tbuckley/cabot-search huggingface dataset:
Abstract 4134306: Menopausal Status Protects Against Vascular Dysfunction Induced by Breast Cancer Chemotherapy
Authors: Piotr Szczepaniak, Tomasz Mikolajczyk, Ewelina Jozefczuk, Diana Hodorowicz-Zaniewska, Joanna Streb, Jakub Jurczyk, Katarzyna Gara, Mateusz Siedlinski, Jaroslaw Krolczyk, Joanna Sulicka-Grodzicka, Iwona Laksa, Tomasz Grodzicki, Tomasz Guzik
Journal: Circulation (2024)

Introduction: Breast cancer chemotherapy is associated with an increased risk of cardiovascular events, particularly pronounced in postmenopausal women. Vascular damage and docetaxel-caused endothelial dysfunction may underlie these effects, although the role of estrogens and menopausal status remains undefined. Hypothesis: Estrogens protect premenopausal women from neoadjuvant chemotherapy-induced endothelial dysfunction (NACT regimen: docetaxel, doxorubicin, cyclophosphamide) and its component docetaxel. Methods: We studied vascular function and its molecular determinants in mammary artery branches from pre- and postmenopausal women undergoing breast cancer surgery, with or without prior NACT. Mechanisms were investigated in bilaterally ovariectomized female C57BL/6J mice treated with docetaxel or placebo. Results: While NACT evoked endothelial dysfunction characterized by the loss of nitric oxide bioavailability in blood vessels from postmenopausal women, premenopausal women were protected from this phenomenon (Fig. 1) . Furthermore, premenopausal women’s blood vessels exhibited resilience against NACT-induced vascular oxidative stress. In particular, NOX4 expression was markedly lower in NACT-treated arteries from premenopausal women compared to their postmenopausal counterparts. No differences were seen in the non-NACT groups. At the molecular level, NACT incited lower inhibitory phosphorylation of Thr495 eNOS in premenopausal women's arteries compared to those of postmenopausal women post-NACT. In mice following bilateral ovariectomy, docetaxel caused endothelial dysfunction, but did not perturb acetylcholine-induced vasodilation in non-ovariectomized mice. Docetaxel induced blood pressure only in the group of ovariectomized mice. Conclusions: NACT-induced vascular dysfunction, often observed in breast cancer survivors, is absent in premenopausal women. This can be partially attributed to the protective role of estrogens, which prevent excessive production of reactive oxygen species and inhibitory eNOS phosphorylation.
Abstract 4145876: <i>Prognostic significance of somatic mutations in myeloid cells of men with chronic heart failure – interaction between loss of Y chromosome and clonal hematopoiesis</i>
Authors: Sebastian Cremer, Moritz von Scheidt, Klara Kirschbaum, Lukas Tombor, Silvia Mas-Peiro, Tina Rasper, Wesley Abplanalp, Johannes Krefting, David Leistner, Thimoteus Speer, Heribert Schunkert, Stefanie Dimmeler, Andreas Zeiher
Journal: Circulation (2024)

Introduction: Age-associated clonal hematopoiesis of indeterminate potential (CHIP) has been associated with increased incidence and worse prognosis of chronic heart failure. CHIP is driven by somatic mutations in hematopoietic stem and progenitor cells (HSPC). Mosaic loss of the Y chromosome (LOY), the most common somatic mutation in blood cells of men, also correlates with clonal expansion of myeloid cells, increases with age and was experimentally shown to lead to diffuse cardiac fibrosis and subsequent heart failure in mice. However, the prognostic significance of LOY as well as its potential interaction with CHIP in patients with chronic heart failure is unknown. Aims/Methods: We investigated the prevalence and prognostic significance of the extent of LOY and the two most common CHIP-driver mutations DNMT3A and TET2 in 705 male patients with established chronic heart failure across the entire spectrum of left ventricular ejection fraction. Results: Both, LOY and DNMT3A/TET2 mutations, increased with age, and LOY co-occurred with DNMT3A/TET2 mutations in 27.1% of men at age &gt; 70 years. LOY was an