baseline first degree heart block (HB) remain unknown. Methods: The purpose of this study was to evaluate outcomes of TAVI in patients with a baseline first degree HB. We utilized the National Inpatient Sample (NIS) data from the year 2011 to 2018. Results: A total of 215,938 weighted hospitalizations for TAVI were included in the analysis. Of the patient undergoing the procedure, 11000 had baseline first degree HB (5.1%) and 204938 (94.9%) patients did not have first degree HB. Patients with first degree HB had higher rates of PPM implantation (17.1% vs. 10.1%, p&lt;0.01). At baseline, age greater than 75 (Odds Ratio [OR], 1.26[confidence interval (CI), 1.10-1.45]), male gender (OR, 1.22[CI, 1.09-1.37]), atrial fibrillation (OR, 2.01[CI, 1.68-2.4]), hypertension (OR, 1.54[CI, 1.27-1.88]) and chronic kidney disease (OR, 1.22[CI, 1.08-1.37]) were significant predictors of PPM implantation in patients undergoing TAVI with a baseline first degree HB. In terms of resource utilization, patients with baseline first degree HB had higher median cost of stay ($ 48083 vs. $ 47081) Conclusions: In conclusion we report that PPM implantation rate is higher in patients with first degree HB and that age greater than 75, male sex, hypertension and chronic kidney disease are significant predictors of this adverse event.
Abstract 6925: Association of Increased Risk of Atherosclerotic Cardiovascular (ascvd) Event With Progression of Liver Disease to Cirrhosis
Authors: Leila Hashemi, Cachet Magdolna Wenziger, Tran Do, Matthew Budoff, Elani Streja
Journal: Circulation (2021)

Introduction: The current data on the association of advanced liver disease with ASCVD outcomes is conflicting. Hypothesis: Hyperinflammatory state due to decrease in bioavailability of nitric oxide, gut hyperpermeability, recurrent infection causing persistent immune system deregulation in advanced liver disease could increase the risk of development and progression of ASCVD. Method: Our cohort included 486,887 patients with diagnosis of non-alcoholic fatty liver disease, or viral hepatitis liver disease from VA National Database from January 1, 2000 to December 31, 2019. Cohort then further divided into patients with diagnosis of cirrhosis and without cirrhosis. Cox models were used to estimate the association between severity of liver disease (defined as cirrhosis vs no cirrhosis) with time to the first ASCVD event hospitalization defined as myocardial infarction (MI), ischemic stroke (CVA). Model was adjusted for age, sex, hypertension (HTN), diabetes (DM) and smoking history, systolic and diastolic blood pressure (BP), Low Density lipoprotein (LDL) and high- density lipoprotein (HDL). Results: The cohort included 4.6% female, 21% African American, 12% diabetes and 23.5% HTN. The prevalence of HTN and DM were higher in patients with cirrhosis but LDL and systolic BP were much lower in cirrhosis. The time to ASCVD event was 37 vs 73 months in cirrhosis vs no cirrhosis. The Kaplan Meier curve for composite ASCVD is shown in figure 1. In a fully adjusted model, risk of first ASCVD hospitalization was 9% higher in patients with cirrhosis (HR: 1.09, 95%confidence interval, CI (1.07-1.11)). In individual event analysis, risk of time to the first MI and CVA hospitalization were also higher in cirrhosis, with HR 1.01 and 1.20 respectively as shown in figure 1. Conclusion: As liver disease advances to cirrhosis the risk of ASCVD events increases and time to the first ASCVD decreases. The inflammatory state of advanced liver disease could be a possible explanation.
Is It Better to Start Treatment with ABVD and Continue with PET2-Adapted Approach or Should We Use 2 Cycles of Beacopp Escalated and 2 Cycles of ABVD and Irradiation in Early Unfavorable Hodgkin Lymphoma?
Authors: Heidi Mocikova, Jana Markova, Lubica Gaherova, Maria Maco, Alice Sykorova, David Belada, Marie Lukasova, Vit K Prochazka, Katarina Hradska, Juraj Ďuraš, Ondrej Havranek, Tomas Kozak
Journal: Blood (2021)
Abstract 13409: A Substantial Proportion of Patients With Transthyretin Cardiac Amyloid (ATTR) Present With Impaired Left Ventricular Ejection Fraction: Implications for Diagnosis and Race Disparities
Authors: Trejeeve M Martyn, Joshua Saef, Rola Khedraki, Lauren Ives, Wael A Jaber, Jerry Estep, Mazen A Hanna, Wai Hong W Tang
Journal: Circulation (2021)

