tbuckley/cabot-search huggingface dataset:
Abstract 4146970: Comparative Computational Modeling of Mitral Valve Translocation and Transcatheter Edge-to-Edge Repair in Secondary Mitral Regurgitation
Authors: Zachary Darby, James Gammie, Jiang Yao, Ifeanyi Chinedozi, Shawn Reginauld, Ashley Masterson, Hannah Rando, Jin Kook Kang, Jessica Briscoe, Tom Battisti, Rachael Quinn
Journal: Circulation (2024)

Introduction/Background: Secondary mitral valve regurgitation (SMR) results from left ventricular or left atrial remodeling. Conventional surgical repair with restrictive mitral annuloplasty has demonstrated poor durability in randomized trials. We have described a novel surgical approach, mitral valve translocation (MVT) in which a circumferential, frustum-shaped pericardial patch favorably improves the geometry of the mitral apparatus and abolishes MR. To gain a better understanding of MVT, we sought to compare it in a computational model of SMR vs Transcatheter edge-to-edge repair (TEER). Research Questions/Hypothesis: We sought to compare the effect of MVT to transcatheter edge to edge repair (TEER) on valvular function and hemodynamics using computational modeling. Methods: Using an adaptation of a 3D model developed from a patient specifc mitral valve apparatus model, simulations for TEER and MVT were conducted. Pre- and post-procedure hemodynamics including flow rates, pressures, and geometric measurements were extracted. Results/Data: Mitral valve (MV) pansystolic effective orifice area decreased by 72.6% for MVT and 66% for TEER (Table1), while MV minimal regurgitation area went from 25mm 2 in the native valve to 6mm 2 and 9mm 2 for MVT and TEER respectively. Left ventricular ejection fraction was reduced by 15.3% post-MVT and 11% post-TEER. Left atrial end-diastolic volume (EDV) decreased by 11.2% post-MVT and 8.8% post-TEER. Transmitral pressure gradient decreased by 16.7% post-MVT but increased by 600% post-TEER. Left ventricular (LV) diastolic pressure decreased by 17.0% for MVT, compared to a 51.7% reduction for TEER. LV systolic pressure increased by 14.4% post-MVT and 13.2% post-TEER. Systolic pulmonary arterial pressure rose by 3.9% post-MVT and 4.7% post-TEER Conclusion: Both MVT and TEER effectively improved cardiac function in SMR, with MVT showing greater benefits in certain hemodynamic parameters. Future research will focus on developing patient-specific models to optimize surgical outcomes and explore new repair strategies.
Abstract 4146910: Impact of Catheter Ablation on Atrial Fibrillation Outcomes in Various Cardiomyopathies: Findings from LGE-MRI Quantified Atrial Fibrosis Analysis
Authors: Ahmad Kassar, Nadia Chamoun, Yaacoub Chahine, Lee Bockus, Hala Al Yasiri, Tori Hensley, Nazem Akoum
Journal: Circulation (2024)

Background: Atrial fibrillation(AF) is the most prevalent arrhythmia in patients with cardiomyopathies(CMs) with and without left ventricular dysfunction. Catheter ablation is widely performed for rhythm control in these patients. Hypothesis: Patients with cardiomyopathies have an increased risk of AF recurrence after catheter ablation. Aims: Characterize the difference in AF recurrence following ablation in Hypertrophic(HCM), ischemic(ICM), and non-ischemic cardiomyopathy(NICM) patients. Characterize the degree and distribution of left atrial(LA) fibrosis among the various CM groups. Methods: Patients undergoing their first catheter ablation for AF were included, assessed for left atrial fibrosis using pre-ablation late-gadolinium enhancement cardiac magnetic imaging(LGE-MRI), and followed for AF recurrence after pulmonary vein isolation, excluding those with prior ablations. Results: A total of 552 patients: 39(7%) HCM, 39(7%) ICM, 115(21%) NICM, and 359(65%) patients without CM were analyzed. Patients with HCM were younger(63±14 years) than other CM subtypes(76.2±8.7 and 68.4±30.8;p&lt;0.001). There was a male predominance noticed across the different groups of cardiomyopathies, except for HCM patients, who had a higher percentage of females(41%vs15%vs22%;p&lt;0.001). Patients with any CM had more LA fibrosis and a higher left atrial volume index(LAVI) compared to patients with no CM(19.1±7.5%vs16.5±6.9%;p=0.01 and 44.9±12.1vs40.8±8.8;p&lt;0.001)respectively. HCM and ICM had higher LA fibrosis compared to NICM(21.3±8.7% and 21.9±9.1% respectively vs17.5±6.3;p=0.01). There was no significant difference in the regionality of fibrosis among the various groups. Multivariate analysis revealed that individuals with HCM had a three-fold increase in the risk of arrhythmia recurrence compared to individuals with no CM(HR=3.07,95%CI:2.06–4.58,p&lt;0.001). Left atrial fibrosis and LAVI were also independently associated with an increased risk of recurrence(HR=1.03,95% CI:1.01–1.06,p=0.01 and HR=1.02,95% CI:1.01–1.03,p=0.01) respectively. Conclusion: HCM had a higher arrhythmia recurrence risk than other CM types in AF patients undergoing catheter ablation, with overall fibrosis and volume predicting recurrence despite similar fibrosis patterns.