independent predictor of death during 3-years of follow-up across the entire spectrum of left ventricular ejection fraction. The co-occurrence of harboring LOY and DNMT3A/TET2 mutations significantly contributed to the observed increased mortality observed in carriers of DNMT3A/TET2 mutations. The detrimental effect of LOY on prognosis was confirmed in a validation cohort of patients with ischemic heart disease.scRNA sequencing of peripheral blood cells in patients with chronic ischemic heart failure showed increased profibrotic signaling in LOY monocytes with elevated markers of monocyte mediated inflammation and profibrotic cardiac remodeling (S100A8, TLR2, CLEC4D) and reduced expression of TGF-b inhibiting genes (SMAD7, TGIF2). The proinflammatory phenotype of LOY monocytes was further amplified in LOY monocytes of patients simultaneously harboring DNMT3A mutations, who displayed heightened expression of alarmins (S100A8, HMGB2) and interferon signaling related genes (IFNGR1, TRIM56, CD84) compared to patients without CHIP mutations. Conclusion: The age-associated acquisition of somatic mutations in blood cells of men with chronic heart failure is associated with increased mortality, with loss of Y chromosome emerging as an independent predictor of all-cause death across the entire spectrum of left ventricular function.
Abstract 4143267: Bicaudal-C Homolog 1 Plays a Significant Role in Cardiac Development and Congenital Heart Defects
Authors: Chia-Feng Liu, Steven Leon, Oliver Wessely, Wai Hong Tang
Journal: Circulation (2024)

Background: Congenital heart defects (CHDs) are the most common birth defects globally and often require palliative surgical interventions with limited long-term effectiveness. Prenatal detection of CHDs is challenging due to the absence of heart failure signs in most fetuses. Thus, early detection methods and therapeutic drugs to correct abnormal heart development are crucial. We have discovered that the RNA-binding protein Bicaudal-C homolog 1 (Bicc1) influences normal and abnormal heart development. Bicc1 is involved in post-transcriptional regulation and interacts with RNA interference (RNAi) components. While its role in left-right patterning, kidney development, and the interaction with PKD genes ( Pkd1 and Pkd2 ) is documented, the role of Bicc1 and its expression in heart development and whether it relies on interaction with Pkd1/Pkd2 are not understood. Methods and Results: To start addressing these knowledge gaps, we used a transgenic mouse line with an in-frame fusion of Bicc1 and the LacZ reporter gene to perform β-galactosidase staining, RNAscope and immunostaining to identify the cardiac cell types expressing Bicc1 . High Bicc1 expression was observed in embryonic and neonatal hearts, particularly in the ventricles, atria, and endothelial cells of blood vessels. Expression decreased in adulthood but persisted at basal levels. We observed that Bicc1 knockout (KO) developed heterotaxy of the heart and enlarged atria. Next, to elucidate the gene and miRNA regulatory networks involved in cardiac development disrupted by the absence of Bicc1, we carried out RNA- and miRNA-seq on hearts from wild-type and Bicc1 KO embryonic hearts at different developmental stages. Several genes and miRNAs associated with ciliopathy and heterotaxy, including miR-196 , Hand1 , and Lefy2, were significantly altered in Bicc1 KO mice. Moreover, as reported for the kidney, Pkd2 mRNA expression was altered in Bicc1 KO mice, while Pkd1 expression remained unchanged. Finally, we detected changes linked to lipid metabolism and related pathways, such as members of aldehyde dehydrogenase ( Adlh1a ) and cytochrome P450 family ( Cyp5a1 ), that were altered in the absence of Bicc1 . Conclusions: Our study reveals additional role(s) for Bicc1 in heart development suggesting its involvement in regulating heart metabolism in fetuses. These findings provide a conceptual basis for future investigations into the function of Bicc1 in heart development and how its disruption contributes to CHDs.
