tbuckley/cabot-search huggingface dataset:
Abstract 11290: Mechanical Loading Enhances the Ability to Predict Hypertrophic Cardiomyopathy Phenotypes with Human Induced Pluripotent Stem Cell Derived Cardiac Micro-Tissues
Authors: Jingxuan Guo, Huanzhu Jiang, Jonathan Moreno, Druv Bhagavan, Allie Li, Ralph Damiano, Jonathan R Silva, Sharon Cresci, Nathaniel Huebsch
Journal: Circulation (2021)

Introduction: Modeling hypertrophic cardiomyopathy (HCM) with human induced pluripotent stem cell (hiPSC) derived cardiomyocytes is challenging because of the immaturity of hiPSC-derived cardiomyocytes along with the need to recapitulate non-genetic factors that contribute to HCM pathogenesis. We assessed the effects of mechanical loading on the action potential waveform morphology of hiPSC-derived micro-heart muscle. We benchmarked these results against action potential morphology measured in primary human cardiomyocytes from HCM patients. Hypothesis: Mechanical loading is necessary for expression of HCM phenotypes in genotype-positive hiPSC cardiomyocyte engineerd tissues Methods: Control and MYBPC3 +/- iPSC were differentiated into cardiomyocytes which were used to form micro-heart muscle atop soft silicone rubber substrates with rigidity matching healthy (15 kPa) or fibrotic heart (65 kPa) muscle. Micro-tissues were stained with voltage sensitive dye to assess action potential duration (APD) under field pacing. Contractility was measured by monitoring the motion of fluorescent beads embedded into the substrates. Freshly isolated surgical specimens from HCM patients were enzymatically digested into single ventricular myocytes and compared to discarded WT donor hearts as controls. Adult cardiomyocytes were stained with the same voltage sensitive dye to measure APD. Results: MYBPC3 +/- micro-tissues had similar action potential waveforms to controls when the tissues worked against a 15 kPa substrate, although the MYBPC3 +/- tissues had higher contractility. On 65 kPa substrates, the degree of hypercontractility in MYBPC3 +/- tissues was less substantial. However, the action potential duration (APD) of these tissues was significantly longer than controls. This increase in APD of hiPSC-cardiomyocytes with an HCM-causing mutation was consistent with an increase in APD observed in primary HCM cardiomyocytes as compared to controls. Conclusions: Mechanical loading may be required to induce electrophysiological aspects of HCM phenotypes in genotype-positive cells to facilitate modeling this disease with iPSC-derived heart tissues.
Abstract 10527: Clinical Characteristics and Cardiovascular Outcomes of Atrial Fibrillation (af) with Coexisting Left Bundle Branch Block (lbbb)-Analyses from National Inpatient Sample (2013-2014)
Authors: Sardar H Ijaz, Shakeel Jamal, Beth Bailey, Abdul Minhas, Asim Kichloo, Jawad Hassan, Khalil Kanjwal
Journal: Circulation (2021)

Introduction: Left bundle branch block (LBBB) because of dyssynchrony is a risk factor for heart failure (HF). We evaluated the baseline characteristics and comparative outcomes of atrial fibrillation (AF) patients with co-existing LBBB. Hypothesis: AF with concomitant LBBB is associated with poor cardiovascular outcomes. Methods: We conducted a retrospective analysis of hospitalizations for AF with and without LBBB from the National Inpatient Sample (NIS) between 2013 and 2014. Billing codes (International classification of diseases, 9th revision) were used to identify the target population. Results: A total of 1,531,704 hospitalizations for AF were identified, out of these, 1,496,742 hospitalizations had no LBBB and 34,952 hospitalizations had LBBB. AF with LBBB cohort was older with mean age (77.8 vs 75.3, p &lt;0.001), had slightly lower proportion of females (48.4% vs 48.9%, p &lt;0.04), higher proportion of white race (85.2% vs 82.3%, p &lt;0.001) and had a statistically significant higher disease burden including hypertension (73.3% vs 70.2%, p &lt;0.001), diabetes mellitus (27% vs 26.3%, p &lt;0.001), ischemic heart disease (58% vs 43.3%, p &lt;0.001), peripheral arterial disease (8% vs 6.9%, p &lt;0.001), congestive HF (59% vs 40.7%, p &lt;0.001) and tobacco use (27.8% vs 27%, p 0.001) when compared to AF without LBBB cohort. AF with LBBB had worse inpatient cardiovascular outcomes including cardiogenic shock (adj OR 1.81, CI 1.68-1.96), cardiac arrest (adj OR 1.71, CI 1.58-1.84), ventricular arrhythmias (adj OR 2.05, CI 21.97-2.12) and complete AV block (adj OR 3.36, CI 3.11-3.65). Conclusions: LBBB is a poor prognostic indicator in patients admitted for AF and is associated with worse cardiovascular outcomes. Aggressive management of AF in patients with LBBB may improve the clinical outcomes. Further clinical studies are required to study this relationship.