Abstract 4147276: Gender-specific characteristics and in-hospital outcomes of active smokers with STEMI: contemporary data from the FRENCHIE cohort.
Authors: Marianne Zeller, Claire Bouleti, Yves Cottin, Philippe Steg, Alexandra Rousseau, Soufiane Lebal, Frederic Chague, Guillaume Cayla, Denis Angoulvant, pierre coste, Jules Mesnier, Gilles Lemesle, Tabassome Simon, Nicolas Danchin
Journal: Circulation (2024)

Background: Although the number of women who smoke is growing among patients with ST-segment elevation myocardial infarction (STEMI), this population is poorly documented. Aim: Using a French nationwide MI cohort, we aimed to analyze gender-specific characteristics and hospital outcomes of active smokers hospitalized for acute STEMI. Methods: The French Cohort of Myocardial Infarction Evaluation (FRENCHIE) is a large ongoing AMI cohort, collecting data from all patients hospitalized for AMI within 48 h of symptom onset in 21 French centers. STEMI patients admitted from 2019 to 2022 were analyzed. Smoking status was self-declared. Past or never smokers were excluded from the analysis. Combined in-hospital events included death or ventricular fibrillation (VF). Results: Among the 9258 STEMI patients, 3761 (40.6%) were current smokers, of whom 702(18.7%) were women. Women were in average 4 years older than men (57.9 ± 11.0 vs 54.3 ± 10.0 y, p&lt;.0001), and had higher rates of cardiovascular (CV) risk factors including hypertension (p&lt;.0001), familial history of CAD (p=0.02), obesity (p=0.001), and co-morbidities such as respiratory failure (p=0.001) or systemic auto-immune diseases (p&lt;.0001). However, they were 3 times less likely to use illicit drugs (p&lt;.0001). The rate of peripheral artery disease was similar for both genders, while history of CAD was lower in women (8.5% vs 12.4%, p=0.004). Their left ventricular ejection fraction was higher (49.3 ± 10.6% vs 47.8 ± 10.7 %, p=0.002). Chest pain was the most prevalent symptom in both genders, but women more frequently exhibited atypical chest pain (12.5% vs. 7.5%, p&lt;.0001). Additionally, syncope was almost twice more common in women (6.4 vs. 3.6%, p=0.0007). Although the difference was not significant, there was a trend toward higher mortality or VF in women (5.6 vs. 4.3%, p=0.1671), which persisted after adjustment for confounding factors (OR(95%CI): 1.46 (0.94 ; 2.27), p=0.0940). Conclusion: Our contemporary findings in smokers with STEMI showed that women present with specific characteristics including an older age, an elevated burden of CV risk factors and more atypical chest pain or syncope. The rate of death or FV in women who smoke was higher than their male counterpart, although not reaching significance. FRENCHIE was supported in part by the RHU iVASC grant ANR-16-RHUS-00010 from the French National Research Agency (ANR) as part of the Investissements d’Avenir program.
