tbuckley/cabot-search huggingface dataset:
Abstract 14056: The Role of Immune Activation in Trametinib-Induced Cardiomyopathy
Authors: Samantha M Morrissey, Ju Youn Beak, Melissa Schroder, Peyton B Sandroni, Brian C Jensen
Journal: Circulation (2023)

Introduction: Trametinib (Trm) is a highly selective inhibitor of MEK1/2, downstream targets of the RAS signaling pathway that has been used widely for the treatment of BRAF V600E/K-mutant melanoma. Multiple clinical trials are also underway investigating its use in colorectal, prostate cancer, leukemia, and triple negative breast cancer. Trm is generally well tolerated but can be associated with potentially serious cardiotoxicity in 5-20% of treated patients. The specific mechanisms driving Trm-induced cardiomyopathy (TIC) are largely unexplored. The goal of this project is to investigate the role that resident and infiltrating inflammatory cells play in TIC. Hypothesis: Our data suggest that Trm provokes cardiomyocyte immune responses including increased production of inflammatory cytokines, NF-KB signaling, and macrophage infiltration. We hypothesize that this activation occurs through DAMP-driven activation of the TLR and cGAS-STING pathway. Methods: C57BL/6 mice were gavaged with Trm 3mg/kg/day for 3 days prior to sacrifice. Heart tissue was analyzed via RNAseq, confocal microscopy, and flow cytometry. In vitro assays were completed using neonatal rat ventricular myocytes (NRVM). Results: RNAseq data of whole heart tissue from Trm treated mice surprisingly demonstrated increased expression of transcripts in inflammatory pathways. In vitro stimulation of NRVMs with Trm demonstrated increased production of inflammatory cytokines including IFNy and increased NF-KB signaling. Confocal microscopy of Trm treated heart tissue demonstrated increased CD68+ macrophage recruitment compared to control. None of these findings would have been predicted by our previous knowledge of cardiomyocyte MEK biology. Conclusions: Trm treatment is associated with cardiomyopathy in up to 20% of patients. Understanding the mechanisms driving this disease pathogenesis may help reduce likelihood of adverse cardiac events associated with future MEK inhibitor therapy used alone or in combination with other agents. Our novel findings suggest that Trm causes immune dysregulation and inflammation in the heart. Future studies will focus on further characterization of immune cell subsets involved and mechanisms of innate immune activation in TIC.
Abstract 14868: Association Between Social Vulnerability Index and Cardiovascular Disease Outcomes Among New York State Counties
Authors: Eduardo Gonzalez Negrete, Ko-Yun Chang, Cheng-Chen Li, Raj Thapar, Asim Tameez Ud Din, Prakruti Pandya, Shu-Yen Chan, Manasik Abdu, Akash Parashar, Stephen G Chrzanowski, Yu-Che Lee
Journal: Circulation (2023)

Introduction: Cardiovascular disease (CVD) is the leading cause of death and poses a significant economic burden in the USA. Social Vulnerability Index (SVI) is a tool developed by the Centers for Disease Control and Prevention (CDC) to assess social vulnerability to disasters. The relationship between SVI and CVD outcomes in New York State (NYS) has not been explored. Our aim is to examine the association between county-level SVI and CVD hospitalization and mortality rates in NYS. Methods: Hospitalization and mortality rates for CVD and its subtypes (heart diseases, coronary heart disease, heart attack, congestive heart failure, and stroke) between 2016 and 2018 were obtained from the NYS Community Health Indicator Reports. The SVI is based on 4 subindices: Socioeconomic Status, Household Composition &amp; Disability, Minority Status &amp; Language, and Housing Type &amp; Transportation. Higher SVI indicates greater vulnerability. We examined the CDC SVI 2018 data for NYS. The associations between CVD and its subtypes outcomes and SVI and its 4 subindices were analyzed by negative binomial regression. Results: Among counties, Bronx had the highest SVI (most vulnerable) and Saratoga had the lowest SVI (least vulnerable). Counties with higher SVI were associated with worse CVD outcomes. (hospitalization, incidence rate ratio [IRR]: 1.205 [95%CI: 1.035-1.402], per 1-unit increase; mortality, 1.201 [1.093-1.320]). Regarding the 4 subindices, Socioeconomic Status and Household Composition &amp; Disability were independently associated with CVD mortality (1.137 [1.000-1.292] and 1.201 [1.066-1.354]). Minority Status &amp; Language was independently associated with CVD hospitalization. (1.344 [1.130-1.599]).There was no association between Housing Type &amp; Transportation and CVD outcomes. Conclusions: County-level SVI was associated with CVD outcomes in NYS. This underscores the need for improved prevention strategies and targeted interventions for CVD in vulnerable areas.
Abstract 17214: Sex Difference in Outcomes of Redo-Surgical Aortic Valve Replacement (redo-SAVR) for Failed Bioprosthetic Aortic Valves: Insights From the National Inpatient Sample
Authors: Frederick B Rivera, Linjie Yan, Jiahe Zhao, Sarang Choi, Lia Veronique Priela, Fareed Moses M Collado
Journal: Circulation (2023)

