tbuckley/cabot-search huggingface dataset:
Abstract 15440: Efficacy of Statins in Counteracting Anthracyclines and/or Trastazumab-Induced Cardiotoxicity: A Systematic Review and Meta-Analysis With Trial Sequential Analysis
Authors: Youssef Soliman, Adel Mouffokes, Basma E Amer, Nada Ibrahim Hendi, Alaa Ramadan, Ahmed M Abozaid, John Magdy Daniel, noha yasen, Ahmed Nasr, Hatem Hassaballa
Journal: Circulation (2023)

Aim: Statins have been suggested as potential agents for mitigating chemotherapy-induced cardiotoxicity, particularly in the context of anthracyclines and/or trastuzumab treatment. However, conflicting findings have emerged from randomized controlled trials (RCTs) and observational studies. Therefore, the primary objective of this study is to comprehensively investigate the effectiveness of statins in ameliorating chemotherapy-induced cardiotoxicity in the case of anthracyclines and/or trastuzumab. Methods: We conducted a systematic search in major databases, including PubMed, Scopus, Web of Science, and Cochrane, up to May 10, 2023. Our main outcomes were the risk ratio (RR) of cardiotoxicity and the mean difference (MD) in left ventricular ejection fraction (LVEF%). We performed Trial Sequential Analysis (TSA). Results: A total of 9 studies (6 observational and 3 RCTs) were included. Although the pooled results from all studies favored statins in the incidence of cardiotoxicity (RR 0.54, 95% CI [0.37, 0.79]), evidence from RCTs only (n = 2) did not indicate any significant change in risk (RR 0.50, 95% CI [0.17, 1.45]). Similarly, while the overall change in LVEF% was significant when pooling all studies (MD 4.38, 95% CI [0.41, 8.35]), RCTs only (n = 3) showed no significant change (MD 3.94, 95% CI [-1.07, 8.96]). The TSA curve for RCTs evaluating LVEF% did not cross the conventional boundary for statistical significance, indicating that the cumulative evidence did not reach the predefined level of statistical significance threshold, with no strong evidence to establish a statistically significant relationship. Conclusion: The effectiveness of statins in mitigating chemotherapy-induced cardiotoxicity remains inconclusive, and the current evidence from randomized controlled trials does not demonstrate significant associations. Further research is necessary to clarify the role of statins in chemotherapy-induced cardiotoxicity.
Abstract 17077: Pulmonary Artery Compliance: Resistance is (Not?) Futile
Authors: Jacqueline T DesJardin, Matthew J Broerman, Melissa Saul, Mehdi Nouraie, Marc A Simon
Journal: Circulation (2023)

Introduction: Small studies have suggested that low pulmonary artery compliance (PAC) — quantified by dividing stroke volume by the pulmonary artery pulse pressure — is an early indicator of pulmonary hypertension (PH). However, the relationship between PAC and mortality, and the clinical utility of PAC in all-comers remains in question. Research Questions: How does the risk of mortality in all-comers change with PAC? Does the PAC provide prognostic information over established hemodynamics (i.e., pulmonary vascular resistance [PVR], mean pulmonary artery pressure [mPAP])? Methods: Analysis was conducted on adult patients undergoing right heart catheterization at the University of Pittsburgh Medical Center Presbyterian Hospital 2005 - 2020, excluding those with prior heart/lung transplant, ventricular assist devices, and missing/non-physiologic hemodynamics. A cubic spline model was constructed to describe the relationship between PAC and the predicted risk of death. Multivariable Cox models for mortality were compared by plotting the distribution of 100 Harrell’s Concordance indices derived from Monte Carlo cross-validation. The fully-adjusted model was compared to models with one variable removed, thereby assessing the relative contribution of the withdrawn variable to model performance. Results: The cohort included 12,948 patients (median age 64, 55% male, 84% White); 29% had combined post- and pre-capillary PH, 24% pre-capillary PH, and 17% isolated post-capillary PH. The predicted risk of mortality 1) increased linearly as PAC decreased below 3 mL/mmHg, 2) tapered for PACs between 3 - 5 mL/mmHg, and 3) remained constant at PACs above 5 mL/mmHg (Figure 1). Removal of PAC from Cox models predicting mortality did not substantially affect model performance (Figure 2). Conclusions: A PAC below 5 mL/mmHg, and especially below 3 mL/mmHg, is associated with increased mortality; however, PAC does not improve prognostic information over the mPAP and PVR.
Abstract 14872: A Nationwide Telehealth Heart Failure Program: Can Remote Patient Monitoring and Guideline Directed Treatment Protocols Benefit HFpEF Management?
Authors: David I Feldman, Dmitri Repnikov, Marcus L Campbell, Sarine Babikian, Diana Sanchez, Ashwyn Sharma, Randall Curnow, Theodore Feldman, Marat Fudim
Journal: Circulation (2023)

