tbuckley/cabot-search huggingface dataset:
Abstract 4139216: The tolerability, safety, pharmacokinetics, and pharmacodynamics of TX000045, a long-acting Fc-relaxin fusion protein after single doses in healthy volunteers
Authors: Marcella Ruddy, Mary West, Mark Milton, Anthony Muslin
Journal: Circulation (2024)

Introduction: TX000045 (TX45) is a long-acting Fc-relaxin fusion protein with vasodilatory, anti-fibrotic and anti-inflammatory activity due to selective agonism of the G protein-coupled relaxin family peptide receptor 1 (RXFP1). It is being developed for Group 2 pulmonary hypertension associated with heart failure with preserved ejection fraction (HFpEF). This first-in-human study evaluated the safety/tolerability, pharmacokinetic and pharmacodynamic profile of TX45 in healthy volunteers after single doses. Methods: This phase 1a, randomized, double-blind, placebo-controlled single ascending dose study was performed in seven cohorts of healthy volunteers. Six cohorts consisted of eight patients receiving intravenously (IV) or subcutaneously (SC) one of several doses of TX45 (n=6 on treatment) or placebo (n=2), including 0.3 mg/kg IV, 1 mg/kg IV, 3 mg/kg IV, 150 mg SC (x2 cohorts), and 300 mg SC. One cohort consisted of seven patients receiving 600 mg SC TX45 (n=5 patients) or placebo (n=2 patients). The goals of the study were to assess the tolerability and safety, immunogenicity, pharmacokinetic (PK) and pharmacodynamic (PD = renal plasma flow, RPF) properties of TX45 in healthy volunteers after single doses. RPF was determined by analysis of steady-state para-aminohippurate (PAH) blood levels in response to a PAH IV infusion. Results: 55 healthy volunteers were randomized. TX45 was well tolerated. Most adverse events were mild to moderate in intensity. The most common treatment emergent adverse event was transient orthostatic tachycardia, not associated with hypotension. TX45 demonstrated linear pharmacokinetics across the dose range with a terminal half-life estimated to be 13-23 days. Treatment with TX45, across dose levels, increased renal plasma flow by 16-42%, consistent with known relaxin effects. Leveraging repeated measures of renal plasma flow post dose, TX45 demonstrated prolonged maintenance of a pharmacodynamic effect. There was no evidence of immune mediated clearance of TX45. Conclusions: TX45 was generally well tolerated with a safety, pharmacokinetic and pharmacodynamic profile to support further clinical development. Its maximum effect on RPF is similar to previously described effects of native relaxin. Its half-life will support a prolonged dosing interval. These findings support further evaluation of TX45 in patients with Group 2 pulmonary hypertension associated with HFpEF.
Abstract 4139251: Right Atrial and Ventricular Strain Analysis in Patients with Carcinoid Heart Disease
Authors: Mohamad Saleh Alabdaljabar, Francisco Alexandrino, Nader Al-Shakarchi, Hilal Olgun, James Lloyd, Sushil Luis, Sorin Pislaru, Patricia Pellikka, Heidi Connolly
Journal: Circulation (2024)

Background: Carcinoid heart disease (CaHD) typically affects tricuspid and pulmonary valves and is associated with poor survival. To date, the role of right ventricular (RV) and atrial (RA) strain has not been evaluated in such cohort. Research Questions: To evaluate RV and RA strain patterns and assess their impact on survival and congestive heart failure (CHF) development. Methods: Retrospective study of CaHD patients (ICD 9/10 diagnosis of neuroendocrine tumor and echocardiographic evidence of CaHD prior to any surgical intervention; 2004-2019). Longitudinal strain was evaluated using speckle-tracking, RV/RA-focused view was used. RV strain was averaged from 3 and 6 segments for free wall (FWS) and global strain (GS), respectively. Auto-tracking with manual adjustment was done to ensure optimal tracking. The tracing of RV/RA endocardium was done with 15 points using the tricuspid valve annulus as a reference. The impact of strain parameters