tbuckley/cabot-search huggingface dataset:
Abstract 17407: A Small-molecule Screening Strategy to Promote Cardiomyocyte Proliferation That Protects the Heart From Ischemic Injury
Authors: Zhenhe Zhang, Miles Freeman, Danny O El-nachef, Yan Lu, Haodong Xu, W Robb MacLellan
Journal: Circulation (2023)

Restoring the ability of adult cardiac myocytes (ACMs) to proliferate and promote heart regeneration have been proposed as a promising therapeutic strategy. We have demonstrated that selective depletion of H3K9me3 by lysine demethylase 4D (KDM4D) overexpression increases ACM cell cycle activity, but proliferation was limited. To improve this, we performed a small-molecule screening in combination with KDM4D on neonatal rat cardiomyocytes (NRVMs), using a library of kinase inhibitors targeting different signaling pathways. Our study revealed that compounds targeting the PI3K and JAK signaling pathways significantly potentiated the effects of KDM4D and promote NRVM proliferation in vitro. Specifically, a JAK inhibitor (JAKi2) in combination with Ad-KDM4D treatment resulted in approximately 100%, 34%, and 62% increase in EdU+, phospho-H3+, and total cell number compared to control, respectively. To validate these findings in vivo, we tested JAKi2 in an inducible KDM4D transgenic mouse model (iKDM4D). The animals underwent ischemia/reperfusion (I/R) to induce infarction, and JAKi2 was administrated orally for up to 8 weeks. We found both early and late effects. 48 hours after I/R, the infarct size in iKDM4D+JAKi2 hearts was approximately 4-fold smaller than that in vehicle-treated or JAKi2 alone groups, and the combination increased EdU+, Ki67+, and phospho-H3+ CM number separately by 3.2-fold, 2.9-fold, and 6.5-fold. At 2 weeks post-I/R, the scar size was smaller in iKDM4D+JAKi2 hearts compared to vehicle-treated mice (9.0% vs 1.8%, P &lt;0.05), and the combination resulted in a 3-fold, 5.5-fold, and 8.5-fold increases in EdU+, Ki67+, and phospho-H3+ CMs, respectively. Moreover, the iKDM4D+JAKi2 hearts demonstrated progressive improvement in left ventricular ejection fraction (26.8%, 27.3%, and 25.5%) and fraction shorten (37.9%, 38.1%, and 35.0%) at 2 weeks, 4 weeks, and 8 weeks post-I/R. The increased estimated ACM number and mononucleated CMs at 8 weeks post-I/R support that CM division was increased in the iKDM4D+JAKi2 hearts. These findings suggest that a combination therapy involving JAKi2, along with KDM4D, promotes robust CM proliferation and protects the heart after ischemic injury.
Abstract 17447: Effects of Inflammatory Biomarkers on Epigenetic Age Acceleration in Adult Congenital Heart Disease
Authors: Parag N Jain, Beryl Zhuang, Joanne Whitehead, Michael S Kobor, Paul Checchia
Journal: Circulation (2023)

Introduction: DNA methylation (DNAm) changes reflect alterations in the immune response to cardiac surgery in older adults. However, the role of inflammation on epigenetic age acceleration (EAA) in adults with congenital heart disease (ACHD) who underwent palliative cardiac surgery during childhood is unknown. Hypothesis: ACHD patients with Fontan(F) procedures would have advanced EAA due to higher DNAm predicted IL-6 and CRP levels compared to healthy adults or ACHD patients who underwent single surgery as an infant, likely capturing chronic inflammation associated with the abnormal pathophysiologic state. Methods: A case-control study in young adults (aged 20-30 years) with Fontan circulation or single surgery (SS) as an infant at a tertiary ACHD hospital. DNAm were measured by the EPIC Array. DNAm predicted IL-6 and CRP level differences were tested by robust linear model (rlm) adjusted for age, sex, cell types, and self-reported ethnicity. EAAs were calculated by extracting residuals by regressing epigenetic ages on chronological age in linear regression models. EAA differences were tested by rlm adjusted for the same covariates. Contribution analysis was performed to determine contribution of IL-6 and CRP to EAA. Results: Thirteen Fontan patients (6 female: 7 male, median age: 23) and 5 SS patients (3 female: 2 male, median age: 23) were compared with 20 age-matched controls (15 female: 5 male, median age: 27). Each subgroup had a predominant white race and non-Hispanic ethnicity. The F group has a statistically higher predicted IL-6 and CRP level (p&lt;0.001). Also, the F group had significantly higher EAA for mortality predictor Grimage (p&lt;0.001) and PhenoAge (p&lt;0.001). Conclusions: Patients who underwent Fontan procedure experience advanced EAA contributed by inflammatory biomarkers at a young age. Future studies evaluating the key predictors that drive EAA difference is needed to understand the impact of chronic alteration of physiology.
Abstract 17084: Impact of Hereditary Gene Mutations on Outcomes in an Ethnically Diverse Patient Cohort With Nonischemic Dilated Cardiomyopathy
Authors: Cody Kelso, Apurv Prabhakar, Jeffrey Ding, Pooja Nair, Anjali Kumar, Rachel White, Quan M Bui, Eric Adler, Kimberly N Hong
Journal: Circulation (2023)