Introduction: Heart failure (HF) patients experience unnecessary morbidity and mortality due to inadequate use and dose of GDMT. While RPM has proven to help HFrEF patients achieve higher rates of GDMT, its value in optimizing comorbidities and GDMT in HFpEF patients is less clear. Hypothesis: A team of multi-disciplinary HF clinicians can leverage RPM and guideline directed treatment protocols to bridge the gaps in HFpEF management. Methods: Cadence enrolled Medicare patients with HFpEF across 11 states into a virtual HF program from December 2021 to April 2023. Eligible patients had either an ICD-10 code for diastolic HF, diastolic dysfunction on TTE, or an EF&gt;50% and a prior HFH or active treatment for HF by their clinician. Patients were given a cellular enabled BP cuff and weight scale to measure vitals. Coupling a technology enabled vitals and symptoms tracker with a guideline directed clinical protocol algorithm, symptom, vital and medication optimization was achieved. Results: Two-hundred fifteen patients (mean (SD) values: age 76 (9); white 64%, women 49%; BP 141/79 (9/6) mmHg; EF 60% (0.1)) were followed for a mean of 223 (82) days. Comorbidities, including DM (41%), AF (53%) and HTN (92%), were highly prevalent. There was a statistically significant reduction in BP and weight, but not heart rate (BP: -11/6 mmHg, Wt -4 lbs; p&lt;0.001). Patient engagement information, including number of vitals recorded, clinical visits and phone calls completed, and high acuity clinical alerts resolved, is depicted in Figure 1A. There was a 286% and 71% increase in percentage of patients on a SGLT2i and MRA, respectively, at follow-up compared to baseline (SGLT2i: 15 (7%) vs. 44 (20%); p&lt;0.001, MRA: 30 (14%) vs. 50 (24%); p&lt;0.05). Additional changes in use and dose of GDMT are shown in Figure 1B. Conclusion: A telehealth HF program that utilizes RPM and technology enabled treatment protocols can meaningfully improve HF-specific vitals and rates of GDMT in patients with HFpEF.
Abstract 14113: Impact of Clinician Telemedicine Use on Diagnostic Testing for Heart Failure Patients
Authors: Mugdha Joshi, Harrison Koos, Alexander T Sandhu, David Scheinker, Fatima Rodriguez, Neil M Kalwani
Journal: Circulation (2023)

Introduction: Previous studies have reported decreased diagnostic testing with telemedicine visits early in the COVID-19 pandemic. The effect of telemedicine use on diagnostic testing for a panel of heart failure (HF) patients is unknown. We sought to use clinician-level variation in telemedicine use over time to determine the association of telemedicine care delivery with changes in diagnostic testing for HF patients. Methods: Patients with HF diagnostic codes seen at an academic cardiovascular center from May 2019 to Nov 2022 were included. Clinicians performing the majority of cardiology visits for at least 10 HF patients were identified. Early pandemic visits (March 2020-May 2020) were excluded. The remaining time was divided into 4 10-month periods with the first ending before the pandemic. We used a linear regression model with clinician and period fixed effects to estimate the association of the fraction of a clinician’s visits delivered by telemedicine in each period with the number of orders for Holter monitors, EKGs, transthoracic echocardiograms (TTEs), and laboratory tests per visit. Results: There were 6,420 patients seen by 45 clinicians. Clinician telemedicine fraction across periods ranged from 0 to 100 percent. Mean telemedicine fraction decreased from 55.4% to 34.6% from periods 2 to 4. A 25-percentage point increase in telemedicine use was associated with significantly fewer orders for EKGs (-0.078 orders/visit) and TTEs (-0.021 orders/visit), representing decreases of 33% and 13% relative to period 1 respectively. Higher telemedicine use was associated with non-significant decreases in orders for Holter monitors and laboratory tests (Table). Conclusions: Greater clinician telemedicine use was associated with decreased diagnostic testing orders per visit for HF patients. Further research is needed to characterize the value of these potentially avoided tests and understand the impact of telemedicine on the quality of care for HF patients.
Abstract 14417: Regional 4D Cardiac Magnetic Resonance Strain Associates With Late Gadolinium Enhancement in Duchenne Muscular Dystrophy Associated Cardiomyopathy
Authors: Conner C Earl, Larry W Markham, Jonathan H Soslow, Craig J Goergen
Journal: Circulation (2023)