Abstract 4141498: Coronary Atherosclerosis and Prostate Cancer: The Impact of Androgen Deprivation Therapy
Authors: Carlotta Onnis, Marly van Assen, Carlo De Cecco, Luca Saba, Bill Zheng, Ashesh Jani, Anant Mandawat, Nikhil Sebastian, Pretesh Patel, Vishal Dhere, Bruce Hershatter, Stephanie Cantu, Sagar Patel
Journal: Circulation (2024)

Background: Men with prostate cancer (PC) who receive androgen-deprivation therapy (ADT), targeting the gonadotropin releasing hormone (GNRH) axis, are at higher risk of cardiovascular disease (CVD). However, the pathophysiology behind ADT cardiotoxicity is unclear. Hypothesis: We hypothesize that ADT is associated with accelerated atherosclerosis due to GNRH-mediated inflammatory cascade. Aims: To prospectively evaluate coronary plaque progression, using coronary computed tomography angiography (CCTA), in a cohort of PC men treated with versus without ADT. Methods: Sixty-eight men with localized PC receiving radiation (XRT) alone (n=17) or XRT+ADT (n=51) were prospectively enrolled. Patients underwent CCTA, as per clinical protocols , at baseline and 12-month follow-up. Plaque quantification was conducted, blinded to therapy and time-point, using semi-automated software (Coronary analysis research prototype, Siemens Healthineers, Forchheim, Germany), with assessment of total plaque volume (TPV) and plaque volume by subtype (calcified, CPV, high-density non-calcified, HD, low-density non-calcified, LD) on a per-patient basis. CAD-RADS was also evaluated. Results: At baseline, median (IQR) TPV, CPV, HD, LD (mm 3 ) and CAD-RADS among patients who received XRT alone versus XRT+ADT were 341.1 (118.5-778.2) vs 717.3 (207-1158.9), 22.2 (4.9-131.9) vs 74.3 (21.3-205.8), 306.6 (102.1-593.6) vs 585.8 (175-895.2), 14 (2.3-47) vs 22.6 (6.2-50.4), 1 (1-2) vs 2 (2-3), respectively. At 12-month follow-up, TPV, CPV, HD, LD, and CAD-RADS between XRT alone versus XRT+ADT were 410.1 (177-941) vs 904.6 (283.7-1402), 21 (12.1-195.1) vs 102.6 (30.5-259.4), 372.6 (157.6-721.6) vs 686.1 (242.7-1062.7), 11.7 (5.6-69.8) vs 34 (10.4-62.1), 2 (1-2) vs 3 (2-3). A statistically significant difference between baseline and follow-up was noted among patients treated with XRT+ADT for TPV, CPV, LD (p&lt;0.001), and HD (p=0.006). A significant difference in CAD-RADS grade was noted in both cohorts (p=0.025 for XRT and p&lt;0.001 for the XRT +ADT). There was no significant difference in any plaque volume between baseline and follow-up in the XRT alone cohort. Conclusion: Addition of ADT to XRT for localized PC treatment was associated with a significant progression of TPV, CPV, HD, LD, and CAD-RADS grade over a 12-month period. Insights on ADT cardiotoxicity may lead to enhanced cardioprotective strategies tailored to patients with PC undergoing combined therapy, potentially improving cardiac outcomes.