on mortality and CHF was evaluated with the Kaplan Meier and Cox proportional hazard analyses. Results: A total of 138 patients were included (mean age was 63 ± 10 years; 47% females). Median follow-up was 5.0 years (3.7-8.2). Significant RA and RV enlargement (72 and 79%, respectively) was more common than RV dysfunction (10%). The most common valvular disease &gt; moderate was tricuspid regurgitation (TR; 97%) followed by pulmonary regurgitation (PR; 70%). RV GS mean was -21 + 6%, with FWS of -23 + 7%. The mean RA strain analysis revealed (93% sinus rhythm): a reservoir of 26 + 11%, a conduit of 14 + 8%, and an atrial contraction of 12 + 8%. Strain parameters were not associated with overall mortality. As opposed to PR/TR severity and RV/RA enlargement/dysfunction, patients with low RA reservoir strain (&lt;23%) were more likely to develop CHF (adjusted-HR=1.80, p=0.04, 95% CI 1.04 - 3.134). Conclusions: Our findings suggests that CaHD patients have RV/RA dysfunction with overall reduced strain parameters. Patients with low RA reservoir had higher risk of CHF, but none of the RV/RA strain parameters were associated with excess mortality. This shows how strain analysis could complement other echocardiographic parameters in CaHD morbidity assessment.
Abstract 4140393: Targeting Immune-Fibroblast Crosstalk in Myocardial Infarction and Cardiac Fibrosis
Authors: Junedh Amrute, Xin Luo, Vinay Penna, Steven Yang, Tracy Yamawaki, Sikander Hayat, Andrea Bredemeyer, In-hyuk Jung, Farid Kadyrov, Gyu Seong Heo, RAJIU VENKATESAN, Sally Shi, Alekhya Parvathaneni, Andrew Koenig, Christoph Kuppe, Candice Baker, Hannah Luehmann, Cameran Jones, Benjamin Kopecky, Xue Zeng, Tore Blekwehl, Pan Ma, Paul Lee, Yuriko Terada, Angela Fu, Milena Furtado, DANIEL KREISEL, Attila Kovacs, Nathan Stitziel, Simon Jackson, Chi-Ming Li, Yongjian Liu, Nadia Rosenthal, Rafael Kramann, Brandon Ason, Kory Lavine
Journal: Circulation (2024)

Inflammation and tissue fibrosis co-exist and are causally linked to organ dysfunction. However, the molecular mechanisms driving immune-fibroblast crosstalk in human cardiac disease remains unexplored, and there are currently no approved treatments that directly target cardiac fibrosis. Here, we performed multi-omic single-cell gene expression, epitope mapping, and chromatin accessibility profiling in 45 donors, acutely infarcted, and chronically failing human hearts. We identified a disease-associated fibroblast trajectory marked by cell surface expression of fibroblast activator protein (FAP), which diverged into distinct myofibroblasts and pro-fibrotic fibroblast populations, the latter resembling matrifibrocytes. We lineage traced FAP fibroblasts in vivo and showed that they contribute to the POSTN lineage but not the myofibroblast lineage. We assessed the applicability of experimental systems to model tissue fibrosis and demonstrated that 3 different in vivo mouse models of cardiac injury were superior compared to cultured human heart and dermal fibroblasts in recapitulating the human disease phenotype. Ligand-receptor analysis and spatial transcriptomics predicted that interactions between C-C chemokine receptor type 2 (CCR2) macrophages and fibroblasts mediated by interleukin 1 beta (IL-1) signaling drove the emergence of pro-fibrotic fibroblasts within spatially defined niches. In vivo , we deleted the IL-1 receptor on fibroblasts, the IL-1 ligand in CCR2 monocytes and macrophages, and inhibited IL-1 signaling using a monoclonal antibody and showed fewer pro-fibrotic fibroblasts, decreased cardiac fibrosis, and improved cardiac function. Herein, we characterize fibroblast lineage diversification in the failing heart and showed a subset of macrophages signal to fibroblasts via IL-1 and rewire their gene regulatory network and differentiation trajectory towards a pro-fibrotic fibroblast phenotype. These findings highlight the broader therapeutic potential of targeting inflammation to treat tissue fibrosis and preserve organ function.