Abstract 4147387: Outcomes of Heart Failure with Preserved Ejection Fraction with GLP1RA plus SGLT2i vs SGLT2i alone: A Propensity-Matched Nationwide Cohort Study
Authors: Talal Almas, Sadeer Al-Kindi, Absam Akbar, Amal Qureshi, Jaime Abraham Perez, Elleson Grace Harper, Saif Syed, Hosam Alazazzi, Claire Sullivan, Ian Neeland, Abhishek Deshmukh, Nandan Anavekar
Journal: Circulation (2024)

Introduction: Metabolic pharmacotherapies [Glucagon-like peptide-1 receptor agonists (GLP1RA) and sodium-glucose cotransporter type 2 inhibitors (SGLT2i)] have shown benefit in patients with heart failure and preserved ejection fraction (HFpEF). It remains unclear whether the two classes would have additive effects. Methods: We performed a retrospective study using a de-identified federated database with 89 contributing health care organizations (HCO), including over 126 million patients (TriNetX Research Network, Cambridge, MA; date of data access: May 23, 2024). TriNetX regularly aggregates clinical data directly from participating HCOs, and performs extensive data quality and accuracy assessment. While TriNetX obfuscates institutional information relating to participating HCOs, a typical HCO includes a large academic health center with inpatient, outpatient, and specialty care services. We identified all patients with a diagnosis of Heart failure with preserved ejection fraction (HFpEF, ICD-10: I50.3), and SGLT2i usage. We then categorized this patient population into two cohorts, including patients with concomitant GLP1RA use, and patients without GLP1RA use. For both cohorts, we collected data on patient demographics, and the outcomes of all-cause mortality, and all-cause hospitalization, occurring up to 10-years after the index diagnosis. We evaluated differences in outcome risk using hazards ratios and 95% confidence intervals. Results: Prior to propensity score matching, we identified 114,329 patients, with 7931 patients receiving SGLT2i +GLP1RA vs 106398 receiving SGLT2i-alone. Majority (55.7%) identified as white and 24.4% as African Americans and &gt;90% of the patients had a diagnosis of type 2 diabetes mellitus. After propensity matching, the rate of all-cause hospitalization within the combination group was lower than SGLT2i group (29.6% vs 32.4%, HR 0.76 [0.73- 0.79], P&lt;0.001). All-cause mortality for the combination group was 6.8% versus 10.6% within the SGLT2i-alone group (HR 0.52 [0.47-0.56], P&lt;0.001)). Conclusion: In this propensity-matched cohort, patients with HFpEF receiving GLP1RA and SGLT2i had lower rates of hospitalizations and all-cause mortality compared with those receiving SGLT2i alone. Large randomized controlled trials are warranted to corroborate these findings.
Abstract 4146982: A Rationally Designed Cardioprotective Nanoparticle to Treat Chemotherapy-Induced Cardiotoxicity
Authors: Zehedina Khatun, Andrew Kung, Asma Boukhalfa, Anna-Lee Thompson, Sydney Weng, Lan Wei, Lin Meng, Gregory Martin, Choukri Mekkaoui, Robert Blanton, James Baleja, Vicky Yang, Hushan Yuan, Howard Chen
Journal: Circulation (2024)

Introduction: Chemotherapy-induced cardiotoxicity is a growing clinical challenge lacking effective FDA-approved interventions to delay the onset of heart failure. Lysosomal dysfunction is a hallmark of a myriad of cardiovascular diseases, including doxorubicin (Dox)-induced cardiotoxicity. We hypothesize that maintaining cardiomyocyte (CM) lysosomal pH can mitigate Dox-induced cardiac dysfunction and presents a viable cardioprotective strategy for translation. Methods: FDA-approved PLGA polymer composed of lactic and glycolic acids was chosen to modulate lysosomal pH due to biosafety and ease of chemical modifications. PLGA was covalently labeled with near-infrared fluorescent peptides to enhance cellular uptake and facilitate tracking in vivo. PLGA was formulated into nanoparticles of 100 nm and characterized by electron microscopy, NMR and absorbance spectroscopy. In H9C2 rat CMs co-treated with 5 μM of Dox +/- 1 mg/ml of PLGA, we measured PLGA uptake by FACS, cell viability by MTT, lysosomal pH by OG-514, and autophagy by western blot. PLGA’s impact on breast cancer