tbuckley/cabot-search huggingface dataset:
Abstract 12241: Low-Efficiency Gene Editing is Capable of Suppressing Arrhythmogenesis in Long QT Syndrome Type II: Computer Simulation Study
Authors: Allison Navarrete-Welton, Tae Yun Kim, Peter Bronk, Zhilin Qu, Gideon Koren, Bum-rak Choi
Journal: Circulation (2023)

Background: Long QT Syndrome Type II (LQT2) is a congenital cause of arrhythmia and sudden cardiac death due to mutations in ion channel hERG responsible for the rapid inward rectifying potassium current (I Kr ). Progress in gene therapy may result in a viable treatment for LQT2. However, the gene transduction efficacy required to prevent cardiac arrhythmias in LQT2 is unknown. We used computer simulation to examine the minimum gene transduction efficacy necessary to suppress early afterdepolarizations (EADs). Hypothesis: Low transduction efficacy of hERG is sufficient to suppress EADs through electrotonic coupling between transduced I Kr (+) and non-transduced I Kr (-) cardiomyocytes (Fig 1A). Methods: Computational models of rabbit and human cardiac tissue were implemented in 2D (100 x 100 cells) and 3D (13 x 13 x 13 cells) with a multi-state Markov model for I Kr and a dynamic gap junction resistance model. Gene transduction efficacy was modeled by varying the percentage of I Kr (+) cardiomyocytes from 0-100%. Spatial heterogeneity in gene delivery was modeled by varying the cluster size of I Kr (+) cells from 1-400 cells. I Kr (+) cell clusters were distributed randomly in the tissue. Results: In 2D, EADs were suppressed with 14% I Kr (+) cells (rabbit model) and 12% I Kr (+) cells (human model) (Fig 1B). In 3D, the minimum transduction efficacy was further reduced to 10% (rabbit model) which likely reflects the impact of increased cell-cell coupling. Clustering I Kr (+) cells required greater transduction efficacy (Fig 1C). Detailed ionic current trajectory analysis suggests that the sufficiently large gap junction current from I Kr (+) cells during phase 2 of the action potential can prevent I Kr (-) cells from undergoing the Andronov-Hopf bifurcation that leads to EADs. Conclusions: Computational models suggest low-efficiency gene editing is a viable approach for suppressing arrhythmogenesis in LQT2 patients.
Abstract 12226: Aging Impairs the Neuro-Vascular Interface in the Heart
Authors: Julian U Wagner, Lukas Tombor, Pedro F Malacarne, Nivethitha Manickam, Wesley T Abplanalp, David John, Giulia Karolin K Buchmann, Stephan Angendohr, Ehsan Amin, Katharina Scherschel, Klöcker Nikolaj, Malte Kelm, Dominik Schüttler, Sebastian Clauss, Stefan Guenther, Thomas Braun, Thomas Boettger, Christian Baer, Minh-Duc Pham, Jaya Krishnan, Susanne S Hille, Oliver Mueller, Tarik Bozoglu, Christian Kupatt, Eleonora Nardini, Selma Osmanagic-Myers, Christian Meyer, Andreas M Zeiher, Ralf P Brandes, Guillermo Luxan, Stefanie Dimmeler
Journal: Circulation (2023)