Abstract 14460: Mitochondrial Dysfunction is Involved in Diabetic Cardiomyopathy
Authors: Frank Xu, Li-Lun Ho, Tzongshi Lu
Journal: Circulation (2021)

Introduction: Diabetes is a strong risk factor not only for cardiovascular disease (CVD) but also for the development of chronic kidney disease (CKD) and represents a large and threatening public health challenge. We previously reported the deficiency of heat shock proteins and translocase of inner mitochondrial membrane (TIM) proteins are involved in the pathogenesis of hypertensive and uremic cardiomyopathy. Hypothesis: In this study, we further study the mechanism of mitochondrial dysfunction in the development of CVD and diabetic cardiomyopathy in CKD. Methods: Commercially available primary human atrial and ventricular cardiac myofibroblast and primary human aortic endothelial cells from 3 different age-matched sources were used in our type 2 diabetic cell model, in vitro. Immunohistochemistry, western blotting, Next-Generation RNA Sequencing, and real-time polymerase chain reaction (qPCR) were used in our proposed study. Results: Our data show that ATP5F1E (ATP Synthase F1 Subunit Epsilon), and cAMP regulator, Phosphodiesterase 8B are significantly (P&lt;0.01) preserved in the normal cardiac myofibroblast and aortic endothelial cell. In addition, gene expression of the key ATP synthesis: OPA1, MFN1, TIM, and inflammation marker: MSR1, WNT5 were also significantly (p&lt;0.05) increased in the non-diabetic cardiac myofibroblast and aortic endothelial cell. We next showed that key PPAR pathway regulators, Perilipin 1 (PLIN1) and PPARγ were significantly (p&lt;0.05) increased in our in vitro diabetic cell model. Furthermore, PPARγ inhibitor, FABP4 (fatty acid binding protein-4) which functions as an atherosclerosis promoter was significantly up-regulated in (p&lt;0.05) the non-diabetic cardiac myofibroblast and aortic endothelial cell. Conclusions: Mitochondrial ATP production is the main energy source for intracellular metabolic pathways and our study shows that mitochondrial dysfunction and down-regulation of ATP production may inhibit the hydrolysis of the second messenger cAMP that promotes the development of CVD and diabetic cardiomyopathy in CKD.