cell viability was measured by MTT. In C57Bl/6 wildtype mice challenged with Dox (15 mg/kg, i.p.) +/- co-injection of PLGA (10 mg/kg, i.v.), myocardial PLGA uptake at 4 hours and apoptosis (by Annexin V) at 24 hours were assessed by direct imaging. Echocardiography to assess cardiac function was performed in a separate cohort of mice injected with weekly Dox (4 mg/kg, i.p.) +/- PLGA (10 mg/kg, i.v.). Moreover, PLGA biocompatibility was evaluated in 3 healthy beagle dogs by echocardiography and blood chemistry. Results: In Dox-treated murine CMs, PLGA significantly improved survival by restoring lysosomal acidity and autophagy, a key homeostatic process. No protective effect was observed with non-acidifying control polymer. PLGA also did not alter viability in human breast cancer cells (MCF7, MDA-MB-231) treated with Dox. When injected in mice, PLGA fully permeated the myocardium within 4 hours, significantly reduced Dox-induced apoptosis by 24 hours, and significantly improved cardiac function 4 weeks after Dox injection. In healthy canines, PLGA can be safely administered, supporting further clinical trials. Conclusions: PLGA represents a novel class of translatable cardioprotective therapeutic that acidifies lysosomes, restores autophagy, mitigates CM apoptosis, and enhances cardiac function. PLGA holds translational potential to mitigate lysosomal dysfunction and treat cardiovascular disease.
Abstract 4147865: Single Nucleus Transcriptomics Supports a Role for CCNA2-Induced Human Adult Cardiomyocyte Cytokinesis
Authors: Esmaa BOUHAMIDA, Sangeetha Vadakke-Madathil, Prabhu Mathiyalangan, Amaresh Ranjan, Cherrie Sherman, Paul Miller, Andre Ghetti, Najah Abi, Hina Chaudhry
Journal: Circulation (2024)

Background: Cyclin A2 (CCNA2) is a hallmark cell cycle regulator typically silenced in postnatal mammalian cardiomyocytes (CMs). We previously demonstrated successful myocardial regeneration in infarcted porcine hearts, showing a 55% increase in new CMs and significantly enhanced cardiac function following CCNA2 gene therapy. Hypothesis: We hypothesize that CCNA2 gene delivery can induce cytokinesis in isolated adult human CMs. Methods and Results: We designed a human gene therapy vector featuring a replication-deficient, E1/E3-deleted human adenovirus five encoding human CCNA2 driven by the cardiac Troponin T promoter (Ad5-cTnT-hCCNA2, vector lacking CCN2 control). We utilized time-lapse microscopic live imaging of cultured adult human CMs isolated from a 55-year-old male, 41-year-old female, and 21-year-old male. We quantified cytokinesis events in human adult CMs compared to controls and observed a significant increase in cytokinesis rate in the aging heart, particularly in the 55-year-old male (17.52 + 1.72 vs. 8.33 + 2.25, p=0.003) and the 41-year-old female (9.27 + 2.22 vs. 2.5 + 1.16, p=0.005). No significant difference was observed in the 21-year-old male (3.63 + 1.77 vs. 3.00 + 1.52, p=0.789). We measured the calcium flux in transfected CMs compared to controls after cell division under pacing conditions (0.5 Hz and 1 Hz current) and detected sarcomere structures using fluorescence microscopy. Approximately 4-5% of Ad5-cTnT-hCCNA2 transfected adult human CMs exhibited active Ca 2+ mobilization. We now report that CCNA2 can induce complete cytokinesis in in adult human CMs, preservation of sarcomere integrity in the resultant daughter cells.To understand further CCNA2 signaling pathways involved in CM cytokinesis, we conducted single nucleus transcriptomics analysis in hearts isolated from adult transgenic mice that constitutively express CCNA2 in CM (Tg) and non-transgenic mice (nTg). We identified a subpopulation of CMs enriched with cytokinesis ( Aurkb, Anln, Sept7, and Rho ), proliferative ( Mki67 and Kif23 ), and reprogramming ( Pou5f1, Klf4, Gata4, Myc, and Sox2 ) genes in Tg mice compared to nTg mice. Bulk RNA sequencing of human adult and fetal hearts unveiled key reprogramming genes involved in CCNA2-induced cytokinesis. Conclusion: Our findings highlight promising mechanisms for the clinical development of cardiac regenerative therapy through strategic manipulation of the CM cell cycle.