Abstract 4139494: Impact of Statins on Major Adverse Cardiovascular Events in Lung Cancer Patients Treated with Chest Radiation
Authors: ELVIS OBOMANU, Olayinka Adebolu, Abiodun Idowu, Tochi Okwuosa
Journal: Circulation (2024)

Introduction: Chest radiation has been well-documented to predispose to major adverse cardiac events (MACE). However, preventing radiation-induced adverse cardiac events is still a research gap. There is limited data assessing the preventive value of statins in cardiovascular outcomes and mortality in chest radiation-treated cancer patients. This study aimed to bridge the knowledge gap. Methods: Retrospective propensity-matched analysis of lung cancer patients aged 30-75 years treated with chest radiation in the TriNetX database. Patients were divided into statin users (started within 3 months before or after radiation exposure) and non-users, and a 1:1 nearest-neighbor propensity-score matching was used to reduce cofounders. We calculated adjusted odds ratios (aOR) for outcomes and performed a 5-year follow-up Kaplan-Meier survival analysis using R software. Result: Both cohorts consisted of 448 patients each, and they were balanced in terms of demographics, comorbidities, and baseline medications (Table 1). The statin cohorts were followed for a median of 591 days, while the non-statin groups were followed for 549 days. At follow up, the incidence of MACE (a composite of all-cause mortality, heart failure, myocardial infarction, and cerebrovascular accident) was significantly higher in the statin cohort compared to the non-statin cohort (21.4% vs 0.4%, aOR: 7.36, 95%CI: 4.26-12.73, P&lt;0.001). The survival probability was also significantly 6-fold lower in the statin cohort compared to the non-statin cohort (HR: 6.21, 95% CI (3.66 – 10.54), Log-Rank Test p&lt;0.001) (fig 1). Conclusion: Among lung cancer patients, statin use around the time of chest radiation was associated with higher MACE and lower survival compared with non-statin users. Future prospective studies are needed to better assess the effects of statins on cardiovascular outcomes for patients with cancer receiving chest radiation.
Abstract 4140299: A Model-Sharing Approach for Quality Improvement of Diabetes and Cardiovascular Disease
Authors: Kyle Elligers, Stacey Greenway, Patricia Lambro, Steven Sadiku, Rona Schechter, JOHN WHELAN, Bianca Pressley, Renee Sednew, Sara Duckett, Meghan Pollner, Katherine Overton, Michelle Congdon
Journal: Circulation (2024)

INTRODUCTION: Opportunities exist to improve health outcomes for patients with diabetes and cardiovascular disease (CVD), or at an increased risk for CVD. The American Heart Association (AHA) established the Target: Type 2 Diabetes (TT2D) national award program to recognize hospitals and health centers for adherence to guidelines for diabetes and CVD. To focus on gaps and strategies for team-based care, coordination of care, and guideline-implementation models for diabetes and CVD, the AHA launched the TT2D Quality Collective in 2023. METHODS: Three health systems and three Federally Qualified Health Centers (FQHCs) were invited to participate in the TT2D Quality Collective from January 2023 – February 2025. Participation includes targeted technical support for diabetes program management, peer-supported model sharing and integration, and ongoing quality improvement support as part of AHA’s inpatient and outpatient TT2D award programs. Peer-supported model sharing is conducted through nine quarterly meetings for each Quality Collective participant to first share a successful component of their diabetes care pathway, followed by space to solicit feedback, comments, and/or suggestions for identified challenges related to diabetes care within their respective systems. Technical and quality improvement support includes seven system-specific meetings with AHA staff to inform deeper discussions around site-level barriers and strategies related to guideline-directed care. Questionnaires are administered during the initiative - at baseline, midpoint, and end - to monitor quality improvement change over time associated with participation in the initiative. RESULTS: Findings are displayed in Table 1. CONCLUSION: Diverse health systems can utilize peer-supported model-sharing and rapid feedback to identify opportunities, solutions to known barriers, and resources to improve implementation of guideline-directed care for type 2 diabetes and CVD. Initial findings from this ongoing initiative reveal the need for deeper discussions in areas such as (1) availability, access, and barriers to evidence-based pharmacological treatments, (2) treatment decision-making algorithms, (3) full integration and utilization of pharmacists as part of team-based care, and (4) strategies for increasing patient engagement in diabetes self-management.