Introduction: Nonischemic cardiomyopathy (NICM) is a leading cause of heart failure (HF). Heritable gene mutations are found in a subset of these cases and help to identify at risk individuals. The purpose of this study is to characterize the impact of genotype on clinical outcomes. Methods: Data from a single center registry of patients who underwent cardiomyopathy and arrhythmias gene panel testing between 2018 and 2022 was used. Patients with an LVEF &lt; 50% without a history of hypertrophic, infiltrative or ischemic cardiomyopathy were included. Genotyping, demographics, and clinical data including HF and major ventricular arrhythmia (MVA) outcomes were collected. Patients were stratified by genotype ((+): Pathogenic/Likely Pathogenic; (-): VUS/Likely Benign/Benign/no variant). Genotype (+) patients were also grouped by functional gene class. Chi Square and Wilcoxon testing were used for between group comparisons. Kaplan Meier with log-rank testing was used for time to event analyses. Results: This study included 350 patients with a median age of 54 years (IQR: 42-65 years) at last follow up. Table 1 shows demographics and outcomes. Genotype (+) patients had more HF and MVA events. There was a trend towards genotype predicting HF and MVA at all ages, with curves separating after age 26 (p = 0.0475) Figure 1. Genotype (+) LMNA patients had HF and MVA events at earlier ages compared to Genotype (-) (n=6, 85.7 %, p = 0.005). Conclusion: NICM patients with a hereditary gene identified have worse outcomes than those without, suggesting an opportunity to improve risk stratification and guide patient management decisions with genetic testing.
Abstract 17808: Neuroprotective Effects of 4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid Inhibition on Voltage-Dependent Anion Channel 1 or Ruthenium Red Inhibition on Mitochondrial Calcium Uniporter After Cardiac Arrest
Authors: Xin Sui, Chengke Yin, Zhaoyi He, Wenjia Xu, Lei Zhang, Fei Han
Journal: Circulation (2023)

Introduction: Mitochondrial dysfunction is associated with poor neurological outcomes after resuscitation. Over the past decade, identification of the mitochondrial outer membrane voltage-dependent anion channel 1 (VDAC1) and inner membrane mitochondrial calcium uniporter (MCU) has provided insight into the roles that mitochondrial Ca2+ regulation plays in neuronal function after cardiac arrest (CA). Hypothesis: The neuroprotective effects of 4,4'-Diisothiocyanostilbene-2,2'-disulfonic Acid (DIDS) inhibition on VDAC1 or Ruthenium red (RUR) inhibition on MCU after asphyxial CA in rats were investigated. Methods: Male SD rats, 240-340 g, were subjected to 8 min asphyxial CA and followed by manual cardiopulmonary resuscitation. Sham, Control, DIDS, RUR, DIDS+RUR groups were included. The rats in the DIDS, RUR, DIDS+RUR groups received 7 mg/kg DIDS, 3 mg/kg RUR or 7 mg/kg DIDS combined with 3 mg/kg RUR immediately after return of spontaneous circulation (ROSC). Survival and Neurologic Deficit Score were assessed at 24 h after ROSC. Neurological outcome was assessed. Hippocampal mitochondrial apoptosis was measured. Results: Survival was significantly higher in the RUR group compared to the Control group (85% vs. 40%, P &lt; 0.05). NDS in the DIDS and RUR groups were significantly better than in the Control group (P &lt; 0.05). Neurons were less damaged in the DIDS, RUR, DIDS+RUR groups than in the Control group (Figure). Cyt.C was lower in the DIDS, RUR, DIDS+RUR groups than in the Control group (P &lt; 0.05). Bax was lower in the RUR, DIDS+RUR groups than in the Control group (P &lt; 0.05). Bcl-2 was highly expressed in the RUR group than in the Control group (P &lt; 0.05). Cleaved caspase-3 was lower in the DIDS+RUR group (P &lt; 0.05). AIF was higher in the DIDS and RUR groups compared to the Control group (P &lt; 0.05). Conclusions: Inhibiting VDAC1 or MCU significantly improved survival, neurological outcome and inhibited hippocampal mitochondrial apoptosis after CA.
Abstract 15774: Cu Uptake Transporter CTR1 Cys189 Oxidation Protects Against Atherosclerosis via Limiting Mitochondrial Dysfunction and Endothelial Senescence
Authors: Archita Das, Sudhahar Varadarajan, Shikha Yadav, Sheela Nagarkoti, Malgorzata McMenamin, Jack H Kaplan, Masuko Ushio-Fukai, Tohru Fukai
Journal: Circulation (2023)