INNV-40. REAL WORLD INTEGRATION OF THE NEUROLOGIC ASSESSMENT IN NEURO-ONCOLOGY (NANO) SCALE IN CLINICAL PRACTICE IN PATIENTS WITH IDH-WT GBM
Authors: Mary Jane Lim-Fat, Marie Allen, Timothy Smith, Gilbert Youssef, Brian Andersen, Oluwatosin Akintola, Tamar Berger, Joshua Budhu, Annie Hsieh, Elisa Aquilanti, Tracy Batchelor, Rameen Beroukhim, Ugonma Chukwueke, L Nicolas Gonzalez Castro, Eudocia Quant Lee, J Ricardo McFaline-Figueroa, Lisa Doherty, Jennifer Stefanik, Christina Taubert, Alexandra Torres, Patrick Wen, David Reardon, Lakshmi Nayak
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND The neurologic assessment in neuro-oncology (NANO) scale was developed as a standardized metric to objectively measure neurologic function in patients with brain tumors and complement radiographic assessment in defining overall outcome. The scale has been incorporated in clinical trials. Early data is suggestive of feasibility and that NANO contributes to overall outcome assessment. However, real-world use of the NANO scale to drive clinical-decision making and the predictive value of the NANO scale to determine overall survival remains unclear in IDH-wt GBM. METHODS We report on an ongoing study using the NANO scale to evaluate neurologic function in patients with IDH-wt GBM, seen at Dana-Farber Cancer Institute (DFCI). Patient demographics, tumor histology and molecular status, treatment history and progression dates are being captured. NANO score, as collected by a built-in scale in our institutional electronic medical record (EMR), functional status (Karnofsky performance status) and corticosteroid dose are collected at prespecified time points (prior to start of therapy, and during each subsequent MRI visit). Changes in the NANO score will be correlated to overall survival. Statistical analyses including descriptive data analysis and generalized linear models will be performed using R (version 3.4.3). RESULTS Since June 2020, 50 patients have been enrolled in this study, including 42 (84%) with ≥2 follow up visits. Study accrual was initially impacted by the COVID-19 pandemic, but adaptation to a virtual platform for NANO allowed for improved recruitment and follow up of patients. Study results will be available for discussion at the 2021 SNO conference. CONCLUSIONS Evaluation of neurologic function by NANO is feasible in a virtual framework in a prospective study in patients with GBM, aided by integration of the scale in our institutional EMR. NANO is able to objectively track neurologic function throughout disease course in IDH-wt GBM.
Abstract 11400: Circulating Glutathionylated Cardiac Myosin Binding Protein C as a Diagnostic Biomarker for Diastolic Dysfunction
Authors: Xiaoxu Zhou, Euy-Myoung Jeong, Man Liu, Hong Liu, Feng Feng, Samuel C Dudley
Journal: Circulation (2021)

Introduction: Cardiac myosin binding protein-C (cMyBP-C) is a thick filament-associated protein localized to the crossbridge-containing C zones of striated muscle sarcomeres, contributing to regulate cardiac contraction and relaxation. Phosphorylation status of cMyBP-C determines cardiac function, and S-glutathionylation of cMyBP-C is increased in human heart failure (HF). In animal models, we demonstrated that elevated S-glutathionylation of cMyBP-C but not phosphorylation correlates with diastolic dysfunction (DD). Hypothesis: S-glutathionylated cMyBP-C would be a biomarker for DD. Methods: Humans, African Green monkeys, and mice with DD determined by echocardiography (E/e’ ratio &gt; X) were matched by age and gender to controls. Blood samples were acquired and analyzed for S-glutathionylated cMyBP-C by immunoblotting. Results: Circulating S-glutathionylated cMyBP-C in DD patients (N=28) was elevated (fold, 1.57± 0.12, P&lt;0.01, t-test) when compared to controls (N=16). We confirmed these results in mice and monkeys with DD demonstrated by echocardiography. In DD monkeys (N=6), the circulated S-glutathionylated cMyBP-C levels were upregulated (fold, 2.7 ± 0.57, P&lt;0.05, t-test) as compared to those in control (CTL) monkeys (N=6). Similarly, S-glutathionylated cMyBP-C was elevated (fold, 1.61 ± 0.23, P&lt;0.05, t-test) in mice with DD (N=5) as compared to controls (N=5). Conclusions: Glutathionylated cMyBP-C has been associated with DD in animal models, and circulating glutathionylated cMyBP-C was elevated in humans, monkeys, and mice with DD. Glutathionylated cMyBP-C may represent a disease-specific biomarker for the presence of DD.