Abstract 4146686: Carvedilol Exerts Evolutionarily Conserved Cardioprotective Effects via Autophagy Modulation and Energetics Restoration
Authors: Asma Boukhalfa, PEI-TSZ SHIN, Dawn Meola, Annie Showers, Ada Yu, Jenica Upshaw, Cheryl London, Iris Jaffe, Lakshmi Pulakat, Vicky Yang, Howard Chen
Journal: Circulation (2024)

Carvedilol (CAR) is an FDA-approved adrenergic blocker commonly given to cardiovascular disease patients. Interestingly, CAR also shows anti-cancer potential in reducing cancer-specific mortality in breast cancer patients. To advance CAR usage in cardio-oncology, we hypothesize that elucidating the molecular mechanism of the energy sensing and homeostasis pathways underlying CAR’s cardioprotective capabilities can enhance its clinical translation. Canine cardiac slices were generated from 3 euthanized pet dogs free of cardiovascular disease. CAR pretreatment (1μM, 4 hrs) with or without a 24-hr exposure to 5μM of cardiotoxic doxorubicin (DOX) was performed. Murine slices from 5 C57Bl6 mice with the same treatments as above was also performed. Direct tissue imaging on IVIS Spectrum was carried out to assess apoptosis by Annexin V staining, autophagy with autophagy detecting nanoparticle (ADN) developed in-house, and DOX retention in tissue by the inherent DOX fluorescence. Tissue was analyzed by histological staining of apoptosis and Western blot of autophagy and energy sensing pathways. Energetics quantified by Seahorse assay was performed in isolated mitochondria from cardiac slices in rat cardiomyoblasts (H9C2 cells) and human iPSC-induced cardiomyocytes (iCells). In both canine and murine cardiac slices, autophagy was significantly reduced (p&lt;0.05) by DOX while apoptosis was significantly increased (p&lt;0.05), both of which were reversed by CAR. CAR did not change DOX fluorescence in tissue. Western blot of autophagy biomarkers LC3, p62 and Beclin-1 confirmed that autophagy impaired by DOX was restored by CAR. The beneficial autophagy restoration by CAR was modulated by a significantly increased phosphorylation of AMP kinase (AMPK), a key energy sensing pathway that activates autophagy via significantly reducing mTOR (p&lt;0.0001). In mitochondria isolated from cardiac slices, basal respiration and ATP production that were significantly impaired by DOX were rescued (p&lt;0.0001) by CAR. Similar rescue of basal respiration and ATP production by CAR was seen in murine and human cardiomyocytes, suggesting that CAR exerts a direct protective effect on the at-risk cardiomyocytes during DOX stress. We demonstrated for the first time in human, canine, and murine that CAR targets the AMPK pathway to activate autophagy, reduce cardiomyocyte apoptosis, and restore mitochondrial energetics, thus with immense translational potential in cardioprotection.