Background: Copper (Cu) is an essential micronutrient, but excess Cu is toxic. Role of copper in atherosclerosis remains unclear. The major Cu-uptake transporter CTR1 provides Cu to Cu chaperone/transcription factor Atox1 to promote inflammation as well as mitochondrial cytochrome C oxidase (COX) to regulate mitochondrial (mito)function. We reported that growth factor VEGF induced CTR1 Cys189 oxidation promotes VEGFR2/CTR1 internalization and angiogenesis in endothelial cells (ECs) while excess Cu induces CTR1 internalization to prevent Cu toxicity. However, role of CTR1-Cys189 in ROS-dependent mito dysfunction and senescence in ECs involved in atherosclerosis remains unknown. Results: Here we showed that inducible EC-specific Ctr1 -/- /ApoE -/- mice with high fat diet (HFD) reduced atherosclerosis (72%) and Mac3+ inflammatory cell (62%) vs. atherosclerotic ApoE -/- /HFD mice aorta which showed Ctr1-CysOH formation vs. control ApoE -/- mice. CRISPR-generated “redox-dead” Ctr1-Cys189A knock-in ApoE -/- /HFD mice aorta inhibited Ctr1-CysOH formation but enhanced atherosclerotic lesions and Cu accumulation (ICP-MS) vs. ApoE -/- /HFD mice. This in turn enhanced senescence (β-gal and markers), DNA oxidation, macrophage recruitment and mitochondrial hyperfusion (by TEM). In cultured human EC, proatherogenic cytokine TNFα stimulation rapidly induced CTR1-CysOH formation and CTR1 internalization, which were inhibited by CTR1-C189A or Nox4 shRNA. CTR1-C189A overexpression increased intracellular Cu and its downstream p-Drp1-S637 that promotes mitochondrial hyperfusion, mito dysfunction and mitoROS. This was associated with CTR1-C189A binding to mito Cu transporter SLC25A3, which might facilitate mito Cu overload and mito dysfunction. These CTR1-C189A-induced responses were inhibited by Cu chelator TTM and mito O 2 - scavenger Mito-TEMPO. Conclusions: CTR1-Cys189 oxidation-induced internalization limits excess Cu entry to protect against pro-atherogenic phenotype of CTR1/Cu. Preventing CTR1-Cys189 oxidation increases mito dysfunction via enhancing novel Cu-pS637-Drp1 axis as well as CTR1-SLC25A3 axis, which promotes mitoROS and EC senescence, thereby accelerating atherosclerosis.
Abstract 15055: Annual Healthcare Costs After Acute Pulmonary Embolism: Results From a Prospective Multicenter Cohort Study
Authors: Katharina Mohr, Philipp Mildenberger, Luca Valerio, Klaus Kaier, Konstantinos Christodoulou, Ioannis T Farmakis, Stefano Barco, Irene Schmidtmann, Harald Binder, Stavros V Konstantinides
Journal: Circulation (2023)

Introduction: Analysis of administrative data has helped to determine hospitalization costs related to acute pulmonary embolism (PE) in several countries, but estimating long-term costs of patient care after discharge is a more challenging task. Aims: To determine the direct annual costs related to the care of PE survivors based on data from a longitudinal cohort study performed at 17 German large-volume hospitals. Methods: The Follow-up of Acute Pulmonary Embolism (FOCUS) study enrolled unselected patients with acute PE. In addition to a structured ambulatory follow-up (FU) program (Figure) , we prospectively recorded duration and type of anticoagulation and the main and accompanying causes of all rehospitalizations during the first year of FU. Annual per-patient costs of post-PE care were calculated in 2022 euro (є) and converted to US$ adjusting for purchase parity power. Results: A total of 1,017 patients (45% women; median age 64 years [IQR, 52-74]) were included. Average costs of scheduled ambulatory FU visits and tests were estimated at є136.37 ($189.40) per patient; costs of oral anticoagulation after hospital discharge for the index event amounted to є827.72 ($1,149.61). The annual all-cause hospitalization rate was 31.96% (95% CI, 28.0-35.91%); the Table shows the primary indications and mean hospital costs (overall, and per indication). Of the є1,104.48 ($1,534.0) average rehospitalization costs per patient, 8.9% were related to recurrent thrombosis/PE or bleeding. Conclusions: Our results, derived from the population of a prospective multicenter study, help to dissect the direct annual costs of chronic post-PE care and may inform ambulatory care programs.
Abstract 18539: The Impact of Prophylactic Heparin on Pocket Hematoma Formation After Cardiac Implantable Electronic Device Implantation a Real-World Experience
Authors: Harsh P Patel, Garrett Peters, Ashish Kumar, Siddharth Agarwal, Sula Mazimba, Abhishek Deshmukh, Nishaki M Mehta
Journal: Circulation (2023)