Introduction: Redo surgical aortic valve replacement (SAVR) remains the gold standard for the management of failed bioprosthetic valves (BV). We aim to determine if there are sex differences in in-hospital outcomes among patients who underwent redo-SAVR for failed BV. Methods: We obtained the data from the National Inpatient Sample from 2013-2020. Our primary outcome was in-hospital mortality. Secondary outcomes included acute stroke, acute myocardial infarction (MI), acute kidney injury post-operative bleeding and blood transfusion. (See figure 1). Multivariable regression analyses were done to adjust for confounders. Results: There were more men who underwent the procedure compared to women. (62.3% versus 37.7%, p&lt;0.001) Hypertension, coronary artery disease and smoking were commonly seen among men. Obesity is more common among women. There was no difference in in-hospital mortality. Men were less likely than women to have vascular complications (adjusted odd ratio (aOR) 0.63, p&lt;0.005; acute kidney injury aOR 0.63, p&lt; 0.01, and acute stroke (aOR 0.6, p&lt; 0.002). Conclusions: Men underwent more redo-SAVR procedures than women. There were no sex difference in in-hospital outcomes, however, men were less likely to have AKI, stroke and vascular complications from the procedure. Further research is needed to explore these sex disparities.
Abstract 15021: Effect of Eplerenone on Cardiac Reverse Remodeling in Patients With Acute Heart Failure: A Sub-Analysis of the Earlier Randomized Double-Blind Trial
Authors: Shin Ito, Masanori Asakura, Masafumi Kitakaze
Journal: Circulation (2023)

Background: Activation of the renin-angiotensin-aldosterone system promotes left ventricular (LV) remodeling and dysfunction. In the EARLIER trial, we reported that the early initiation of eplerenone in patients with acute heart failure (AHF) reduced re-hospitalization for heart failure; however, its effect on cardiac reverse remodeling remains unclear. Hypothesis: Eplerenone attenuates LV remodeling in AHF patients with reduced ejection fraction (EF). Methods: In the EARLIER trial, hospitalized AHF patients with reduced EF (n = 300) were assigned randomly to either eplerenone (n = 149) or placebo (n = 151), once daily for 24 weeks. In this post-hoc analysis, absolute change in LVEF from baseline to 24 weeks was assessed by analysis of covariance adjusted for the baseline data. All participants treated with the study drug at least once were included in the analysis (eplerenone n=148, placebo n=149). Results: The absolute change in LVEF was not statistically different between the eplerenone and placebo groups (least square mean [LSM]difference: 2.81 ± 1.49, 95% CI: –1.25-5.21, P=0.06). The etiology of AHF consisted of acute myocardial infarction (AMI) (n=35) and non-AMI (n=265). LVEF was significantly improved by eplerenone in AMI patients (LSM difference: 8.04 ± 3.49, 95% CI: 0.90-15.18, P&lt;0.05), but did not in non-AMI patients (LSM difference: 1.98 ± 1.64, 95% CI: –1.25-5.21, P=0.23). Eplerenone showed a 39% reduction in CV death and HF hospitalization in AHF patients with non-AMI, despite no significant difference compared with the placebo (Hazard ratio:0.61, 95% CI: 0.24-1.57, P=0.30). Conclusions: Treatment with a mineralocorticoid receptor antagonist of eplerenone for 24 weeks induced LV reverse remodeling in AHF patients with reduced EF due to AMI. Further extended observation is needed to investigate the effect of eplerenone on LV remodeling in AHF patients with reduced EF due to non-AMI.
Abstract 14968: Clonal Hematopoiesis and Cardiotoxic Risk After Hematopoietic Stem Cell Transplantation
Authors: Cooper J Quartermaine, Zachary Braunstein, Miguel Ruiz, Adnan Shaaban, Alma Habib, Onaopepo Kola-Kehinde, Eric McLaughlin, Sana Sughra, Sanam Ghazi, Mussammat Ferdousi, Patrick Ruz, Stephen Sansoterra, Woo Yul Byun, John C Byrd, Jonathan Brammer, Daniel Addison
Journal: Circulation (2023)