Aging is a major risk factor for impaired cardiovascular function. The aging heart is characterized by vascular dysfunction, increased hypertrophy, fibrosis and electrophysiological alterations. However, the interaction between the different age-associated changes in cardiac remodelling is poorly define. Since vessels are aligned with nerves, and this interplay is critical for tissue homeostasis, we investigated whether an impairment of the neuro-vascular interface may contribute to age-associated pathologies in the heart. We show that aging reduces sympathetic and sensory nerve fibers, which both align to arteries and arterioles. Aging induced a dysregulation of vascular-derived neuro-regulatory genes, especially the axon repellent factor Sema3A, which was augmented by 2.4±0.1-fold in old heart endothelial cells. Consistently, endothelial Sema3a overexpression reduced axon density in vivo, thus mimicking the observed aged heart phenotype. Since cellular senescence was induced at the same time point when nerve density declined (16 months of age) and senescence endothelial cells showed a higher expression of Sema3a, we hypothesized that endothelial senescence may contribute to cardiac denervation. Indeed, supernatants of senescent endothelial cells reduced neurite outgrowth in vitro in a Sema3A-dependent manner. In vivo studies further confirmed that endothelial-specific induction of senescence by overexpression of Progerin induced left ventricular denervation and induced Sema3a expression. By contrast, the pharmacological removal of senescent cells by the senolytic drugs dasatinib and quercetin rescued age-induced denervation and prevented the age-induced induction of endothelial Sema3a expression. Functional studies additionally demonstrated that endothelial senescence reduced heart rate variability, while senolytics preserved heart rate variability, restored age-associated declines in sympathetic and parasympathetic activity and reduced age-associated increase in arrhythmias. These data suggest that senescence-associated regulation of neuro-regulatory genes in endothelial cells is associated with reduced nerve density and, thereby, contributes to age-associated cardiac dysfunction.
Abstract 12240: A Systematic Review and Network Meta-Analysis of Metastatic Hormone-Sensitive Prostate Cancer Therapy Cardiotoxicity
Authors: Moez K Aziz, Donald Molony, Catrin T Smith, Travis Holder, Neal Mody-Bailey, Oliver Brunckhorst, Resa Magill, Mariya Fatakdawala, Jerry Roland, Gabriela Kostrzanowska, Alexander Samuel Iacobucci, Andrew Zarker, Emma Thames, Justin Swaby, Daniel Xiao, Lily Choi, Christopher Owen, Jacob Galan, Darren Sanchez, Shreyas Ranganath, Giorgio Gandaglia, Skyler Howell, Efstratios Koutroumpakis, Ali Ziaolhagh, Abdelrahman Ali, Juan C Plana, Cezar Iliescu, Wamique Yusuf, Steven E Canfield
Journal: Circulation (2023)

Introduction: The European Association of Urology (EAU) guidelines consider efficacy and safety when recommending metastatic hormone sensitive prostate cancer (mHSPC) therapies but do not account for cardiotoxicity. For patients with low tumor burden ineligible for docetaxel, first-line therapies include androgen deprivation therapy (ADT) plus either apalutamide, enzalutamide, or abiraterone with prednisone. Hypothesis: We expect differences among first-line therapies for the five International Cardio-Oncology Society (IC-OS) cardiotoxicity domains: heart failure, myocarditis, vascular toxicity, hypertension, and arrhythmias. Methods: We searched Ovid Medline, Elsevier Embase, and the Cochrane Library for randomized clinical trials (RCTs) from inception until August 2022. Studies reporting at least one first-line therapy and cardiotoxicity domain were included. Network meta-analysis with a frequentist fixed-effect model was performed to estimate risk ratio (RR) and 95% confidence intervals (CI). Results: For heart failure and arrhythmias, 3 studies with 3376 patients were found with a similar placebo population treated with ADT alone (Figure 1). Four studies with 4526 patients were found assessing hypertension and vascular toxicity. Median follow-up times of studies ranged from 22.75 to 41.00 months. There were no statistically significant differences in heart failure, vascular toxicity, or arrhythmias. However, hypertension was significantly lower in patients treated with ADT plus apalutamide compared to ADT plus abiraterone with prednisone (RR 0.69, 95% CI 0.49 to 0.95). No studies reporting myocarditis were found. Conclusions: Apart from hypertension, no major differences in cardiotoxicity were found among mHSPC first line treatments. Therefore, when selecting therapy, clinicians can prioritize treatment efficacy over concerns regarding cardiotoxicity as long as blood pressure is appropriately controlled.
Abstract 12294: Poldip2 Mediates Brain Vascular Permeability by Regulating ZO-1 Phosphorylation and Localization at the Interendothelial Border
Authors: Keke Wang, Qu Hongyan, Bernard Lassegue, Douglas C. C Eaton, Chang Song, Jianjun Mu, Kathy K Griendling, Marina S Hernandes
Journal: Circulation (2023)