Introduction: Intravenous heparin is strongly associated with pocket hematoma (PH) formation in patients undergoing cardiac implantable electronic device (CIED) implantation. However, there is no data on subcutaneous prophylactic heparin in this population Hypothesis: We hypothesized that the subcutaneous heparin may increase the odds of PH in patients undergoing CIED implantation using data from a large, nationally representative sample of the US population. Methods: The Premier Healthcare Database was analyzed from 2016-2019 to identify patients &gt;18 years old undergoing CIED implantation. Patients with PH were then identified by using ICD-10 CM codes. A multivariable logistic regression model was used to adjust for confounders Results: A total of 267,650 patients underwent CIED implantation between January 1, 2016, and December 31, 2019, of which 4,496 (1.68%) \developed PH. Single chamber pacemaker in 7.22%, dual-chamber pacemaker was implanted in 58.3% of patients, and CRT-P in 4.59%, ICD in 18.58%, CRT-D in 11.31%. Of the total cohort, 559 Patients received subcutaneous heparin within 3 days of the CIED implant procedure. Of these 559 patients, 91 (16%) patients were on subcutaneous heparin (pre-procedural: 19; post-procedural: 57) and developed PH. Subcutaneous heparin is associated with increased odds (OR :13.8,p&lt;0.01) of PH formation. Conclusions: This study suggests that subcutaneous heparin is a strong risk factor for the development of PH. This may independently drive up the rates of PH in the inpatient population. Further studies on the timing of subcutaneous heparin need to be conducted.
Abstract 18068: Isometric Handgrip Exercise Myocardial Perfusion Reserve Correlates With Coronary Microvascular Dysfunction and Abnormal Left Ventricular Strain: A Report From the Women’s Ischemia Syndrome Evaluation Pre-Heart Failure With Preserved Ejection Fraction Study
Authors: Amer Muhyieddeen, Michael Nelson, Marie Lauzon, Alan C Kwan, Behzad Sharif, Daniel Berman, Debiao Li, Eileen M Handberg, Carl Pepine, C Noel N Bairey Merz, Janet Wei
Journal: Circulation (2023)

Background: Impaired coronary artery response to isometric handgrip exercise (IHE) has previously been demonstrated to reflect endothelial dysfunction, an important contributor to ischemia with no obstructive coronary arteries (INOCA) and coronary microvascular dysfunction (CMD). Stress perfusion cardiac magnetic resonance (CMR) imaging is typically performed with pharmacologic stress using myocardial perfusion reserve index (MPRI) as a measure of CMD. IHE-MPRI has not been comprehensively studied in patients with INOCA, who are at risk for heart failure with preserved ejection fraction (HFpEF). Hypothesis: IHE-MPRI is related to CMD measured by pharm-MPRI and left ventricular (LV) structural and functional abnormalities in INOCA patients at risk for HFpEF. Methods: Participants with INOCA underwent comprehensive CMR with first-pass perfusion with adenosine or regadenoson, rest, and IHE. MPRI was adjusted to rest rate-pressure product (RPP). Lack of a satisfactory IHE response (defined as increase in heart rate≥10 bpm or systolic blood pressure ≥10 mmHg) was excluded. CMR measures of LV structure, function, MPRI, T1 and T2 mapping were analyzed using commercial software, blinded to clinical data. Pearson correlations were performed. Results: Of the participants (n=44) with IHE-MPRI, mean age was 55±11 years, body mass index 27±7 kg/m 2 , and 98% female, 31% hypertension, 12.5% diabetes, 19% hyperlipidemia. IHE-MPRI adjusted for rest RPP significantly correlated positively with pharm-MPRI and inversely with time to peak strain, diastolic strain measures and myocardial T2 ( Figure ). IHE-MPRI was not related to resting or IHE heart rate, systolic strain, LV mass, volumes, mass-volume ratio, native T1 or extracellular volume. Conclusion: IHE-MPRI relates to CMD and LV strain among patients with INOCA. Measurement of IHE-MPRI may improve understanding of CMD and LV structural and functional abnormalities that may contribute to development of HFpEF.
Abstract 12972: Trained Innate Immunity Through Toll-Like Receptor 4/Interferon Signaling Establishes Cardioprotection in a Stress-Induced Cardiomyopathy Model
Authors: Kenji Rowel Q Lim, Tomohiro Hayashi, Sajal K Tiwary, Attila Kovacs, Abhinav Diwan, Douglas L Mann
Journal: Circulation (2023)