Abstract 11934: Lipoprotein(a) Serum Concentrations in Children Are Not Affected by Age, Sex, or Body Mass Index
Authors: Paulina Stuerzebecher, Wieland Kiess, Antje Koerner, Ulrich Laufs
Journal: Circulation (2021)

Background: Lipoprotein(a) (Lp(a)) has emerged as an inherited marker of premature atherosclerotic cardiovascular disease (ASCVD). Current ESC guidelines recommend Lp(a) measurement once in the lifetime to identify individuals with high ASCVD risk. Limited data are available on Lp(a) serum concentrations in children. Methods: We analyzed 1189 blood samples of 605 healthy children aged 5 to 17 enrolled in the population-based LIFE CHILD (German civilization diseases cohort study). Lp(a) was quantitated using the Cobas/Roche assay. Results: The mean Lp(a) of the 605 children was 20.8 ± 1.0 mg/dl (SEM). 74 children (12.2%) showed Lp(a) concentrations between 30 and 50 mg/dl. 78 children (12.8%) exhibited Lp(a) &gt; 50 mg/dl. The mean Lp(a) serum concentrations were distributed evenly between age 5 to 17 years without effects of age on Lp(a) concentrations. Repeated measurements were available in 207 children (2- 6 measurements at least 1 year apart). The measurements were highly reproducible over time (mean percentual difference between repeated measurements of Lp(a) concentration 38.5%, SEM 5%) with a clinically relevant dynamic of Lp(a) values in only 3% of cases. There was no significant correlation between sex and Lp(a) (r=0.09) or body mass index and Lp(a) (r=0.06) whereas higher LDL-cholesterol levels occurred more often in children with elevated Lp(a) (r=0.44, p&lt;0.0001). 6 children with both Lp(a) &gt;50 mg/dl and LDL-cholesterol &gt;150 mg/dl were identified (1% of the 605 children). Conclusions: In conclusion, lipoprotein(a) serum concentrations in children between 5 and 17 years are not significantly affected by age, sex, or body weight. These data indicate that Lp(a) may be useful as a marker to identify children at increased lifetime risk for ASCD and suggest that Lp(a) could be used for reverse family screenings. Therefore, Lp(a) may be a valuable addition to screening examinations in children.
Abstract 14295: Exploratory Findings Of A Quality Improvement Collaborative To Optimize Care Provided To Heart Failure Patient In A Network Of Heart Failure Clinics In Argentina
Authors: Ezequiel Garcia-Elorrio, Facundo Jorro-Barón, Bibiana De la Vega, Fernanda Ditata, Alvaro D Facta, David Flores, Simón Fernández-Nievas, Alberto Fernández, Cristian Mastantuono, Raquel Saa, Esteban San Damaso, Gustavo Vega, Inés Suarez-Anzorena, Tomás Vita
Journal: Circulation (2021)

Introduction: The in-patient management of heart failure (HF) in Argentina has shown profound gaps in performance. Measurement and feedback as well benchmark comparisons showed increase in the use of evidence-based therapies, adherence to performance measures, and shortened lengths of stay in patients hospitalized with HF. Quality improvement collaboratives (QICs) have been used to improve health care for several decades. Our aim was to adopt a HF discharge bundle of care in 50% of enrolled subjects on discharge will reduce readmission by 10%. Methods: we are conducting a learning QIC, evaluated through a before-after design, from august 2020 to may 2021 (interim analysis), in 8 HF clinics of Argentina, where patients with newly diagnosed or known HF (LVEF &lt;40%) were enrolled when their discharge process was started after an hospital admission. We implemented a HF bundle of care based on four categories that comprised 12 specific interventions: medication, continuum of care, lifestyle habits, pre-discharge exams. Local hospital teams were trained in improvement and change facilitation. The implementation of the bundle was laid out along 8 learning sessions and periods of action using Plan-Do-Check-Act-cycles and an online platform to register interventions and performance.This an ongoing collaborative to be ended in July 2021. IRB approval was granted in all sites. Results: we enrolled 84 patients during baseline (BP) and 96 patients so far after the start of the intervention (IP). No differences were observed related to age, sex, morbidities and left ventricular ejection fraction (LVEF) between periods. Few more patients had history of stroke in the IP period (BP 3.6% vs IP 9.3%, p&lt;0.001). There wasn’t a statistical difference in the accomplishment of all the items of the intervention -all or nothing approach- (BP 10.7% vs IP 17.7%, p=0.183). However, there was a difference in the continuum of care category (BP 27.4% vs IP 53.6%, p&lt;0.001). No differences were observed in the rate of readmissions (BP 8.3% vs IP 3.8%, p=0.231). Conclusions: Initial results of a QIC to improve care before discharge of in-patients with HF NYHA class II-III showed an increase in the adoption of an evidence based practices bundle and no changes were observed in the rate of readmissions.