Introduction: Poldip2 is a novel regulator of cerebral vascular permeability involved in aggravating blood-brain barrier disruption following ischemic stroke; however, the underlying mechanisms are incompletely understood. Tight junctions are crucial for the formation of endothelial barriers and are composed of transmembrane proteins and adaptor proteins such as ZO-1. Cerebral ischemia and inflammation lead to ZO-1 redistribution resulting in vascular permeability. Hypothesis: We hypothesized that Poldip2 may mediate ZO-1 phosphorylation and promote brain endothelial monolayer permeability following cerebral ischemia. Methods: Cerebral ischemia was induced in endothelial-specific Poldip2 knockout and control mice. Vascular permeability was assessed by Evans blue dye extravasation. For in vitro analysis, primary rat brain microvascular endothelial cells were used to investigate the effect of Poldip2 depletion by siRNA on TNF-α-induced permeability and trans-endothelial electrical resistance (TEER). Immunocytochemistry was carried out to investigate the effects of Poldip2 depletion or overexpression on ZO-1 localization. Results: Endothelial-specific Poldip2 deletion abolished Evans blue dye extravasation after cerebral ischemia induction (p&lt;0.05). Poldip2 knockdown in vitro suppressed TNF-α-induced endothelial cell (EC) monolayer permeability (FITC-dextran and biotin-avidin assays, p&lt;0.05 and p&lt;0.001) and prevented decreases in TEER (p&lt;0.01). Poldip2 depletion prevented TNF-α-induced ZO-1 disruption at interendothelial junctions (p&lt;0.05). Poldip2 overexpression increased endothelial permeability (p&lt;0.05), decreased TEER (p&lt;0.05), reduced ZO-1 localization at cell-cell junctions (p&lt;0.0001) and enhanced reactive oxygen species (ROS) production (p&lt;0.05). Treatment with the antioxidant N-acetyl cysteine (NAC) abrogated Poldip2-induced ZO-1 disruption (p&lt;0.0001). Immunoprecipitation studies demonstrated that Poldip2 overexpression induced tyrosine phosphorylation of ZO-1 (p&lt;0.0001), an effect prevented by NAC treatment (p&lt;0.01). Conclusions: Poldip2 induces ROS-mediated tyrosine phosphorylation of the TJ protein ZO-1 and promotes EC permeability following cerebral ischemia
Abstract 12145: Intraoperative Anemia Mediates Sex Disparity in Operative Mortality After Coronary Artery Bypass Grafting
Authors: Lamia Harik, Robert Habib, Arnaldo Dimagli, Mohamed Rahouma, ROBERTO PEREZGROVAS OLARIA, Giovanni Soletti, Talal Alzhgari, Kevin An, Lisa Q Rong, Sigrid Sandner, C Noel N Bairey Merz, Björn Redfors, Leonard N Girardi, Mario F Gaudino
Journal: Circulation (2023)

Introduction: Women undergoing coronary artery bypass grafting (CABG) have higher mortality compared with men, yet its drivers are unclear. Hypothesis: The association of female sex with the risk of operative mortality after CABG may be mediated by intraoperative anemia. Aim: To investigate the relationship between sex, intraoperative anemia, and operative mortality. Methods: Retrospective cohort study of 1,434,225 isolated primary CABG patients (344,357 women) from the Adult Cardiac Surgery Database of the Society of Thoracic Surgeons (2011-2022). The primary outcome was operative mortality. The attributable risk (AR, quantifying the risk-adjusted strength of the association of female sex with CABG outcomes) was calculated. Causal mediation analysis adjusted for 42 baseline risk factors was used to derive the total effect of female sex on mortality risk and the proportion of that effect mediated by intraoperative anemia (nadir hematocrit). Spline regression evaluated the relationship of operative mortality and nadir intraoperative hematocrit. Results: Women had lower median preoperative hematocrit (36.9%, interquartile range [IQR] 33.3-40.0 vs 41.0% [37.4-44.0], standardized mean difference [SMD] 74.0%) and nadir intraoperative hematocrit (22.0% [20.0-25.0] vs 27.0% [24.0-30.0], SMD 97.0%) compared with men. Women had higher operative mortality than men (2.8% vs 1.7%, p&lt;0.001, adjusted odds ratio 1.36, 95% confidence interval [CI] 1.30-1.41). The AR of female sex for operative mortality was 1.21 (95% CI 1.17-1.24). After adjusting for nadir intraoperative hematocrit, the AR was reduced by 43% (1.12, 95% CI 1.09-1.16). Intraoperative anemia mediated 38.5% of the increased mortality risk associated with female sex (95% CI 32.3-44.7%). Spline regression showed a stronger association between operative mortality and nadir intraoperative hematocrit at hematocrit values below 22.0% (p&lt;0.001). Conclusions: The association of female sex with increased CABG operative mortality is mediated to a large extent by intraoperative anemia. Avoiding nadir intraoperative hematocrit values below 22.0% may reduce sex differences in CABG operative mortality.
Abstract 12293: Subclinical Leaflet Thrombus on Transcatheter Heart Valve in Patients With Severe Aortic Stenosis and Atrial Fibrillation
Authors: Yasuhiro Otsuka, Masanobu Ishii, Sou Ikebe, Noriaki Tabata, Seitaro Oda, Masafumi Kidoh, Yuichiro Shirahama, Koichi Egashira, Naoto Kuyama, Taku Rokutanda, Katsuo Noda, eiji horio, Tomohiro Sakamoto, Takashi Kudoh, Hideki Shimomura, Tomokazu Ikemoto, Ryusuke Tsunoda, Taishi Nakamura, Kunihiko Matsui, Koichi Kaikita, Kenichi Tsujita
Journal: Circulation (2023)