Background: ATTR cardiomyopathy is classically described in patients with heart failure with preserved ejection fraction (HFpEF). We sought to understand the prevalence, characteristics, and survival of patients at the time of diagnosis, had heart failure with HFpEF (≥50%), HfmrEF: (41-49%), HFrEF ( ≤40%). Methods: A retrospective institutional amyloid registry study of 585 patients diagnosed with wild-type (WT) or variant ATTR-CM from 2011-2020. Cox proportional hazards models were used to assess probability of transplant-free survival. Results: In our cohort, (median age 77 [71,83], 84% male, 25% African-American (AA), median eGFR 58 [46,73], 28% had HFrEF (n= 165), 17% HFmrEF (n=97), and 55% with HFpEF (n=323). After adjusting for Age, sex, race, NT-proBNP, and eGFR, HFrEF patients had worse survival than those with HFpEF (HR, 0.47[95% CI, 0.33-0.68, p&lt;0.001]) and HmrEF (HR, 0.47[95% CI, 0.29-0.77, p=0.002]) (Fig 1a) AA patients had higher rates of HTN, DM, and variant TTR (72% vs. 9%, p&lt;0.001) as well as lower rates of CAD compared to Caucasian patients. AA patients were predominantly V122I variant (n=109/146, 74%) and more likely to present with HFrEF (n=60/146, 41%) than Caucasian patients (n=102/440, 23%), p&lt;0.001. AA WT (n=18/41, 44%) patients were also more likely to present with HFrEF than Caucasian WT (n=98/400, 25%), p=0.017 (Fig 1b). AA variant (43/108,41%) were more likely to present as HFrEF than Caucasian variants (4/41, 9.8%), p=0.001. Conclusions: Forty-five percent of patients diagnosed with ATTR-CM presented with LVEF ≤50% at the time of diagnosis, confirming that clinical suspicion for diagnosis of ATTR-CM should extend beyond HFpEF presentation. Reduced LVEF is an independent prognostic factor in patients with ATTR-CM. Racial disparities in the LVEF at presentation are present in both variant and WT ATTR. Further investigation into co-morbid, genetic, and racial factors associated with the presenting phenotype of ATTR amyloid is needed.
Abstract MP237: Multi-omics Profiling Reveals Stearoylcarnitine As A Novel Biomarker Of Cardiometabolic Disease Development In Rat Offspring Exposed To Gestational Diabetes
Authors: Stephanie M Kereliuk, Prasoon Agarwal, Gabriel Brawerman, Laura Cole, Bo Xiang, Mario Fonseca, Grant Hatch, Jonathan M McGavock, Vernon Dolinsky
Journal: Circulation Research (2021)

Through unknown mechanisms, fetal exposure to gestational diabetes mellitus (GDM) increases the risk for cardiovascular disease development later in life. We hypothesize that fetal exposure to GDM alters offspring cardiomyocyte metabolism and left ventricular (LV) function with age. To induce GDM, female rats were fed a high fat (45% kcal) and sucrose diet prior to mating, throughout pregnancy and lactation. Lean controls received a low fat (10% kcal) diet. Fetal rat ventricular cardiomyocytes (FRVC) were isolated from e20 offspring for U-13C glucose metabolic flux analysis, mitochondrial respiration and calcium handling. The cardiac transcriptome and metabolome were measured in 3-month old offspring. LV morphology and function was assessed in the offspring from e18 to 12-months of age by transthoracic ultrasound. Offspring exposed to GDM exhibited increased LV posterior wall thickness and impaired LV filling across their life course (fetal to 12-months of age; p&lt;0.05). Consistent with the development of diastolic dysfunction in vivo, alterations in calcium flux and sarcoplasmic reticulum-dependent calcium re-uptake (1.5 and 1.6-fold greater, respectively) were observed in FRVC isolated from GDM offspring (p&lt;0.05). When FRVC were treated with isoproterenol, U-13C glucose metabolic flux through glycolysis and the citric acid cycle was reduced in GDM offspring, compared to Lean controls. In 3-month old GDM offspring serum and cardiac metabolomics revealed an altered acylcarnitine profile, with specific elevation in long chain acylcarnitine species including stearoylcarnitine. Alterations in the metabolome corresponded to changes in gene expression patterns identified by RNA-Seq associated with glucose metabolism and fatty acid transport pathways (e.g. Irs2, Slc2a4, Pfkfb2, Pdk4 and Cpt1a). These alterations corresponded with mitochondrial dysfunction, impaired cardiomyocyte metabolic flux and contractility, in concert with LV hypertrophy and diastolic dysfunction in the rat offspring. Multi-omics profiling reveals stearoylcarnitine as a novel biomarker and implicates mitochondrial oxidative metabolism as a mechanism that links early-life GDM exposure to the development of cardiovascular disease later in life.
Oxidative damage and delayed replication allow viable <i>Mycobacterium tuberculosis</i> to go undetected
Authors: Kohta Saito, Saurabh Mishra, Thulasi Warrier, Nico Cicchetti, Jianjie Mi, Elaina Weber, Xiuju Jiang, Julia Roberts, Alexandre Gouzy, Ellen Kaplan, Christopher D. Brown, Ben Gold, Carl Nathan
Journal: Science Translational Medicine (2021)