Abstract 4139651: Cardiac Rehabilitation Following Thoracic Aortic Dissection Surgery: A Multi-Center Retrospective Study
Authors: Kiyan Heybati, Domenic Ochal, Keshav Poudel, Eric Zuberi, Kevin Tayon, Elizabeth Dineen, Bryan Taylor, Sam Farres, Kevin Landolfo, Brian Shapiro
Journal: Circulation (2024)

Background: Despite expert opinion recommending patient-tailored cardiac rehabilitation (CR) after acute aortic dissection, both patient participation in CR and the associated risk factor modification after CR following aortic dissection repair are poorly understood. Objectives: To describe the characteristics of patients referred to CR, as well as the enrollment rate and outcomes of those referred to CR following thoracic aortic dissection. Methods: We reviewed electronic health records of adults (≥18) discharged alive following thoracic aortic dissection surgery across the Mayo Clinic Enterprise (01/01/2020-11/15/2022) with follow-up to 05/15/2024 (IRB #24-001141). Data are presented using summary statistics. Results: During the study period, 85 patients were included (median [IQR] age: 65 [50-75] years; 40% female; Table 1 ). Across 84% (N=71) who were referred to CR at discharge, 55% (N=39) enrolled. In those patients referred versus not referred to CR, the prevalence of type A dissection (75% vs. 43%), end-organ involvement (27% vs. 0%), and underlying CAD (54% vs. 21%) were greater while current tobacco use (9% vs. 29%) was lower. Of those enrolled at Mayo Clinic (N=16), CR was started 35 (28-65) days following surgery. These patients completed 21 (13-30) CR sessions at an exercise intensity of 59% (50-65%) maximum predicted heart rate. CR was discontinued in 44% (N=7) due to non-cardiac reasons ( Table 2 ). Of the 9 patients who completed CR, general health status (Dartmouth index: 19 [17-21] vs. 26 [22-34]), depressive symptoms (PHQ-9: 1 [0-1] vs. 4 [1-4]), and exercise capacity (6MWT: 214 [196-244] vs. 384 [305-597] meters) improved ( Table 2 ). There were no reported complications or deaths, with stable aortic sizes reported at 18 months. Conclusions: CR improves functional capacity and well-being without complications in patients after thoracic aortic dissection surgery. Further investigation is needed to better assess CR efficacy and usage in this population.