Abstract 4146856: Aberrant Regulation of endMT in Turner Syndrome: Implications for the Pathogenesis of Congenital Cardiovascular Disease
Authors: Eric Ivan Garcia Huitron, Xiaoying Zhang, Lance Babcock, Kathryn Grande-Allen, Siddharth Prakash
Journal: Circulation (2024)

Introduction: Turner syndrome (TS) is caused by the partial or complete absence of one sex chromosome and affects 1 in 2500 liveborn infants. Hypertension, bicuspid aortic valve, and thoracic aortic aneurysms are more prevalent in TS compared to the general population. We hypothesize that persistent abnormalities of endothelial-mesenchymal transition (endMT) in the embryo and adult mediated in part by abnormal responses to shear stress predispose to cardiovascular disease in TS. The objective of this study was to define functional and transcriptomic differences between euploid 46,XX and aneuploid 45,X induced pluripotent stem cell (iPSC)-derived endothelial cells (ECs) from adult donors with mosaic TS. Methods: iPSCs were reprogrammed from peripheral blood mononuclear cells. Individual colonies were genotyped to identify isogenic euploid and aneuploid iPSC subclones, which were differentiated into ECs using standard methods. After selection for CD31 expression, baseline EC properties and response of EC monolayers to shear stress using a cone and plate viscometer system were characterized using fluorescence microscopy, qPCR, RNA sequencing, and functional assays. Results: We generated 45,X, 46,X,iso(X)(q10) [iso], and 46,XX iPSCs from one mosaic donor. After confirming genomic integrity and pluripotency, we successfully differentiated multiple iPSC subclones of each karyotype into ECs. EC morphology, tube formation, and uptake of DiI-conjugated acetylated low-density lipoproteins were not significantly different between subclones, although 45,X ECs proliferated more slowly than 46,XX or iso ECs. Collagen gel contraction and migration by 45,X ECs was significantly higher than 46,XX or iso ECs at baseline and in response to exogenous TGF-β peptide. Comparative RNAseq and qRT-PCR analysis of 45,X and 46,XX ECs showed that VCAM1 , SNAI1 , ACTA2, TWIST1 , and other endMT-associated genes were significantly upregulated at baseline in 45,X ECs and were only partially suppressed by shear stress, while expression of CDH2 was decreased in 45,X ECs. We also observed that 45,X ECs but not 46,XX or iso ECs underwent spontaneous endMT in static culture conditions. Conclusion: Despite similar baseline EC phenotypes, the threshold for endMT activation appears to be lower in 45,X ECs compared to 46,XX or iso ECs. Dysregulation of endMT, possibly due to chronic derepression of SNAI1 expression, may contribute to congenital cardiovascular disease in TS.
Abstract 4147345: Sex differences in cardiac allograft rejection states using Tissue gene-expression profiling (MMDx)
Authors: Andrea Fernandez Valledor, Cathrine Moeller, Daniel Oren, Salwa Rahman, Julia Baranowska, dor lotan, Afsana Rahman, Boaz Elad, Ersilia DeFilippis, Matthew Regan, Adil Yunis, Ruben Salazar, Carolyn Hennecken, Justin Fried, Jayant Raikhelkar, Kevin Clerkin, Farhana Latif, Gabriel Sayer, Nir Uriel
Journal: Circulation (2024)

Introduction: Limited knowledge exists regarding the influence of sex on rejection-related gene-expression profiling using the Molecular Microscope (MMDx). Methods: We prospectively included all heart transplant recipients who underwent endomyocardial biopsy for clinical indication from November 2022 to May 2024 at New York Presbyterian. During the biopsy procedure, four samples were sent for histologic evaluation, and two for molecular analysis. Donor-derived cell-free DNA levels (dd-cfDNA%), peripheral gene-expression profiling (pGEP) scores, MMDx rejection scores, and rejection rates on histology and MMDx were compared based on sex. Results: A total of 414 samples were included, 130 (31.4%) were from female recipients. dd-cfDNA levels were higher in females compared to male recipients ( 0.30% [0.15-0.80] vs. 0.22% [0.11-0.45]; p=0.02). Despite similar rates of pGEP scores (32 [28-34] vs. 32 [29-35]; p=0.70) or pGEP positivity (14.6% vs 17.0%; p=0.18), there was a trend towards a higher prevalence of donor-specific antibodies in female recipients (51.5% vs. 44.4%; p=0.20). Overall, rejection rates on MMDx (30.8% vs. 19.1%; p=0.01) and MMDx rejection scores ( 0.40 [0.17-0.63] vs. 0.27 [0.11-0.55]; p=0.005) were higher in female recipients ( Figure 1 ), primarily due to increased rates of antibody-mediated rejection ( ABMR ) diagnosis in this group ( 21.5% vs. 10.8% ; p=0.003). No differences in rejection rates were noted when assessed by histology (6.9% vs 8.0%; p=0.37). Conclusion: In a cohort of heart transplant recipients biopsied due to suspected rejection, female recipients were associated with increased MMDX-rejection scores and higher rejection rates, primarily driven by a twofold higher frequency of ABMR detection by MMDx compared to males.