Introduction: Although extensively studied, the mechanisms responsible for the development of cardioprotection following preconditioning stimuli are not known. Our group showed that isoproterenol (ISO) mediated cardiac injury induces potent cardioprotection against a second ISO challenge for up to 5 weeks. The lack of an immune response after the second ISO dose and the durability of protection suggested that trained innate immunity might represent a novel mechanism for cardioprotection. Hypothesis: We hypothesized that ISO confers cardioprotection through trained immunity via Toll-like receptor 4 (TLR4) signaling that is activated by damage-associated molecular patterns released by ISO-induced cell necrosis. Methods: Wild-type C57BL/6J mice were intraperitoneally injected with TLR agonists or diluent (saline), and then 300 mg/kg ISO a week later. Mice were assessed before and after receiving ISO via serum cardiac troponin analysis, flow cytometry, and 2-D echocardiography. Results: The TLR4 agonist lipopolysaccharide (LPS), but not TLR1/2 or TLR3 agonists, induced cardioprotection as shown by decreased troponin I release (p&lt;0.01), reduced cardiac neutrophil influx (p&lt;0.05), and decreased left ventricle wall motion abnormalities (p&lt;0.05) following ISO injury compared to saline treated controls . RNA sequencing identified interferon signaling as commonly upregulated (p&lt;0.05) in mouse hearts a week after LPS or ISO pre-treatment. Blocking type I/II interferon receptors partially abolished LPS-induced cardioprotection, while pre-treatment with recombinant interferon β+γ conferred cardioprotection as shown by decreased troponin I release post-ISO (p&lt;0.01). Given that β-glucan reverses the epigenetic tolerizing effects of LPS in immune cells, we treated mice with β-glucan following LPS pre-treatment and observed that the cardioprotection to ISO was abolished. Conclusions: Viewed together this study shows for the first time that TLR4/interferon signaling confers cardioprotection against ISO-induced injury. Our findings further suggest that this cardioprotective response may be secondary to TLR4 mediated epigenetic changes that dampen immune responses following tissue injury, consistent with trained innate immunity.
Abstract 15564: Iron Deficiency Treatment Among Hospitalized Heart Failure Patients
Authors: Megan Nordberg, Rick Foust, Jori May, Kara Morton, Joanna M Joly, Anna Tankersley, Stephen Clarkson
Journal: Circulation (2023)

Introduction: Iron deficiency (ID) is prevalent among patients with heart failure (HF). ID is associated with impaired quality of life and increased heart failure hospitalizations and is often missed or untreated. We examined clinical data spanning 10 years, comparing males and females overall and stratifying by admission date to further elucidate undertreatment of ID. Methods: We assessed patients who were admitted to UAB with a primary diagnosis of HF and were tested for ID from January 1, 2012, to July 7, 2021. We included patients during their index admission, who were iron deficient based on ferritin levels and/or transferrin saturation, dividing patients into two time periods based on changes in iron treatment patterns. We then compared males and females during each of the time periods. We used logistic regression to explore the association between sex and iron treatment modality, adjusting for relevant covariates. Results: In total, 1855 patients were iron deficient and treated with iron. Females were more likely to have a ferritin value less than 50 μ g/L (48% M vs 55% F, p=0.0006). Despite lower ferritin values, females had lower odds of receiving IV iron than males, both unadjusted (0.66, CI 0.55-0.79, p&lt;0.0001) and adjusted for covariates (0.72, CI 0.59-0.87, p&lt;0.0001). Conclusions: When comparing the two time periods, there is an increase in patients with more severe ID, indicated by ferritin values less than 50 μ g/L, and an increase in utilization of IV iron. Despite being disproportionately affected by severe, iron-deficiency anemia, women received IV iron therapy significantly less often than men across the 10 years studied. Even with improvement in the use of IV iron, treatment disparities remain, and more effort is needed to identify and reduce these disparities.