Abstract P472: Edil3 Autoantibodies Do Not Distinguish Kawasaki Disease (KD) From Febrile Controls, But Are Acutely Lower In Children With Cardiac Involvement.
Authors: R. Ross Welliver, Mark Hicar
Journal: Circulation Research (2021)

Kawasaki Disease (KD) is a childhood vasculitis, marked by prolonged fevers and coronary artery inflammation/aneurysms. Epidemiologic and demographic data support that a single preceding infectious agent may lead to KD, however, the cause remains unknown. The leading theory on pathogenesis is a post-infectious self-limiting autoimmune response, but this is still controversial. A recent study of individuals with KD demonstrated an association with autoantibody response to EDIL3 (also known as DEL-1). EDIL3 is a structural glycoprotein expressed by both macrophages and vascular endothelium. This presents an attractive potential target for investigation, as EDIL3 is known to modulate inflammation via leukocyte binding and infiltration through vessel walls. Additionally, EDIL3 is highly expressed in aortic and coronary artery tissue samples, showing some of the highest non-neural expression. Genetic variants of Del-1 have been associated with risk of intracranial aneurysms. Due to this burgeoning literature, we interrogated our cohort of plasma samples from febrile children, including Kawasaki disease, to confirm specificity of targeting to EDIL3. Plasma samples from febrile children and children with KD, including timecourse samples, were interrogated with ELISA assays using full-length recombinant EDIL3 (LSBio). In contrary to the published report, EDIL3 binding does not appear to be specific to KD when compared to febrile controls inclusive of a variety of disease etiologies (viral, bacterial, etc.). On serial samples (pre-IVIG, post-IVIG and convalescent) from the two different patient cohorts, antibodies binding EDIL3 are elevated in post-IVIG samples. This further supports general autoantibody reactivity against EDIL3 as IVIG is a pooled blood product from thousands of individuals typically. Intriguingly, in comparison of samples from children with or without any coronary artery Z scores above 2.5, EDIL3 autoantibody responses were actually lower in those with dilated coronary arteries. Current efforts are focused on identify specific human autoantibodies against EDIL3. Implications of these findings will be explored.