Introduction: Cardiomyopathy (CM) is the leading cause of death in Duchenne muscular dystrophy (DMD). Onset and clinical progression are varied. Cardiac magnetic resonance (CMR) late gadolinium enhancement (LGE) can detect fibrofatty replacement prior to decreased left ventricular ejection fraction (LVEF) but requires administration of gadolinium contrast agents. Non-contrast methods to characterize CM onset and progression could decrease scan time and exposure to gadolinium. Using a novel 4D (3D+time) regional strain analysis method, we hypothesized that the regional magnitude of surface area strain (E a ) would be significantly decreased in DMD patients with LGE and that E a would correlate with decreased LVEF . Methods: Short-axis cine CMR images for 43 pediatric DMD patients (13.6 ± 4.2 years) were compiled into 4D sequences for regional strain analysis (Fig. 1A). For all 4D sequences, epi- and endocardial borders were segmented across one cardiac cycle for kinematic analysis using a custom-built MATLAB graphical user interface (MathWorks, Natick, MA). Regional E a was measured by determining the relative change in the localized 4D endocardial surface mesh compared to end-diastole. Unpaired t-test and Spearman’s rho were used to determine statistical significance and correlation. Results: DMD patients had a range of CM severity: 13 with reduced LVEF of &lt;55% (30% of total) and 28 with LGE (65% of total). Peak E a was significantly different between patients with and without LGE in the basal inferior ( p =0.022), basal inferolateral ( p &lt;0.001), basal anterolateral ( p =0.002), mid inferolateral ( p =0.004), mid anterolateral ( p =0.018), and apical anterior ( p &lt;0.032), regions (Fig.1B). Basal E a also correlated significantly with LVEF ( rho =-0.45, p&lt; 0.001; Fig. 1C). Conclusion: Regional E a from 4D CMR in DMD was reduced in patients with LGE compared to those without LGE particularly in the basolateral regions. Peak basal E a correlated with a reduction in LVEF. LVEF.
Abstract 17705: BAG5 Plays a Critical Role in the Regulation of Cellular Oxidative Stress and Heart Function
Authors: Manish K Gupta, Pierce Ciccone, Avni Mukker, Kim Hong, Yuka Kimura, Isabela Beatriz de Lima
Journal: Circulation (2023)

Introduction: Molecular chaperone and co-chaperone play important roles in maintaining cardiac function by regulating cellular proteostasis and reducing oxidative stress during hypertrophy. Bcl2 binding proteinBAG5 belongs to Bcl-2 associated anthanogene (BAG) family and acts as a co-chaperone to HSP70. Genetic mutation of BAG5 induces dilated cardiomyopathy and arrhythmia. However, the molecular mechanism of BAG5 in heart function is unclear. In this study, we explore the regulatory role of BAG5 in heart function. Hypothesis: We hypothesized that BAG5 is an important Co-chaperone of cardiomyocytes and regulates heart function through the regulation of cellular proteostasis and oxidative stress. Method: We have generated adenovirus to overexpress and knockdown the BAG5 protein in cardiomyocytes. Additionally, we have generated BAG5 knockout mice to test the effect of BAG5 deficiency on cardiac function. Further, we have conducted a proteomics study to explore the role of BAG5 in heart function. Additionally, we tested the role of BAG5 in isoproterenol-induced cardiac hypertrophy. Results: Our results show that deficiency of BAG5 induces cellular hypertrophy and induction of cellular autophagy. Cardiac function analysis by echocardiography shows that the knockdown of BAG5 compromises heart function. Further, a protein interaction study shows that BAG5 participates in several critical heart signaling, including mitochondrial oxphos and glutathione-mediated regulation of oxidative stress. Additionally, we found that the knockdown of BAG5 worsens heart function during isoproterenol treatment. Conclusion: Our study shows a novel function of BAG5 and BAG5 can be exploited in treating cardiac hypertrophy and reducing oxidative stress.
Abstract 16778: Design of a Pan Heart Failure Gene Therapy by Targeting Telomere-p53 Axis
Authors: Yinlong Zhao, Xiaolu Bao, Weiyao Xiong, Yangyang Liu, Euan A Ashley, Wei Han, Alex C Chang
Journal: Circulation (2023)