Mycobacterium tuberculosis that sustains moderate oxidative damage survives undetected on solid media, but growth delay restores replicative ability.
Abstract 12505: Clinical Characteristics of Patients With Vasospastic Angina Subjected to the Spasm Provocation Test Involving the Unavoidable Use of Nitroglycerin
Authors: Hiroki Teragawa, Yuichi Orita, Chikage Oshita, Ryota Akazawa, Yuko Uchimura
Journal: Circulation (2021)

Introduction: Multivessel spasm (MVS) has a prognostic impact in patients with vasospastic angina (VSA). Thus, assessing for the presence of MVS in both left coronary artery and right coronary artery is preferable in the spasm provocation test (SPT). The use of nitroglycerin is necessary to avoid the complications related to SPT; however, this unavoidable use of NTG (U-NTG) may decrease the detection of MVS. Hypothesis: We investigated the frequency of U-NTG during SPT and clarified the clinical characteristics in VSA patients, with U-NTG during STP. Methods: Total 142 patients with positive SPT were evaluated. A positive SPT was defined as &gt;90% constriction in coronary arteries, accompanied by the chest symptoms and/or ischemic ST-T changes. When a coronary spasm occurred, we usually waited for the spontaneous relief of the coronary spasm. However, if a prolonged coronary spasm or unstable hemodynamics occurred, NTG was administered to relieve the coronary spasm promptly (U-NTG). Even when U-NTG was administered in one coronary artery, an additional SPT was performed on another coronary artery. The patients were divided into two groups according to U-NTG: U-NTG(+) (n = 42) and U-NTG(-), (n = 100). The clinical characteristics and frequencies of MVS and complications (unstable hemodynamics) during the SPT were compared between the groups. Results: Except for smoking status, all other clinical characteristics status did not differ significantly between the groups. More current smokers were observed in the U-NTG(+) group (29%) compared with that in the U-NTG(-) group (12%, p = 0.03). The frequency of MVD did not vary significantly between the groups, with 64% in the U-NTG(+) and 52% in the U-NTG(-). No significant difference was found between the groups in the frequency of severe complications during SPT, with 5% in U-NTG(+) and 3% in U-NTG(-). In U-NTG(+), the positive induction of coronary spasm in another coronary artery was 40% (17/42). Conclusions: Our results show that U-NTG occurred in ~30% of VSA patients, especially in current smokers, and that it did not decrease the detection of MVS and prevented severe complications during SPT. Therefore, U-NTG is acceptable during SPT, after which, another test may be performed to assess the presence of MVS.
Abstract 12867: Neuromodulation Of The Renal Nerves In Spontaneously Hypertensive Rats
Authors: Ibrahim M Salman, Omar Z Ameer, Sarah F Hassan, Sheridan McMurray, Arun Sridhar, Yee-Hsee Hsieh, Stephen J Lewis
Journal: Circulation (2021)