Abstract 14278: Lessons From COVID-19 Pandemic: Using Telemedicine in Ambulatory Care Delivery for Pediatric Heart Failure and Heart Transplant Patients
Authors: Maria Bano, David L Sutcliffe, Nathanya B Hernandez, Alyssa Power, Curtis Dubke, Ryan J Butts
Journal: Circulation (2021)

Introduction: COVID-19 related restrictions necessitated a rapid transition to telemedicine (TM) ambulatory services for pediatric heart failure (HF) and heart transplant (HT) patients. The impact on patient related outcomes remains unknown. We report the feasibility of incorporating TM in routine ambulatory care delivery to pediatric HF and HT patients at a large academic center during the COVID era (04/2020-04/2021). Methods and Results: A total of 650 HF patients, median age 10 (0-25) years and 200 HT recipients, median age 10 (0-22) years were followed at our center during the COVID era. A center-specific, risk stratified model based on patient characteristics (Table 1) and local COVID restrictions were used to determine patient eligibility for TM only, TM + in-person (IP) or IP care only. There were 2 unexpected deaths in the HT and 0 deaths in the HF patients during the COVID era compared to 1 death in HT and 0 deaths in HF patients in the pre-COVID era (01/2019-12/2019). Both deaths in the COVID era were due to non-cardiac causes and neither patient utilized the TM platform for care. There was a significant decrease in emergency room use and unplanned hospital admissions during the COVID-19 era compared to pre-COVID era (Table 2, Fig 1). Conclusions: TM can safely be incorporated in routine ambulatory care delivery for appropriately selected pediatric patients with HF and HT.
Preferential siRNA delivery to injured kidneys for combination treatment of acute kidney injury
Authors: Weimin Tang, Yi Chen, Hee-Seong Jang, Yu Hang, Chinmay M. Jogdeo, Jing Li, Ling Ding, Chuhan Zhang, Ao Yu, Fei Yu, Kirk W. Foster, Babu J. Padanilam, David Oupický
Journal: Journal of Controlled Release (2021)
Abstract P448: Role For Btg1 And Btg2 In Postnatal Cardiomyocyte Cell Cycle Arrest And Maturation
Authors: Nivedhitha Velayutham, Frank N van Leeuwen, Blanca Scheijen, Katherine E Yutzey
Journal: Circulation Research (2021)

Background: Adult mammalian cardiomyocytes (CM) are predominantly post-mitotic and cannot proliferatively repair the heart following myocardial infarction (MI). Overexpression of the transcription factor Tbx20 in adult mouse CMs promotes proliferative cardiac repair post-MI, via mechanisms including direct repression of anti-proliferative genes p21 , Meis1 , and Btg2 . Btg2 (B-cell translocation gene 2), a tumor suppressor and transcriptional co-regulator, exhibits high structural and functional similarity with Btg1. However, both Btg1 and Btg2 (Btg1/2) are virtually uncharacterized in the heart. Here, we investigate the role of Btg1/2 in postnatal cardiac maturation. Methods and Results: By immunostaining in embryonic, neonatal, and adult C57BL/6 mouse hearts, the highest expression of Btg1/2 was observed in late fetal and early neonatal ventricles, concurrent with upregulation of other CM cell cycle inhibitors. In neonatal mouse CMs in vitro, siRNA-mediated loss of Btg2 leads to increased CM proliferation. In vivo , Btg1/2 constitutive single- and double- knockout (SKO and DKO respectively) mice exhibit normal heart weight-to-body weight ratios compared to age-matched wildtype (WT) controls, at postnatal day (P)7, P30, and 1 year after birth. Interestingly, at P7, DKO mice have significantly higher CM mitotic activity, as indicated by pHH3 staining, compared to WT. In addition, DKO mice also exhibit significantly smaller CM cross-sectional area at P7 compared to WT. However, by P15, CM mitotic activity and cell size are comparable between WT and Btg1/2 KO mice. Currently, siRNA-mediated knockdown of Btg1/2 in neonatal rat ventricular cardiomyocyte cultures and RNAseq studies are being performed, to assess the transcriptional regulatory roles of Btg1/2 in rodent CMs. Conclusions: Here, we highlight two novel regulators of postnatal CM maturation, Btg1 and Btg2, which are upregulated coincident with CM mitotic arrest in mice. Similar to p21 and Meis1, Btg1/2 depletion in mice induces a brief period of increased CM proliferative activity before onset of CM cell cycle arrest. Our results provide evidence for Btg1/2 working in tandem with other cardiac transcription factors and cell cycle regulators, to control CM mitotic arrest after birth.