Abstract 4134327: Efficacy and safety of aprocitentan in patients with resistant hypertension receiving at least 4 antihypertensive medications including beta (β) blockers
Authors: Michael Weber, George Bakris, John Flack, Krzysztof Narkiewicz, Mouna Sassi-Sayadi, Markus Schlaich, Jiguang Wang, Ajay Ahuja
Journal: Circulation (2024)

Background: Aprocitentan, a dual ET A /ET B endothelin receptor antagonist, was recently FDA-approved for use in combination with other drugs for the treatment of hypertension not adequately controlled on other antihypertensive drugs. β-blockers are used for the prevention of cardiovascular events and have antihypertensive effects. All subjects in the PRECISION study were hypertensive at screening despite receiving ≥3 antihypertensives, with 63.5% on ≥4 and 16.8% on ≥5 antihypertensives. All were switched to a standardized fixed dose triple combination of amlodipine/valsartan/hydrochlorothiazide; and the 456 patients (62.5% of the 730 total) who were on β-blockers at screening continued throughout the study as well. Of these, 173 (37.9%) had a history of ischemic heart disease and 106 (23.2%) a history of congestive heart failure, vs 52 (19%) and 37 (13.5%) not receiving β-blockers. This preplanned subgroup analysis assessed the efficacy and safety of aprocitentan in patients with resistant hypertension on the triple combination with or without β-blockers. Methods: Changes from baseline (BL) in office systolic blood pressure (SBP) and diastolic BP (DBP) were assessed at Week 4, the end of the double-blind treatment phase with aprocitentan 12.5 mg or 25 mg per day or placebo, and at Week 36, at the end of the single-blind aprocitentan 25 mg treatment phase. Results: There was no difference in the efficacy of aprocitentan when patients were on a β-blocker or not. In patients on β-blockers, 12.5 mg and 25 mg aprocitentan decreased SBP from BL to Week 4 by mean -14.9 mmHg and -14.9 mmHg, respectively, vs -11.2 mmHg in the placebo group; and in patients without β-blockers by -16.5 mmHg and -14.9 mmHg vs -11.8 mmHg. Similar results were seen at Week 36, as compared with BL for both subgroups, and at Week 4 for DBP (Table 1). In patients on β-blockers, the incidence of edema/fluid retention at Week 4 was 9.9%, 19.3% and 2.8% in the aprocitentan 12.5 mg, 25 mg and placebo groups, respectively, as compared with 7.6%, 16.7%, and 1.0% in patients without β-blockers. In both subgroups, most events occurred during the first 8 weeks of treatment. The incidence of edema/fluid retention with aprocitentan was comparable with that of the placebo group in both subgroups thereafter. Conclusions: Aprocitentan is effective in lowering BP and has a good safety and tolerability profile in patients with resistant hypertension who are taking 4 or more antihypertensive drugs including β-blockers.
Abstract 4144501: Effect of the Cardiac Myosin Activator Omecamtiv Mecarbil on Risk of Ventricular Arrhythmias in Heart Failure with Reduced Ejection Fraction: the GALACTIC-HF Trial
Authors: Alberto Foa', Muthiah Vaduganathan, Brian Claggett, Govini Mani, Rafael Diaz, Fady Malik, Stephen Heitner, Gary Felker, Marco Metra, John McMurray, John Teerlink, Scott Solomon
Journal: Circulation (2024)

Introduction: The selective cardiac myosin activator, omecamtiv mecarbil (OM), has been shown to benefit individuals with HFrEF but the clinical experience of cardiac myosin activators and incidence of ventricular arrhythmias (VA) is limited. We investigated the prognostic role of VA and the associations between OM, VA occurrence, and outcomes in the GALACTIC-HF trial. Methods: GALACTIC-HF was a placebo-controlled trial testing the efficacy and safety of OM in participants with symptomatic chronic HF and LVEF≤35%. VA were captured based on safety adverse event reporting. Severe HF was defined according to the ESC-HFA criteria. Poisson regression models using restricted cubic splines model were used to assess the association between baseline LVEF and incidence rates of VA. Associations between incident VA and subsequent clinical outcomes were evaluated using time-updated Cox proportional hazard models. Results: Over a median follow-up of 21.8 months, 594 out of the 8,232 individuals randomized in the GALACTIC-HF trial experienced VA, with no statistically significant differences between study arms. Individuals with lower LVEF values were at greater risk of incident VA (per 10% decline: HR 1.37; 95% CI 1.21-1.55; p&lt;0.001) with no significant differences between study arms ( Figure, panel A ). Following VA occurrence, participants were at higher risk of the primary endpoint of CV death or HF events (adj HR 1.67; 95% CI 1.42-1.97; p&lt;0.001) and all-cause mortality (adj HR 2.07; 95% CI 1.77-2.42; p&lt;0.001). The treatment effects of OM on clinical outcomes were consistent in patients not experiencing VA and after VA events. Among the 2,258 participants with severe HF, OM did not affect the risk of VA (adj HR 0.95; 95% CI 0.70-1.29) and this was consistent across the range of LVEF; Figure, panel B . Conclusions: The occurrence of VA among patients with HFrEF is associated with a substantially higher risk of subsequent fatal and non-fatal events. OM did not increase the risk of VA and the beneficial treatment effects were maintained irrespective of VA occurrence. These findings reinforce the safety of OM use among individuals with HFrEF who are at risk of arrhythmic events.
