tbuckley/cabot-search huggingface dataset:
Abstract 4141935: Targeting Tyrosine Kinase Inhibitor-Associated Cardiotoxicity with NPA7: A Novel Dual Activating Peptide
Authors: Xiaoyu Ma, JC Malsawmzuali, Dante Moroni, Ye Zheng, Jeson Sangaralingham, John Burnett
Journal: Circulation (2024)

Background: Tyrosine kinase inhibitors (TKIs), such as sunitinib, are highly effective in treating cancers. However, they have severe cardiovascular (CV) side effects that include cardiotoxicity via cardiomyocyte injury and death resulting in myocardial dysfunction. There are no FDA-approved drugs to prevent or treat cardiotoxicity, which have been linked mechanistically to mitochondrial dysfunction and oxidative stress, highlighting the need for new therapeutics. Two recognized CV protective pathways are the particulate guanylyl cyclase A receptor (GC-A)/cGMP and the Mas receptor (MasR)/cAMP pathways. We recently engineered NPA7 a novel peptide that activates both pathways. Aim: Here we investigated NPA7’s ability to protect against sunitinib-induced cardiotoxicity in human cardiomyocytes (HCMs) and defined its role on mitochondrial function. Methods: HCMs were treated with DMSO or sunitinib (10 µM) together with PBS or NPA7 (10 µM). Intracellular reactive oxygen species (ROS) was assessed by DHE staining. CCK8 assay was performed to measure cell viability. TOM20 staining were performed by immunofluorescence and the mitochondrial length was analyzed. The protein levels of mitochondrial dynamics markers (fission: MFF, Fis1; fusion: OPA1 and MFN1) proteins were measured by western blot. Cell surface area was assessed by phalloidin staining with mRNA levels of hypertrophic gene markers (NPPA and MYH7) in HCMs using real-time PCR. Results: Sunitinib increased DHE staining and intracellular ROS in HCMs, which was decreased with NPA7 treatment. NPA7 enhanced HCM cell viability in the presence of sunitinib. TOM20 staining showed a marked reduction in mitochondrial length in sunitinib group, compared to DMSO group, whereas NPA7 treatment rescued mitochondria length (DMSO= 6.15 ± 0.94 μm, Sunitinib= 2.42 ± 0.63 μm, NPA7= 5.4 ± 1.19 μm; P &lt; 0.05). Moreover, NPA7 inhibited mitochondrial fission protein levels (MFF and Fis1) and increased mitochondrial fusion protein levels (OPA1, MFN1) in HCMs treated with sunitinib. Sunitinib treatment notably increased HCM cell surface area and hypertrophic gene markers (NPPA and MYH7), whereas NPA7 abolished these markers of hypertrophy. Conclusions: We report, for the first time, that NPA7 protects against sunitinib induced oxidative stress, mitochondrial fragmentation, hypertrophy and cell death in HCMs. These data support a novel therapeutic approach against TKI-induced cardiotoxicity with NPA7 to which no therapies exist.