Introduction: Hypertension is a global burden. Renal denervation has been touted as a possible therapeutic strategy for the treatment of hypertension. However, neuromodulation of the renal nerves’ traffic in hypertension has yet to receive a similar attention. Aim: This study investigated cardio-respiratory responses to renal nerve stimulation in a genetic model of hypertension, the spontaneously hypertensive rat (SHR). Methods: In pentobarbital-anesthetized male SHRs (n = 9), the left renal nerve was stimulated 5 times (5-6 minutes apart) at 5 Hz, 0.5 ms, 0.5 mA for 30s. Mean arterial pressure (MAP), heart rate (HR), left renal cortical blood flow (CBF) and cortical vascular resistance (CVR), hindquarter aortic blood flow (ABF) and vascular resistance (AVR), upper (UAP) and lower (LAP) airway pressure, airway flow (AF), airway resistance (AR), respiration rate (RR) and diaphragmatic EMG (dEMG) were measured and averaged. Results: Cardiovascular responses to renal nerve stimulation were characterized by reductions in MAP, HR, CBF and AVR, which were associated with increases in ABF and CVR. Respiratory responses to renal nerve stimulation, on the other hand, demonstrated increases in AF, RR and dEMG, decreases in AR and no change in UAP and LAP. Conclusions: Under hypertensive conditions, the renal nerves not only modulate cardiovascular function but also improve respiratory function. These studies suggest that neuromodulation of the renal nerves may offer a therapeutic alternative for hypertensive patients.
TAMI-74. SPATIOTEMPORAL MULTI-OMIC LANDSCAPE OF HUMAN MEDULLOBLASTOMA AT SINGLE CELL RESOLUTION
Authors: Hailong Liu, Xiaoguang Qiu, Tao Jiang
Journal: Neuro-Oncology (2021)

Abstract Medulloblastoma is the most common malignant childhood tumor type with distinct molecular subgroups. While advances in the comprehensive treatment have been made, the mortality in the high-risk group is still very high, driven by an incomplete understanding of cellular diversity. Here we use single-nucleus RNA expression, chromatin accessibility and spatial transcriptomic profiling to generate an integrative multi-omic map in 40 human medulloblastomas spanning all molecular subgroups and human postnatal cerebella, which is supplemented by the bulk whole genome and RNA sequences across 300 cases. This approach provides spatially resolved insights into the medulloblastoma and cerebellum transcriptome and epigenome with identification of distinct cell-type in the tumor microenvironment. Medulloblastoma exhibited three tumor subpopulations including the quiescent, the differentiated, and a stem-like (proliferating) population unique to cancer, which localized to an immunosuppressive-vascular niche. We identified and validated mechanisms of stem-like to differentiated process among the malignant cells that drive tumor progression. Integration of single-cell and spatial data mapped ligand-receptor networks to specific cell types, revealing stem-like malignant cells as a hub for intercellular communication. Multiple features of potential immunosuppression and angiogenesis were observed, including Treg cells and endothelial cells co-localization in compartmentalized tumor stroma. Collectively, our study provides an integrative molecular landscape of human medulloblastoma and represents a reference to advance mechanistic and therapeutic studies of pediatric neuro-oncological disease.
Data Emerge From the UK’s COVID-19 Vaccine Extended Dosing Interval
Authors: Jennifer Abbasi
Journal: JAMA (2021)

Brian Grunau, MD, MHSc; David M. Goldfarb, MD; Michael Asamoah-Boaheng, MPhil; Liam Golding, BSc; Tracy L. Kirkham, PhD; Paul A. Demers, PhD; Pascal M. Lavoie, MDCM, PhD
Abstract 12545: Autologous Induced Mesenchymal Stem Cells-derived Exosomes Exhibit Enhanced Protection Of Cardiomyocytes From Injuries
Authors: Narasimman Gurusamy, VINOTH SIGAMANI, SHEEJA RAJASINGH, Rajasingh Johnson
Journal: Circulation (2021)