Abstract 4144525: An Observation Of Racial Disparities In Patients Admitted With St Segment Elevated Myocardial Elevation
Authors: Godbless Ajenaghughrure, Kenan Rahima, Kamal Shemisa, AAVASH MISHRA, Gehna Kishore
Journal: Circulation (2024)

introduction: This sudy explores the multifaceted nature of racial disparities among patients admitted with STEMI, shedding light on the complex interplay of social, economic, and healthcare factors that contribute to differential outcomes among diverse populations. Methods: we examined the national inpatient sample 2017-2020 for adult admitted with st segment myocardial infarction,we compared the clincal outcome based on racial distribution.STATA 18th edition was used for analyses. Age, gender, race, hypertension, diabetes, obesity, dyslipidemia, and Elixhauser comorbidity index were identified as confounders by univariate analyses and tested further with multivariate logistic regression models. The primary outcome was mortality. Secondary outcomes were the need for intubation, cardiac arrest, length of stay (LOS), and total hospital charges. Results: There were 826315 hospitalizations with STEMI. Mean age was 64 yrs and 62% were male. Among the admitted patients, Caucasians were 593575 (72%), Blacks were 75025(9.1%),Hispanics were 69605(8.4%), Asians were 23734(2.9%). All-cause mortality in patients admitted with STEMI was 88125 where subgroup Analysis with Caucasians, Blacks ,Hispanics and Asians had 60074(10.1%) vs 9135 (12.1%) vs 7645(10.9%) and 2999(12.6%) respectively. Further subgroups analysis revealed that Blacks (13.9%, aOR 1.37 CI 1.28-1.47,P value&lt;0.001) were more likely to require intubation,followed by Asians(13.5% aOR 1.59 CI 1.43--1.76, p value &lt;0.001) ,then Hispanic (13% aOR 1.45,CI 1.35-1.56 P vale &lt;0.001)and caucasians were least likely to require intubation(9.7% ) Finally, racial subgroup showed significant primary andsecondary outcomes that are presented in Table 1. Conclusion: All obtained results revealed statistical significance and we considered Caucasian population as baseline. Mortality waa highest amongst Asians,followed by Blacks then Hispanics and least in the caucasian subgroup. Understanding these disparities is essential for improving healthcare equity and ensuring that all patients receive appropriate and equitable care regardless of their racial or ethnic background.