Abstract 4141905: ROS-Detoxifying Cerium Oxide Nanoparticles Attenuate the Pro-Arrhythmic Effect of Diesel Exhaust Particles in Isolated Rat Hearts
Authors: Gino Freddy Sena Ganse, Cristina Rodriguez, Lena Ernst, Marisol Ruiz-Meana, Javier Inserte, Jose Martinez-Gonzalez, Begona Benito, Victor Puntes, Ignacio Ferreira-Gonzalez, Antonio Rodriguez-Sinovas
Journal: Circulation (2024)

Introduction: Epidemiological evidence suggests a link between acute air pollution exposure and ventricular arrhythmias, with increased reactive oxygen species (ROS) production as a key mechanism. However, a cause-effect relationship remains unclear, studies on chronic effects are lacking, and the impact of strategies limiting ROS production has not been studied in detail. Aims: To analyze the effects of chronic intratracheal instillation of diesel exhaust particles (DEPs) on ventricular arrhythmogenesis, investigate the underlying mechanisms, and assess the impact of cerium oxide nanoparticles (CeO 2 NP) as a ROS-detoxifying strategy. Methods: Male and female Sprague-Dawley rats were intratracheally instilled with saline without or with DEPs (7.5 g/Kg, 0.375 mL/Kg, 3 times/week, for 1-3 weeks). Rats were then sacrificed and hearts perfused through the aorta in a Langendorff system. Incidence of premature ventricular beats (PVBs) and non-sustained and sustained (&gt;30s) ventricular tachyarrhythmias (VT) were assessed by programmed electrical stimulation. Cardiac hypertrophy, collagen content, inflammation and oxidative stress were analyzed by conventional histology, Western Blot, RT-PCR, and the oxidized/reduced glutathione (GSH/GSSG) ratio. The potential protective effect of ROS-detoxifying CeO 2 NP (0.5 mg/Kg/week, i.p.) was also analyzed. Results: DEP exposure increased the incidence and duration of inducible sustained VTs. This pro-arrhythmic effect associated with a moderate rise in interstitial collagen deposition (from 3.11±0.12 in controls to 4.80±0.21 % in DEP-exposed rats, Student’s t test, p&lt;0.001) and prolonged QRS complex and QTc in the ECG. Collagen expression was induced within one weeks of DEP exposure, as shown by RT-PCR. Additionally, the GSH/GSSG ratio decreased after 3 weeks of DEP exposure, while mRNA levels of the ROS-producing NOX1, NOX2 and NOX4 isoforms rose early after DEP exposure, and expression of the antioxidant thioredoxin reductase was reduced. CeO 2 NP attenuated the pro-arrhythmic effects of DEP exposure (sustained VT duration: 0.00±0.00, 51.09±18.99 and 20.00±20.00 ms in hearts from control, DEP-treated and CeO 2 -treated animals, Krustal-Wallis test, p&lt;0.05 between controls and DEP-treated). Conclusion: DEP exposure increases the incidence and duration of sustained VTs in rats, effects associated with increased collagen deposition and oxidative stress. ROS-detoxifying CeO 2 NP attenuate the pro-arrhythmic effects of DEP exposure.
Abstract 4141879: Post-procedure oral anticoagulation following pulsed-field ablation for atrial fibrillation
Authors: Sanghamitra Mohanty, Prem Geeta Torlapati, Paolo Compagnucci, Vincenzo Mirco La Fazia, carola gianni, Bryan MacDonald, ANGEL QUINTERO MAYEDO, John allison, G Gallinghouse, John Burkhardt, Rodney Horton, Amin Al-Ahmad, Luigi Di biase, Michela Casella, Antonio Dello Russo, Andrea Natale
Journal: Circulation (2024)

Background: Current guidelines recommend oral anticoagulation (OAC) for at least two months post-radiofrequency ablation (RFA) in all patients with atrial fibrillation (AF). The endothelial injury during RFA that can promote thrombus formation, does not happen in pulsed-field ablation (PFA). Objective: We evaluated the optimal duration of OAC therapy needed for effective stroke prevention following PFA. Methods: Consecutive patients undergoing PFA for AF were included in the study and prospectively followed-up for 1 year. Based on the duration of post-ablation OAC [non-vitamin K OAC (NOAC)] therapy they were classified into group 1: NOAC for 1 month and group 2: NOAC for ≥2 months. Patients were closely monitored for thromboembolic (TE) events via telemedicine. Stroke/transient ischemic attacks that occurred while the patients were in full compliance with the anti-thrombotic therapy, were counted as the reportable TE events. Results: A total of 120 patients were included in this analysis. The mean age of the study population was 59.80 ± 16.39 years; 70 (58%) were male and the CHA 2 DS 2 -VASc score was 4.27 ± 1.22. Mean number of PFA applications given was 76.64 ± 36.04. G roup 1 included 49 (40.8%) and group 2 was comprised of 71 (59.2%) patients. Baseline characteristics were comparable between the groups. At 1 year, no stroke or transient ischemic attacks were reported in group 1 and 2 . At that time point, 42 (85.7%) and 60 (84.5%) patients were arrhythmia-free in group 1 and 2 respectively (p=0.85). Conclusion: In this series of patients, OAC could be safely discontinued after 1 month following the PFA procedure. Thus, it seems redundant to continue OAC beyond 1 month after PFA.