Introduction: Mesenchymal stem cells (MSC)-derived exosomes containing small non-coding RNAs (sncRNAs) showed protection of the myocardium from injury, infection, and disease. Recently, we have generated a safe and non-viral method of generating induced pluripotent stem cell (iPSC)-derived MSCs (iMSCs) with high replicative, autologous, cardioprotecive potentials, originally derived from human urinary epithelial cells. Hypothesis: We hypothesize that exosomes from iMSC possess a superior cardioprotective, and regenerative characteristics compared to the exosomes from adult umbilical cord MSCs (hereafter referred as MSCs) for the treatment of ischemic cardiomyopathy (ICM). Methods &amp; Results: Exosomes isolated from serum-free conditioned media obtained from iMSCs and MSCs were characterized using Zetasizer, which showed that exosomes from iMSCs had smaller particle size than the MSCs (Fig. A). Exosomal tetraspanin proteins (CD9, CD63 and CD81) were identified by Western blotting. Cardioprotective properties of exosomes were evaluated using functional iPSC-derived cardiomyocytes (iCMCs), which were treated with 50 μg of exosomes 1 hr before subjecting them to either 24 hrs of Ang II treatment (10 μM) or 6 hrs of 1% hypoxia and 24 hrs of reoxygenation. The exosomes from iMSCs elicited a superior cardioprotective characteristic studied through qRT-PCR expression of survival genes and measurement of mitochondrial membrane potentials (JC1 dye), intracellular reactive oxygen species (CM-H2DCFDA), and in situ cell death by apoptosis (Fig. B) when compared to the exosomes from MSCs. Furthermore, the expressions of injury-associated sncRNAs such as SNORD32a, SNORD33, and SNORD35a were identified in both exosomes. Conclusions: In comparison with the exosomes of available MSCs, exosomes from iMSCs showed an enhanced protection of cardiomyocytes from injuries and can be a valuable cell-free source for the treatment of ICM.
ETS Family Transcription Factor Fusions in Childhood AML: Distinct Expression Networks and Clinical Implications
Authors: Jenny L. Smith, Rhonda E. Ries, Yi-Cheng Wang, Amanda R. Leonti, Todd A. Alonzo, Alan S. Gamis, Richard Aplenc, Anders E. Kolb, Benjamin J. Huang, Xiaotu Ma, Timothy I. Shaw, Soheil Meshinchi
Journal: Blood (2021)
Abstract 9777: Acute Anemia and Outcomes in ACS Treated with Mechanical Circulatory Support
Authors: Misak Harutyunyan, Anish Adhikari, Mohammad Hamza, Dmitri Belov, Mikhail Torosoff
Journal: Circulation (2021)

Introduction: Anemia increases mortality in acute coronary syndromes (ACS). Mechanical circulatory devices (MCS) are known to cause anemia due to mechanical shearing, but there is limited data evaluating the prognostic significance of anemia in ACS patients treated with MCS. Methods: A single center retrospective cohort study included 210 consecutive ACS (56% STEMI) patients treated with MCS (IABP in 73%, 27% micro-axial pump Impella®) based on the clinical need. Clinical characteristics, hospital course details, and outcomes were obtained from the electronic health records. Results: The study cohort included 76% males, 66.9±10.9 years old, with atrial fibrillation (AF) in 9%, HTN in 43%, CHF in 37%, CAD in 42%, CABG in 40%, diabetes in 24%, COPD in 8%, and stroke in 6%. Average MCS duration was 4.0±2.8 days, with vascular complications in 17%, bleeding in 42%, transfusion in 40%, and kidney replacement therapy (KRT) in 15%. All-cause mortality was 16.2% with mean time to death of 11.2±1.2 days. There were no differences in pre-MCS Hgb between expired patients and survivors (12.3±2.6 vs. 12.8±2.2 g/dL, p=0.197). Post-MCS 24-hour Hgb was significantly lower in the expired patients (10.4+/-2.4 vs. 11.7+/-2.3, p=0.003) and in patients with prior CAD (11.1+/-2.1 vs. 11.8+/-2.5, p=0.037), while sex, AF, HTN, CABG, DM, COPD, or stroke did not affect Hgb. Admission shock (HR 4.7, 95%CI 2.087-10.783, p&lt;0.001) and KRT (HR 5.4, 95%CI 2.331-12.667, p&lt;0.001) decreased survival, while higher 24-hour Hgb (HR=0.74, 95% CI: 0.61-0.90, p=0.002) and higher presentation GFR (HR 0.968, 95%CI 0.948-0.989, p=0.003) improved survival. Transfusion did not affect mortality (18% vs. 15% in non-transfused patients, p=0.549). In a multivariate analysis, admission shock (HR 2.9, 95%CI 1.192-7.059) and KRT post MCS (HR 3.876, 95%CI 1.574-9.546, p=0.003) remained predictive of reduced survival, while Hgb and GFR were not important. Conclusion: Acute anemia in ACS patients treated with MCS is not prognostically significant. It remains unclear whether there is an optimal hemoglobin level which could alter the prognosis. Ongoing trials (MINT) are evaluating the optimal strategy of managing anemia in AMI.