Abstract 4136952: The Clinical Importance of Arrhythmia Notifications During Use of Wearable Cardioverter Defibrillator
Authors: George Techiryan, Timothy Malinowski, Laura Rodriguez, Crysta Silas, Nicole Bianco
Journal: Circulation (2024)

Introduction: Wearable cardioverter defibrillators (WCDs) record continuous ECG data for the purpose of delivering treatment for lethal arrhythmias, but occasionally capture non-treatable arrhythmias that may be of clinical value. The purpose of this study was to evaluate the usefulness to health care providers (HCPs) of evaluating and reporting these other recorded ECGs and the impact on additional arrhythmia detection and clinical management decisions. Research Questions: Do clinicians find arrhythmias identified during routine WCD useful? What arrhythmias are observed? Can the identification of these arrhythmias, validation through ZOLL’s Independent Diagnostic Testing Facility (IDTF) and notification to the provider lead to changes in clinical management? Methods: A multi-center, observational study of 52 US HCPs enrolled 474 patients with commercial LifeVest prescriptions and followed them for up to 3 months. All routinely transmitted LifeVest ECG strips (corresponding to Baseline, Patient Initiated, or other automatic event recordings) during this period were analyzed by ECG technicians at the IDTF within ZOLL. These arrhythmias were reported to the HCP who completed a questionnaire assessing the utility (scored 1 to 5) and clinical impact (medication changes, tests, and procedures ordered) of these events. Results: At the conclusion of the study, 22% of patients (105/474) monitored had 112 reportable, unique arrhythmia events that were sent to 34 providers who completed questionnaires regarding report utility and clinical management decisions. A significant proportion of reports led to medication changes (40%), additional testing (32%) and procedural interventions (23%). The average usefulness of the reports was 3.63/5 with atrial fibrillation representing the most common arrhythmia, but many variations of ventricular ectopy were also captured which tended to be more clinically useful and impactful. Conclusions: WCD patients experience a high burden of actionable arrhythmias. Monitoring and reporting these arrhythmias over the course of normal wear provides additional clinical value to providers. Those arrhythmias that lead to changes to clinical management are the most useful.
Abstract 4146312: Global Burden and Trend of Atrial Fibrillation and Flutter in the 27 European Union Countries from 1990-2021: A Systematic analysis for the Global Burden of Disease Study 2021
Authors: Lalitkumar Patel, Siri Vummaneni, Paritaben Bhalodia, Rutvij Patel, Simranpreet Singh Daid, Dhruvi Modi, Jobby John, Urvashi Rathod, Akhilesh Sharma, Gunjan Kochhar, HARDIK DESAI
Journal: Circulation (2024)

Introduction: Atrial Fibrillation (Afib) and Flutter ranks as the fifth leading cause of death among all cardiovascular diseases (CVD). Given the scarcity of consistent previous estimates, this study is the first to assess the burden of Afib and Flutter in the European Union (EU) over the past three decades, including the initial two years of the COVID-19 pandemic. Methods: Using global burden of disease study 2021 meta tool, we estimated prevalence, incidence, deaths, disability adjusted life years (DALYs), years lived with disability (YLDs) due to Afib and Flutter by age, sex, year and location across the 27 EU countries from 1990-2021. Results: The total number of prevalence rose from 5 million (95% uncertainty interval: 3.9-6.4 million) in 1990 to 8.6 million (7.2-10.3 million) in 2021. The total percentage of change (TPC) in deaths increased by 130% (110%-143%), and YLDs by 69% (56%-84%) from 1990-2021. Austria saw the highest increase in age-standardized incidence rates (ASIR) at 83%, followed by Czechia at 50%. Sweden experienced the largest rise in mortality rates (ASMR) at 93%, with Estonia at 35%, and in YLD rates (ASYLDR), Austria led with a 90% increase followed by Sweden at 49%. In terms of age, individuals aged 55 and older recorded the highest death toll at 70,269 (57,793-77,019) and the highest incidence at 607,960 (397,686-868,122) in 2021. Regarding gender, males showed an increased TPC in overall burden compared to females, with males observing an increase and females a decreasing trend in ASIR (5% vs -7%), ASMR (7% vs -4%), and ASYLDR (7% vs -5%) from 1990-2021. Conclusion: Deaths due to Afib and Flutter accounted for 4.26% of all CVD in EU. The escalating prevalence and mortality rates of Afib and Flutter across the EU highlight an urgent need for comprehensive healthcare strategies. Effective management should focus on bolstering preventive measures, advancing diagnostic techniques, and enhancing patient care frameworks, particularly for the aging demographic most at risk. Strategic collaboration across sectors, including innovative public health initiatives and policy reinforcement, is essential to curb this growing trend and safeguard public health.