Abstract 4141864: Eosinophil Regulated Necrosis in Murine Model of Eosinophilic Heart Disease
Authors: Immaculeta Osuji
Journal: Circulation (2024)

Background: Many patients with sustained hypereosinophilia develop cardiac complications, and eosinophilic heart disease (EHD) is the major cause of morbidity and mortality in these patients. The mechanism of EHD is poorly understood. Since eosinophil granule proteins can cause cardiomyocyte damage and one mechanism of their release is regulated necrosis, this study tested the hypothesis that eosinophils undergo regulated necrosis in vitro and that this is damaging to cardiomyocytes in a mouse model of EHD. Methods: To develop a model of EHD, hypereosinophilic mice were challenged with cardiac myosin; biomarkers and histologic outcomes were assessed. For in vitro studies, we used bone marrow derived eosinophils and cell death assessed by biochemical and morphologic outcomes (annexin V binding, membrane permeabilization, citrullinated histone 3 (citH3), extracellular DNA and granule protein). Results: EHD mice showed eosinophil-rich inflammation in the heart associated with cardiomyocyte necrosis and later fibrosis. Heart inflammation was decreased in eosinophil-deficient mice. Release of cell-free DNA and troponin was detectable in plasma. Immunohistochemistry for citH3, a marker of regulated necrosis, highlighted eosinophils in the tissue, suggesting they are undergoing regulated necrosis. To study regulated necrosis of eosinophils in vitro , eosinophil were stimulated with known to induce different types of cell death and stimuli that mimic activation by conditions in the inflammatory microenvironment. While all stimuli induced dose and time-dependent cell death, we noted two different patterns: while some stimuli (e.g. CD95 ligation) caused eosinophils to transition through annexinV+/7AAD- stage (early apoptosis), other stimuli (e.g. PMA and ionomycin) had increased ratio of 7AAD+ cells, suggesting they directly enter necrotic pathway. By microscopy, cells stimulated with CD95, PMA and ionomycin were positive for citH3, while only the ones stimulated with PMA had NET-like structures. This was further seen with staining for DNA and an eosinophil granule protein. Conclusion: Together, our data show that mouse eosinophils undergo specific and distinct cell death pathways, and this may have varying effects on disease outcomes.
Abstract 4141868: Circulating immune cells, inflammatory risk, and atherosclerotic cardiovascular disease: an analysis across 5 cohorts of 17,971 diverse adults
Authors: Sascha Goonewardena, Venkatesh Murthy
Journal: Circulation (2024)

Introduction: Inflammation is pivotal in initiating and accelerating atherosclerotic cardiovascular disease (ASCVD). Inflammatory responses result from coordinated actions of circulating molecular mediators and circulating immune cells (CIC). The complete blood count (CBC) is the standard approach to profile CIC. In an analysis across 5 cohorts, we sought to define the relationships between CBC features and ASCVD. Hypothesis: We hypothesized that CBC features are associated with ASCVD endpoints, including stroke, myocardial infarction (MI), revascularization, and mortality. Methods: We examined the relationships between CBC features, traditional risk factors, and mortality in NHANES (n=6162). We then examined individual CBC features and ASCVD endpoints using adjusted Cox proportional hazards models to compute hazard ratios (HR) standardized in each cohort and combined with random effects meta-analysis across four longitudinal cohorts (n=11,809 subjects from Framingham Offspring, Framingham 3 rd Gen, MESA, and CARDIA cohorts). Results: We first examined the prognostic value of CBC features compared with laboratory assessments (lipid panel, HbA1c, hs-CRP, and basic metabolic panel) in NHANES and found that CBC features were significantly associated with all-cause and CV mortality (data not shown). Next, we validated and extended these findings in a meta-analysis across four additional longitudinal cohorts, evaluating the association of individual CBC features with ASCVD endpoints. In the fully adjusted and fully adjusted + hs-CRP models, CBC features (e.g., neutrophils, monocytes, and lymphocytes) were associated with ASCVD endpoints ( Figure 1A ). The meta-analyzed standardized hazard ratio of WBC for MACE3 (stroke, MI, all-cause mortality) was 1.07 (1.01 - 1.14; p=0.02) ( Figure 1B ). Conclusions: To our knowledge, this is the first study to examine the association of CIC features with ASCVD across a large, diverse sample of adults. CIC features are associated with ASCVD endpoints and mortality even after adjustment for traditional risk factors and laboratory values, including hs-CRP. Taken together, our data reveal unexpected insights into the interplay of CIC, inflammatory risk, and ASCVD.