Background: Subclinical leaflet thrombosis is one of transcatheter heart valve (THV) failure that should be avoided after transcatheter aortic valve implantation (TAVI). Although the effectiveness of direct oral anticoagulants (DOACs) on subclinical leaflet thrombosis has been demonstrated, there is insufficiently established evidence for post-TAVI antithrombotic therapy. The aim of this study was to clarify the formation process of subclinical leaflet thrombosis on THV and thrombogenicity during the perioperative period of TAVI. Methods: This multicenter, prospective, single-arm interventional study enrolled 26 patients with atrial fibrillation treated with edoxaban and severe aortic valve stenosis who underwent TAVI between September 2018 and September 2022. After exclusion, 24 patients were finally analyzed. We investigated changes in maximal leaflet thickness detected by contrast-enhanced computed tomography between 1 week and 3 months after TAVI and measured the thrombogenicity by Total Thrombus-formation Analysis System (T-TAS) and flow stagnation volume by computational fluid dynamics (CFD). Results: Of all, subclinical leaflet thrombosis was observed in 16.7% at 1 week, but decreased to 5.9% at 3 months after TAVI. There was no significant difference in maximum leaflet thickness between 1 week and 3 months, however, patients with subclinical leaflet thrombosis at 1 week had a significantly greater difference in that thickness compared to those without thrombosis. Thrombogenicity assessed by T-TAS and platelet count decreased markedly at 1 week and tended to improve at 3 months. Simple liner regression analysis showed that stagnation volume was positively associated with an increase in maximum leaflet thickness, and low-dose edoxaban was associated with a high risk of increased leaflet thickness at chronic phase. Conclusions: This study showed that course of leaflet thrombus formation in neo-sinus of THV and dynamic fluctuation of thrombogenicity in the acute phase after TAVI. These findings were merely hypotheses generation and thus necessitate future hypothesis testing with large sample sizes.
Abstract 12184: Non-ST Segment Elevation Myocardial Infarction in Patients Admitted With Sepsis: A Comparison of Ischemia-Guided Strategy and Early Catheterization
Authors: saleh alhalaseh, Nmair Alziadin, Ahmed Maraey, Apoorva T Raju, Sabrina A Mann, Zaid Alwarawrah, Omar Al Wahadneh
Journal: Circulation (2023)

Introduction: Sepsis and Non-ST Segment Elevation Myocardial Infarction (NSTEMI) are common medical conditions that often coexist and can cause significant morbidity and mortality. The optimal management strategy for these patients remains unclear. The American Heart Association (AHA) recommends an ischemia-guided approach in patients with stable NSTEMI, but it is unknown if this strategy is beneficial in the setting of sepsis. The aim of this study was to evaluate the outcomes of an ischemia-guided strategy in patients with sepsis and NSTEMI who underwent left heart catheterization (LHC) and percutaneous intervention (PCI). Methods: This study utilized data from the National Inpatient Sample (NIS) from 2016-2020. Patients admitted with a principal diagnosis of sepsis and a secondary diagnosis of NSTEMI were included in the study. Patients with cardiogenic shock or STEMI were excluded from the study due to the necessity of urgent or emergent left heart catheterization. Patients were divided into two groups based on the timing of LHC &amp; PCI, within 24 hours or 48-72 hours of admission. Logistic linear regression was used to adjust for multiple factors including patient demographics, hospital characteristics, and comorbidities. Results: A total of 298,855 patients were included in the analysis, with 48% of them being females and a mean age of 73 years. Patients who received an ischemia-guided strategy had lower mortality rates (OR: 0.45, 95% CI: 0.27-0.74, P=0.002) and a lower risk of heart failure exacerbation (OR: 0.74, 95% CI: 0.56-0.97, P=0.030) compared to those who did not receive this strategy. There was no significant difference in length of stay (Coefficient: 0.33, 95% CI: -0.34 - 1.01, P=0.330), cardiac arrest (OR: 0.08, 95% CI: 0.00-28.0, P=0.401), or gastrointestinal bleed (OR: 0.81, 95% CI: 0.49-1.33, P=0.412) between the two groups. Conclusion: This study suggests that an ischemia-guided strategy may be beneficial in patients with sepsis and NSTEMI compared to urgent percutaneous coronary intervention. The strategy was associated with lower mortality rates and a lower risk of heart failure exacerbation. Further studies are needed to confirm these findings and determine the optimal management strategy for this patient population.
Abstract 12466: Targeted Quantitative Plasma Metabolomics Identifies Metabolite Signatures That Distinguish Heart Failure With Reduced and Preserved Ejection Fraction
Authors: Fawaz Naeem, Teresa Leone, Christopher Petucci, John D Groarke, Donald Bennett, Jessica Mancuso, Iphigenia Tzameli, Rachel J Roth Flach, Daniel J Rader, Daniel P Kelly
Journal: Circulation (2023)