Introduction: Cardiovascular disease and heart failure is among the top causes of morbidity and mortality worldwide with a critical need for innovative therapies to reverse the course of ventricular dysfunction. We established that heart failure cardiomyocytes exhibit telomere uncapping and shortening, which leads to DNA damage p53 activation and inhibition of mitochondrial biogenesis. Hypothesis: We hypothesize that reprotection of telomeric ends can prevent p53-induced mitochondrial dysfunction and restore cardiac function. Methods: We designed a pan-HF gene therapy (AAV9-modhTERT) - that acts through telomeric reprotection to turn off p53 and restore myocardial mitochondrial biogenesis - and validate safety and efficacy in Ang II and TAC heart failure murine models. Cardiac specificity in human induced pluripotent stem cell derived cardiomyocytes, biodistribution in mice, and dose titration studies on Ang II and TAC mice were performed. Results: One dose of AAV9-modhTERT sufficiently improved ejection fraction by ~20%, prevented cardiac fibrosis and expression of HF biomarkers. Molecularly, AAV9-modTERT blocked DNA damage activation, reversed mitochondrial biogenesis, restored mitochondrial ultrastructure and respiration, and reversed transcriptomic profiles. Conclusions: These preclinical studies demonstrate considerable potential for the first pan-HF single-dose gene therapy that can reverse cardiac function and prevent myocardial remodeling which would be invaluable clinically and an Investigator Initiated Trial (IIT) (NCT05837143) was launched in April 2023.
Abstract 15271: Modification of Cardiomyocyte Lateral Membrane Composition Promotes Cardiac Function by Regulating Connexome Organization
Authors: Camille BLANDIN, Gilles Dilanian, Nathalie MOUGENOT, Solenne CHARDONNET, Stéphane N HATEM, Basile jules Gravez, Vincent FONTAINE, Pierre BOBIN, Eric VILLARD, Elise BALSE
Journal: Circulation (2023)

Introduction: Loss of contacts between adjacent cardiomyocytes is detrimental to proper electromechanical function. For instance, connexome remodeling is a common feature of both acquired and inherited cardiac arrhythmias. We have shown that the lateral membrane-specific scaffolding protein CASK regulates the trafficking and targeting of certain connexome components, notably the sodium channel. Question: Does compartmentalization of the cardiomyocyte membrane involves lateral membrane proteins? Our hypothesis is that CASK, due to its association with costamere and its developmental expression gradient, may be involved in a more global control of connexome organization. Aims: To demonstrate that CASK, a lateral membrane-specific protein, is crucial for the development and maintenance of connexome integrity. Method: Viral constructs were designed to inhibit the expression of CASK in vivo (AAV-shCASK) and in vitro (Ad-shCASK) both in murine and human cardiomyocytes. Results: In vivo, echocardiography phenotyping of CASK invalidated rats at the neonatal stage revealed, at the adult stage, eccentric ventricular remodeling associated with increased stroke volume and increased cardiac output suggestive of athlete’s heart phenotype. Hemodynamic measurements (pressure-volume loops) confirmed that CASK invalidation increases both myocardium contractility and compliance. Proteomic analysis showed that CASK invalidation in vitro strongly modify immature cardiomyocyte proteome, notably junction signaling. Immunostaining experiments on cultured neonatal rat cardiomyocytes and adult rat hearts confirmed that CASK is required for the correct organization of myofibrils and favors connexome organization. Remarkably, CASK invalidation in a human in vitro model of arrhythmogenic cardiomyopathy (hiPSC-CM PKP2 +/- ) rescues desmosome assembly. Conclusion: CASK regulates the organization of myofibrils and connexome, with major functional consequences for cardiac performance. Our results suggest for the first time the existence of a crosstalk between lateral membrane and connexome proteins. Therefore, targeting CASK to promote electromechanical coupling of cardiomyocytes could be promising in the context of cardiac remodeling.
Abstract 13454: Safe Large Bore Access via the Third Part of the Axillary Artery for Mechanical Circulatory Support Implantation
Authors: Swaiman Singh, ARDAAS S KANWAR, Hilda M Gonzalez Bonilla, Skylar Rizzo, Andrew Rosenbaum, Robert Frantz, Atta Behfar
Journal: Circulation (2023)