Abstract 4141828: Cardiovascular Adverse Events And Comparative Safety Of Ibrutinib Plus Venetoclax In Untreated Patients With Chronic Lymphocytic Leukemia: A Meta-Analysis Of Randomized Controlled Trials And Systematic Review
Authors: Maria Antonia Cruz Akabane, Otávio Toth, Roberto Mazetto, Amanda Park, Douglas Cavalcante, Iury RIBEIRO, Imara Barbosa
Journal: Circulation (2024)

Background: The combination of ibrutinib and venetoclax has emerged as a promising therapeutic option for patients with chronic lymphocytic leukemia (CLL), demonstrating significant advantages compared to traditional chemotherapy-based approaches. However, the potential adverse cardiovascular effects, especially in patients who have not previously undergone treatment, have not been fully elucidated. Hypothesis: The use of ibrutinib and venetoclax is associated with a higher incidence of cardiovascular adverse events. Aims: This study aims to analyze the incidence of cardiovascular adverse effects in patients treated with ibrutinib and venetoclax for CLL, who were previously naïve to treatment. Methods: PubMed, Embase, and Cochrane Central databases were systematically searched in April 2024 for randomized controlled trials (RCTs) that compared ibrutinib plus venetoclax to standard care therapies (ST) (chlorambucil-obinutuzumab; ibrutinib only and fludarabine-cyclophosphamide-rituximab) in untreated patients with CLL and reported the outcomes of (1) atrial fibrillation; (2) hypertension and (3) sudden death. We performed a systematic review and meta-analysis using RStudio version 2024.04.0. Heterogeneity was examined with the Cochran Q test and I2 statistics. Results: We included 4 RCTs in the final analysis, with a total of 885 participants, of whom 450 (50.8%) were on ibrutinib plus venetoclax. Ibrutinib plus venetoclax was associated with a significant increase in the incidence of atrial fibrillation compared with standard care therapy (OR 7.04; 95% CI 3.11-15.92; p&lt;0.01; I2=0%; figure 1A). Hypertension (OR 2.90; 95% CI 0.75-11.25; p=0.124; figure 1B) and sudden death (OR 0.16; 95% CI 0.16-3.11; p=0.655) were not significantly different between groups. Conclusion: In patients with CLL who were previously naïve to treatment, the combination of ibrutinib plus venetoclax was associated with a higher incidence of atrial fibrillation as compared with ST, whereas hypertension and sudden death were not significantly different between groups.