Background: Clonal hematopoiesis (CH) occurs as part of normal hematopoietic stem cell senescence and prior chemotherapy administration. As such, CH is frequent for patients undergoing allogeneic stem cell transplants (ASCT). CH has been identified as a driver of inflammation. In animals, inflammation plays a role in atrial fibrillation (AF) development, the most common cardiotoxicity after ASCT treatment. Yet, whether the presence of post-ASCT CH associates with AF risk is unknown. Methods: We analyzed bone marrow derived mononuclear cells from 201 cancer patients treated with ASCT by deep targeted amplicon sequencing (next generation sequencing) to detect the presence of select CH (defined as DNMT3A, TET2, ASXL1, IDH1, FLT3, JAK2 at VAF of ≥ 2%), irrespective of relapse status; at median 4 months post ASCT. Observed incident AF rates were compared to Framingham heart predicted rates. Cox regression and survival analysis were used to define factors associated with incident AF and MACE, as well as the relationship between the presence of post-transplant CH mutations and MACE risk. Further, we also assessed the effect of CH on post-ASCT survival outcomes. The presence of mutations was analyzed for an association with post-ASCT incident AF and overall survival. Results: Overall, the prevalence of CH in post-ASCT patients was 42.3% (85), including 29.5% with ≥2 mutations. Over a median follow-up of 33 months, 11.5% of patients developed incident AF and 29.9% experienced MACE. In those without prior AF, the weighted average incidence was 407/10,000 person-years compared to the Framingham-predicted 63/10,000 person-years (RR 6.4, P &lt;0.001; AER 344). In follow-up, increased CH burden associated with increased risk of incident AF (HR 3.6, P =0.04), cancer-progression (HR 2.6, P =0.006), and mortality (HR 2.09, P =0.047); Figure . There was no difference in non-AF MACE. Conclusions: The presence of CH in ASCT treated cancer patients appears to associate with increased AF risk.
Abstract 17224: Macrophage Expressed CD36 Promotes Plaque Vulnerability in Atherosclerosis
Authors: Mark Colin Gissler, Timothy Mwinyella, Cynthia Morguet, Simon Heitlinger, Xiaowei Li, Hauke Horstmann, Timoteo Marchini, Florian Willecke, Dirk Westermann, Dennis Wolf
Journal: Circulation (2023)

Introduction: Atherosclerosis is characterised by a chronic lipid-driven inflammation that accounts for the majority of deaths worldwide. CD36 is an immunoregulatory scavenger receptor at the interface of lipid metabolism and inflammation that is critically involved in atherogenesis. However, due to the lack of cell-specific animal models the exact role of CD36 on macrophages in atherosclerosis remains unknown to date. Research Question: Here, we aimed to study the role of macrophage expressed CD36 in atherogenesis. Methods: To screen for a potential role of macrophage expressed CD36 in atherosclerosis we assessed CD36 gene expression across different leukocyte populations in scRNAseq data from atherosclerotic LDLR-/- mice. To evaluate the role of macrophage expressed CD36 in atherogenesis, we generated tamoxifen inducible macrophage (CX3CR1)-specific CD36-deficient mice on a LDLR-/- background. To interrogate a potential role of CD36 in human atherosclerosis, human atherosclerotic plaques were studied by scRNAseq. Results: Analysis of murine scRNAseq data identified macrophages as the main CD36 expressing cell type. In line, CD36 protein expression in aortic cell suspensions from LDLR-/- mice was significantly higher in macrophages compared to B and T cells as assessed by flow cytometry. Notably, macrophage-specific CD36 deficiency substantially reduced lesional necrotic core area after 16 weeks of high cholesterol diet feeding indicating ameliorated plaque vulnerability. In vitro, macrophage-specific CD36 deficiency reduced ROS production and oxLDL uptake. Similar to our observations in mice, cellular CD36 expression was highest in human macrophages/monocytes. Pathway analysis revealed that CD36-expressing macrophages exhibited a more pro-inflammatory gene signature than CD36-negative macrophages. Finally, unstable carotid plaques displayed a significantly higher CD36 expression compared to stable lesions. Conclusion: All in all, our data indicates a pro-inflammatory role of macrophage expressed CD36 in murine and human atherosclerosis. These findings suggest that targeting CD36 on macrophages may represent a potential target for anti-atherosclerotic therapy.
Abstract 17158: Effects of Human Monoclonal Antibodies on ADAMTS13 in Immune Thrombotic Thrombocytopenic Purpura
Authors: Konstantine Halkidis, Chan Meng, Donald L Siegel, X. Long Zheng
Journal: Circulation (2023)