For patients in cardiogenic shock, percutaneous mechanical circulatory support devices (MCSD) have emerged as critical tool to improve hemodynamics and optimize end-organ perfusion; successfully bridging patients to recovery, decision or transplantation. The most commonly utilized MCSD is the femoral intra-aortic balloon pump (IABP). However, femoral access hampers the patient's mobility, quality of life, and capacity to participate in rehabilitation. The advent of the axillary artery approach has served to circumvent limitations associated with the femoral artery approach. However, optimum anatomical placement of IABP within the axillary artery (axIABP) is a topic of debate considering its proximity to the brachial plexus. Here, we report our experince with percutaneous access of the third poriton of the axillary artery which showed promising results with minimal device related complications or adverse events. Methods/Results: Between 2017-2023, a total of 89 patients in cardiogenic shock underwent percutaneous axIABP placement at the Mayo Clinic, MN. All demographic, clinical, and periprocedural data were obtained from hospital chart review and recorded in a database under IRB approval. Indications for axIABP support was determined by multidisciplinary assessment. Complications encountered in the cohort included infection at site 6.7% (n=6), device malfunction [rupture, fracture, leak] 8.98%(n=8), and balloon migration 5.61% (n=5). One patient developed local erythema, 4 (4.49%) patients developed significant vascular complications, including access site bleeding in two patients 2.24%, arterial thrombosis in three patients 3.37%, and self-limited intracranial bleeding in one patient 1.12%. Of note, no nerve injury or damage was observed in the entire patient cohort. Conclusion: Our study highlights the feasibility of percutaneous axIABP in the third portion of the axillary artery, while assessing safety profile and ease of removal. Notably in our review, we did not encounter any brachial nerve damage. Ultrasound was pivotal in identifying and avoiding nerves and nerve bundles during initial access. In conclusion, this approach of axIABP insertion is feasible and can be leveraged for delivery of future innovation in MCSD
Abstract 19018: Unraveling the Regulatory Landscape of NKX2-5 in Human Left Atrial Tissue: Implications for Atrial Fibrillation
Authors: YUEQIN YANG, Natalia S Torres, Scott Cho, Hongchao Guo, Martin Tristani-Firouzi
Journal: Circulation (2023)

Cardiac transcription factors are emerging as crucial modulators of atrial fibrillation (AF), with rare and common variation implicated in AF. Mutations in NKX2-5 and more recently, NFATC1 were reported in families with autosomal dominant young-onset AF. Here, we explore the landscape of NKX2-5 and NFATC1 in human left atrium, using Chromatin Immunoprecipitation Sequencing (ChIP-seq), DAVID functional annotation and HOMER motif analyses. Post-mortem human left atrial tissue samples (n=5) were obtained from the National Disease Research Interchange (NDRI) within a recovery interval of &lt; 4 hours. Preserved microstructural integrity and normal staining patters for TNNT2 and vimentin were verified using confocal microscopy. ChIP-seq analysis revealed an average of 2.62k NKX2-5 binding peaks, with 118 genes bound in all samples. Functional analysis identified significant enrichment in gene ontology categories and pathways (Table 1), including adrenergic and PPAR signaling pathways known to participate in AF susceptibility. Using HOMER, we mapped 55 NFATC1 consensus binding sites to the NKX2-5 ChIP peaks. Two NFATC1 consensus sites localized to an NKX2-5 binding peak located upstream from MEF2A (Figure 1). Published HI-C data from human right atrium indicates the NFATC1 binding sites are adjacent to the promoter of MEF2A in 3D space, suggesting that NKX2-5 and NFATC1 co-regulate MEF2A. In murine atria, mef2A regulates genes involved in fibrosis and adhesion, processes that are crucial in the pathogenesis of atrial fibrillation. Our data, together with published literature, provide a framework for understanding transcriptional networks that may predispose to human AF.