Background: Despite recent advances, heart failure (HF) remains a high burden disease and is largely treated with a “one-size-fits-all” approach. Two phenotypes are recognized: HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). To develop HF disease-specific approaches to define and guide treatment, distinguishing biomarkers are needed. Methods: We conducted quantitative, targeted LC/MS plasma metabolomics on 787 samples collected by the Penn Medicine BioBank from patients with HFrEF (n=219), HFpEF (n=357), and matched non-failing Controls (n=211). Sample collection time from last meal was not controlled. A total of 97 metabolites were analyzed, comprising 30 amino acids, 8 organic acids, and 59 acylcarnitines classified by carbon length. Results: 3-hydroxybutyrate (3-HBA) was uniquely and significantly elevated in the HFrEF group [mean +/- SEM: HFpEF, 108.7(+/-7.15); HFrEF, 148.0(+/-12.4); Control, 86.29(+/-8.01); p &lt;.0001]. The 3-HBA metabolite C4-OH butyryl-carnitine also showed a similar HFrEF-specific pattern. Consistent with previous studies, long/very-long chain acylcarnitines were elevated in the HFrEF group to a much greater extent than the HFpEF group compared to Controls. Branched-chain amino acid (BCAA) levels were not different across the groups; however, acylcarnitine species indicative of BCAA degradation, including C04 Isobutyryl, C04-DC Methylmalonyl, C04-DC Succinyl, and C05 2-Methylbutyryl, were significantly elevated in both HF groups compared to Controls. Lastly, we found that the amino acid, asymmetric dimethylarginine, which promotes endothelial dysfunction and vasoconstriction, was uniquely elevated in the HFpEF cohort [mean +/- SEM: HFpEF, 1.236(+/- .019); HFrEF, 1.105(+/- .027); Control, 1.077(+/- .022); p &lt; .0001]. Conclusions: Taken together, these results identify plasma metabolite signatures that potentially distinguish between HFrEF and HFpEF and suggest patterns of metabolic re-programming in extra-cardiac tissue in the context of heart failure. Future studies will be necessary to define the utility of these metabolites as biosignatures to help guide therapeutics and to identify the underlying physiology responsible for these observations.
Abstract 12449: Association of Left Atrial Function With Mitral Regurgitation Progression: Atherosclerosis Risk in Communities Study
Authors: Chunxiao Zhang, Wendy Wang, Riccardo Inciardi, Yuekai Ji, Khaled Shelbaya, ANNE EATON, Alvaro Alonso, Elsayed Z Soliman, Scott Solomon, Amil M Shah, Lin Y Chen
Journal: Circulation (2023)

Background: Left atrial (LA) enlargement and atrial fibrillation (AF) are associated with functional mitral regurgitation (MR). It is unknown whether lower (worse) LA function is associated with MR progression, independent of LA size, in individuals without AF. Hypothesis: We hypothesized that lower LA function was associated with higher odds of MR progression. Aims: To evaluate the association of echocardiographic-based LA function with MR progression in the Atherosclerosis Risk in Communities (ARIC) Study, a community-based cohort. Methods: We included 2,444 ARIC participants (mean age, 73.8 ± 4.4 years, 42% male, 21% Black) who underwent 2D-echocardiogram at visits 5 (2011-2013) and 7 (2018-2019) and excluded those with AF, heart failure, and heart valve surgery at visit 5. Based on American College of Cardiology/American Heart Association guidelines, MR was graded as stages A-D. MR progression was defined as new onset of MR at visit 7, any increase in MR stage, or mitral valve surgery for MR between visit 5 and 7. LA function was measured using strain analysis and included reservoir, conduit, and contractile strain. Logistic regression models were used for the analysis. Results: After mean follow up of 6.5 ± 2.4 years, MR progression occurred in 504 (21%) participants. As shown in the table, lower reservoir strain was associated with higher odds of MR progression (OR [95% CI] per SD decrement, 1.16 [1.003, 1.34]) after adjusting for demographics, clinical risk factors, LA size and LV mass and function. LA conduit and contractile strain were not significantly associated with MR progression. Conclusion: Lower LA function is associated with higher odds of MR progression, independent of LA size, in individuals without AF. More research is needed to clarify the mechanism to identify novel prevention strategies for MR progression.