Introduction: Immune thrombotic thrombocytopenic purpura (iTTP) is caused by antibody-mediated deficiency of the metalloprotease ADAMTS13, which cleaves VWF. Myocardial infarction and ischemic strokes are common and often fatal sequelae of iTTP. Inhibitory anti-ADAMTS13 antibodies appear to affect catalytic turnover more than apparent substrate binding affinity (PMID 37023370). Exploring how antibodies affect VWF cleavage by ADAMTS13 in physiologic conditions is needed to better understand the pathophysiology of iTTP. Hypothesis: Anti-ADAMTS13 antibodies may influence ADAMTS13 function by affecting catalytic turnover and/or apparent substrate binding affinity differently in physiologic conditions than in standard assay conditions. Aims: Characterize how single chain fragments of the variable loop (scFv’s) previously identified from a phage display library derived from several iTTP patients’ antibodies affect ADAMTS13-mediated VWF cleavage in conditions that more closely represent plasma and see if/how they differ from scFv-mediated effects in standard conditions. Methods: ADAMTS13 in normal human plasma was titrated with increasing concentrations of the substrate FRETS-VWF73 to derive maximum velocity ( V max ) and apparent Michaelis constant ( K M,app ) in standard assay conditions (pH 6.0) and conditions closer to physiologic (pH 7.0). The same parameters were derived in the presence of saturating concentrations of scFv’s. Results: Compared to VWF cleavage by ADAMTS13 in the absence of scFv, the inhibitory scFv4-20 decreased V max at both pH 6.0 and pH 7.0; K M,app decreased at pH 6.0 and increased at pH 7.0. The stimulatory scFv3-3 and scFv4-41 increased V max at each pH, while K M,app in the presence of each scFv decreased only at pH 7.0. Conclusions: Anti-ADAMTS13 antibody-mediated effects on VWF cleavage differ when comparing standard and more physiologic pH conditions, guiding future investigative directions into iTTP pathophysiology.
Abstract 17540: Functional Mitral Regurgitation is Associated With Decreased Papillary Muscle Viability Patients With Non-Ischemic Dilated Cardiomyopathy
Authors: Sabina Frljak, Neza Zorz, Gregor Poglajen, Bojan Vrtovec
Journal: Circulation (2023)

Background: The underlying mechanisms of functional mitral regurgitation (FMR) in non-ischemic cardiomyopathy (NICM) are incompletely understood. Aims: We investigated the correlation between papillary muscle viability and FMR in NICM. Methods: We enrolled 66 patients with NICM (LVEF&lt;40%, NHYA III) undergoing CD34 + cell transplantation. At baseline, patients underwent electroanatomical mapping; papillary muscle viability was quantified by local unipolar voltage (UV) measurement, and decreased viability was defined as UV&lt;8.3 mV. All patients received granulocyte-colony stimulating factor; CD34 + cells were collected by apheresis and delivered by transendocardial injections. Echocardiography was performed at baseline and 6 months after cell therapy; severity of FMR was graded by multi-parametric approach. FMR improvement was defined as a reduction in FMR by ≥1 grade when compared to baseline. Results: At baseline, papillary muscle viability was decreased in 24 (36%) and preserved in 42 (64%) of patients. Moderate to severe (2-3+) FMR was more common in patients with decreased papillary muscle viability (6/24; 25%) than in patients with preserved viability (2/42; 5%, P=0.015). Transendocardial cell injections were performed in the papillary muscle area in 26 patients (Group A) and in other areas of the left ventricle in 40 patients (Group B). The groups did not differ in age (56±11 years in Group A vs. 54±10 years in Group B, P=0.32), sex (male: 96% vs. 85%, P=0.21), creatinine (0.98±0.27 mg/dL vs. 0.96±0.28 mg/dL, P=0.92), bilirubin (0.89±0.37 mg/dL vs. 0.92±0.35 mg/dL, P=0.45), LVEF (34±9% vs. 31±7%, P=0.12), NT-proBNP levels (1196±994 pg/mL vs. 1077±1176 pg/mL, P=0.68), the degree of FMR (1.28±0.78 vs. 1.02±0.38, P=0.20), or papillary muscle viability (9.9±3.0 mV vs. 10.3±3.2 mV, P=0.62). At 6 months after cell injection, FMR improved in 77% of patients in Group A vs. 13% in Group B (P=0.001). On multivariate analysis, cell injection in the papillary muscle area was an independent correlate of FMR improvement (P=0.01). Conclusions: FMR in patients with NICM is associated with decreased papillary muscle viability. Transendocardial injection of CD34 + cells in the papillary muscle area may improve FMR in this patient population.
Abstract 14730: The Effect of Electronic Cigarette Exposure With Nicotine on Expression of Inflammatory Genes and Blood Parameters in a Chronic Myocardial Infarction Model
Authors: Jianru Shi, Wangde Dai, Juan Carreno, Michael T Kleinman, David Herman, Rebecca Johnson, Samantha Renusch, Irene Hasen, Amanda Ting, Robert A Kloner
Journal: Circulation (2023)