Abstract 4141840: SOX17 Deficiency is Additive to High Shear Stress in Reducing Endothelial Genes Linked to BMPR2 and NOTCH and Promoting Inflammation in Pulmonary Arterial Hypertension
Authors: Chongyang Zhang, Tsutomu Shinohara, Yannick Lee-yow, Kathrine Guo, Mauro Lago-Docampo, Jesse Engreitz, Marlene Rabinovitch
Journal: Circulation (2024)

BACKGROUND: Pulmonary arterial hypertension (PAH) is characterized by obliteration of distal pulmonary arteries (PA) in association with endothelial cell (EC) dysfunction, leading to smooth muscle proliferation. SOX17 is a transcription factor (TF) expressed in arterial EC that is critical in vascular development. Deleterious variants causing reduced expression of SOX17 are linked to PAH, particularly in congenital heart defects (CHD) that cause increased PA flow and high shear stress (HSS). HYPOTHESIS: SOX17 deficiency is additive to HSS in compromising PAEC homeostasis and in promoting severe PAH. METHODS: SOX17 was reduced (&gt;70%) by siRNA in primary human PAEC cultured in chamber slides in the IBIDI perfusion system. Computational modeling of distal PA indicated pathological HSS of 100 dyn/cm 2 in CHD with PAH whereas physiological laminar shear stress (LSS) is 15 dyn/cm 2 . EC were preconditioned under LSS for 24h, followed by HSS or LSS for 24h. RESULTS: SOX17 expression was increased under LSS versus static condition, as were known SOX17 target genes (e.g., GJA5 , GJA4 , CGNL1 , JAG1 , and CTNNB1). SOX17 siRNA and HSS similarly reduced SOX17 target genes and when combining SOX17 siRNA with HSS they were further decreased owing to an interaction between SOX17 and ERG, a TF reduced by HSS. Indeed, SOX17 and ERG motifs marked most enhancer and promoter H3K27acetyl marks that were reduced under HSS. We then carried out RNAseq of PAEC to find genes co-regulated by SOX17 and ERG (reduced by siRNA for either TF under LSS), decreased under HSS and more-so with HSS + SOX17 siRNA. Those downregulated included SOX17 targets (e.g., CGNL1 and GJA5 ) and others not previously described, with links to BMPR2 signaling, YAP1 (inducer of BMP ligands and suppressor of NF-kB), SETBP1 (inducer of BMPR2 co-receptor BMPR1b), and TMEM100 and SULT1B1 important in NOTCH signaling and EC specification. We also found novel extracellular matrix target genes, e.g., elastin ( ELN, top DEG ) , HMCN1 , TMTC1 and chromatin remodeler ( TOX) . Among genes upregulated, were NAMPT, FAS, LYN, HPSE related to NF-kB activation and/or inflammation. CONCLUSION: HSS plus SOX17 deficiency profoundly compromises EC homeostatic genes, among which are those affecting BMPR2 and NOTCH pathways, ELN fiber assembly, and those promoting inflammation. This can explain why SOX17 mutations are associated with severe PAH in HSS-related congenital heart defects.
Abstract 4141833: Age and Sex Multiplicatively Moderate the Association of Daily Sedentary Time with Depressive Symptoms in Rural Patients with Cardiovascular Diseases
Authors: JungHee Kang, Geunyeong Cha, Chin-Yen Lin, Jia-Rong Wu, Chizimuzo Okoli, Abigail Latimer, Terry Lennie, Martha Biddle, Misook Chung, Debra Moser
Journal: Circulation (2024)

Background: Depressive symptoms (DS) are highly prevalent in patients with cardiovascular diseases (CVD). Sedentary behavior is associated with DS, and together they worsen CVD health outcomes. Rural patients exhibit greater incidence of DS and physical inactivity than their urban counterparts. While females and younger adults are more likely to experience DS in general, how sedentary time (ST) interacts with age and sex on DS in rural patients with CVD has not been elucidated. Hypothesis: Age and sex multiplicatively moderate the association of daily ST with DS in rural patients with CVD. Methods: A total of 226 (58±12 [range 23-80] years old, 49% female) rural patients with CVD were included. The Patient Health Questionnaire-9 was used to measure DS. Patients wore the ActiGraph GT9X Link for 4 to 7 days to measure ST (minutes/day on average). We used PROCESS to test the moderated moderation model. The pick-a-point approach was used for probing a three-way interaction. Results: We found a significant three-way interaction among daily ST ( X ), age ( Z ), and sex ( W ) [B=-.0016, t (218)=-3.631, p =.0004], which indicates the magnitude of the moderation by sex on the effect of daily ST on DS depended on age. Moderated moderation explained 10.1% of the variance in DS ( p =.002). The pick-a-point approach indicated significant conditional interactions between ST and sex at the youngest and oldest ages (Figure). Among younger adults, there was a significantly positive association of ST with DS in females compared to males [θ XW → Y |( Z =30)=.034; F (1;218)=8.363; p =.004], while a significantly positive association of ST with DS was found in males compared to females among older adults [θ XW → Y |( Z =70)=-.028; F (1;218)=11.431; p =.001]. However, among middle-aged adults, the association of sedentary time with DS was not significantly moderated by sex ( p =.59). Conclusions: The findings of the study indicate a complex interaction of age and sex in the relationship of ST with DS and suggest an age- and sex-stratified intervention to improve depressive symptoms. Future research is warranted to examine factors that influence sex differences in the association of ST with DS in different age groups.