Background: There are no data available regarding the effects of chronic electronic cigarette (eC) exposure on inflammatory gene expressions after myocardial infarction (MI) and whether eC could alter blood counts and chemistries in this setting. We determined the effect of eC on expression of genes for inflammatory cytokines and receptors and blood parameters during the healing phase of MI. Methods and Results: Sprague Dawley rats of either sex were subjected to a proximal left coronary artery occlusion to induce a large anterior wall MI. At 1 week, rats were randomized to exposure to air or E-cig with nicotine (eC Nic + ) for 12 weeks. After 12 weeks of exposure, rat inflammatory cytokine and receptor PCR array was performed (n=4 in each group). The data showed 70 out of 84 inflammatory-related genes were downregulated in the eC Nic+ group versus the air group and 11 downregulated genes reached a significant difference. Interleukin 6 (IL6), Tumor necrosis factor superfamily (TNF), Chemokine (C-C motif) ligand 12 (Ccl12), and C-X-C Motif Chemokine Receptor 3 (Cxcr3) gene expressions were significantly decreased by -6.49 fold, p=0.0048, -2.63 fold, p=0.0227, -2.71 fold, p=0.0146, and -2.28 fold, p=0.0067, respectively, in the eC Nic+ group vs air group. The rats in eC Nic+ group had significantly decreased white blood cell (WBC), lymphocyte and platelet count compared to the air group (Figure). Conclusions: Exposure to eC Nic+ alters the expression of inflammatory genes and decreases blood immune cells during the healing phase of MI. Our findings suggest that chronic inhalation of e-cigarette aerosols can suppress the immune and inflammatory response in the already compromised setting of MI.
Abstract 18616: When Stress Strikes the Heart: Developing Takotsubo Cardiomyopathy With Uncommon Complications
Authors: Sanjay Pujar, Geetha Ramaswamy, Mandvi Pandey, Enrique Rincon
Journal: Circulation (2023)

Introduction: Takotsubo cardiomyopathy (TCM), also known as stress-induced cardiomyopathy or "broken heart syndrome," is a rare condition that predominantly affects postmenopausal women. The etiology of TCM is not entirely understood, but it is thought to be related to catecholamine-induced myocardial stunning. Clinical presentation typically mimics acute coronary syndrome. Left ventricular outflow tract obstruction (LVOTO) is an uncommon complication of TCM, with only a few cases reported in the literature. Case Presentation: A 78-year-old lady presented with chest pain that started a week ago. It was associated with exertion and resolved with rest. It was located substernally, pressure-like, and was 7/10 in intensity. EKG revealed diffuse inferolateral ST segment depression. Her initial troponin was 0.2 which climbed up to 5. She was diagnosed with NSTEMI and was started on IV heparin. Cardiac catheterization revealed no significant CAD. Echocardiography revealed wall motion abnormalities suggestive of Takutsubo Cardiomyopathy (apical ballooning syndrome) with apical hypokinesis and hypercontractile basal segment of the left ventricle. She also had LVOTO with a peak and mean gradient of 80 and 48 mmHg respectively. Her LVEF was calculated to be 40 %. There also was accompanied systolic anterior motion of the mitral valve leaflet. Given the above findings, she was started on a beta blocker along with an angiotensin receptor blocker. Patient’s chest pain resolved with this and was discharged in a stable condition on day three. Follow up appointment at the clinic showed complete resolution of her HOCM and LVOTO. Discussion: The key to managing patients with TCM is to identify LVOTO early, and avoid inotropes and vasodilators. Beta blockers are seen as the cornerstone of treatment. Fortunately, this is a self-resolving condition and the prognosis is excellent with resolution of echocardiographic abnormalities and symptoms within a few weeks’ time.