Abstract 4141819: Platelet Transcriptomic Profiling in Acute Myocardial Infarction
Authors: Tessa Barrett, Florencia Schlamp, Matthew Muller, Angela Lee, Macintosh Cornwell, Elliot Luttrell-Williams, Nathaniel Smilowitz, Judith Hochman, Kelly Ruggles, Harmony Reynolds, Jeffrey Berger
Journal: Circulation (2024)

Introduction: Platelets play a central role in the pathophysiology of myocardial infarction (MI), including thrombosis and inflammation. Nonetheless, few studies have used unbiased transcriptomics to characterize platelets at the time of an MI. Further, the relationship between platelet phenotype and MI subtype is uncertain. Aim: To investigate the platelet transcriptome during acute MI and by MI subtype (MI with obstructive coronary artery disease (MI-CAD) or with no obstructive coronary arteries (MINOCA). Methods: Platelet RNA-sequencing was performed in females referred for invasive coronary angiography for MI (n=40), or for evaluation of stable angina (n=38). MI cases were categorized into either MI-CAD or MINOCA according to the presence or absence of a ≥50% diameter stenosis in ≥1 major epicardial coronary artery. Results: Among females with MI (47.5% MI-CAD, 52.5% MINOCA), the median age was 63 years, 70% were white, 45% Hispanic, and co-morbidities including hypertension (45%), diabetes (22.5%), and dyslipidemia (60%) were common. There were no differences in age, race, ethnicity, BMI, hypertension, diabetes, or dyslipidemia between participants with MI and those with stable angina. In total, 1421 genes were differentially expressed (p&lt;0.05), with 657 up- and 764 downregulated platelet transcripts in MI relative to stable angina. By ingenuity pathway analysis, canonical pathways associated with actin cytoskeleton, integrin, interferon signaling, and mitochondrial dysfunction were positively enriched in MI platelets, and oxidative phosphorylation and RHOGDI signaling were negatively enriched. When stratified by MI subtype, 531 genes (p&lt;0.05) were differentially expressed (334-up, 197-downregulated) in MI-CAD vs MINOCA. MI-CAD platelets were positively enriched in genes in canonical pathways associated with neutrophil degranulation, neutrophil extracellular traps, and atherosclerosis signaling versus MINOCA. Among all patients with MI, unbiased clustering analysis classified participants into 3 distinct groups that differed in composition by clinical MI subtype (group A – 100% MINOCA, B – 80% MINOCA, and C – 0% MINOCA, P&lt;0.001). Conclusions: The platelet transcriptome is enriched in transcripts linked to classical platelet activation responses (actin cytoskeleton, integrin, interferon signaling, and mitochondrial dysfunction) in the setting of MI. Among individuals with MI, platelet RNA sequencing discriminated individuals with MI-CAD versus MINOCA.