Abstract 4139264: Outcomes Of Pulmonary Vein Isolation With Or Without Adjunctive Posterior Wall Isolation In Patients With Paroxysmal Atrial Fibrillation: A Systematic Review and Meta-Analysis
Authors: Usman Ahmed, Farooq Kamran, Shahzaib Ahmed, Danish Ali Ashraf, Muhammad Ibraiz Bilal, Zubair Amin, Eeman Ahmad
Journal: Circulation (2024)

Introduction: Pulmonary vein isolation (PVI) is a catheter ablation (CA) technique employed as a treatment strategy for atrial fibrillation in young patients or those who do not respond to medical therapy. Techniques for PVI include radiofrequency (RFA) ablation and balloon cryoablation. The left atrial posterior wall has been recognized as a significant anatomical area involved in the onset and persistence of atrial fibrillation (AF). However, the impact of additional posterior wall isolation (PWI) during PVI remains uncertain. Research Question: What are the outcomes of pulmonary vein isolation compared to pulmonary vein isolation with adjunctive posterior wall isolation in patients with paroxysmal atrial fibrillation? Goals: To determine the efficacy of adjunctive posterior wall isolation in treating persistent AF. Methods: A systematic literature search was conducted on various databases (Pubmed/Medline, EMBASE, Google Scholar, Scopus) from inception until March 2024, to include studies comparing outcomes of patients undergoing management of paroxysmal AF with either PVI + concurrent PWI versus only PVI. Observational studies and Randomized Controlled Trials were included. Review Manager (v 5.3) was used for pooled analysis of included studies employing risk ratio (RR) as the effect measure (4). Results: We conducted a random-effects meta-analysis, pooling data from 5 studies with a total of 2,441 patients. Our analysis revealed a significant improvement in AF recurrence for the cryoablation technique with PVI+PWI (RR=0.56, 95% CI: 0.41, 0.76, I2=0%, p=0.0002) but no significant result was found for PVI+PWI in RFA (RR=1.37, 95% CI: 0.87, 2.18, I2=0%, p=0.18) for AF. For the recurrence of all arrhythmias, the risk ratios for cryoablation and RFA are 0.60 (95% CI: 0.46, 0.78, I2=0%, p=0.0001) and 1.17 (95% CI: 0.83, 1.65, I2=0%, p=0.37) respectively, significant in the case of cryoablation and non-significant for RFA. Conclusion: Concurrent PWI with PVI with the cryoablation technique in patients for the management of paroxysmal AF reduces the risk of recurrent AF. Due to the limited number of studies included, it is possible that the results were underpowered. Further prospective studies in the future are warranted.
Abstract 4139643: Variability of Ventricular Repolarization: Lessons Learned from Comparing Animal Xenotransplantations and First Human Genetically Modified Cardiac Xenotransplantation
Authors: Justin Brilliant, Ubaid Khan, Bartley Griffith, Oneib Khan, Mahdokht Parsirad, Andrew Tully, Manjula Ananthram, Susie Hong-Zohlman, Erika Feller, Alison Grazioli, Richard Amara, Stephen Shorofsky, Avneesh Singh, Muhammad Mohiuddin, Timm Dickfeld
Journal: Circulation (2024)

Background: The worldwide first genetically modified porcine-to-human cardiac xenotransplant (xeno) in 2022 showed a markedly prolonged ventricular repolarization during the 60-day survival raising concerns for ventricular arrhythmias. Longitudinal QTc intervals in 16 porcine-to-baboon cardiac xenos performed at the University of Maryland from 2017-2022 were compared to the human measurements. Aim: Compare the variability in repolarization between human and simian recipients of genetically modified porcine xenos. Methods: Daily 12-lead ECGs of the human recipient were compared with long-term recordings of implanted monitors in the baboons. Results: The first human xenotransplant patient showed longer repolarization compared to the cohort of 16 baboons with porcine xenos (QTc 570±58ms [range 438-698ms] vs QTc 432±89ms [range 288-627ms]; p&lt;0.01). When dividing 16 baboons into 4 groups from shortest to longest mean QTc intervals (361±34ms vs 399±37ms vs 481±36ms vs 542±38ms; p&lt;0.01 for shortest vs longest QTc quartile), no group approached the mean QTc of the human (p&lt;0.01). However, when compared to the baboon with the longest QTc and similar survival (69 vs 60 days), the QTc intervals were closer approximated (547±37ms [range 474-627ms]; p=0.03) and did not significantly differ after the initial 20 post-operative days (human 551±52ms vs baboon 559±33ms, p=0.38). Conclusion: While the first human xeno showed prolonged repolarization, the baboon cohort demonstrated significant variability of repolarization duration. QTc prolongation of similar magnitude was observed in the baboon with longest repolarization with comparable follow up. Therefore, the prolonged QTc in the single human xeno may either represent the different physiological response in human environment or an outlier similar to the baboon with the longest QTc. A larger human cohort will help answer this question and further assess the potential arrhythmic risk of xenotransplantation.
Abstract 4139507: Impact of Hemodynamic Management on Early Mortality in Patients Undergoing Radiofrequency Catheter Ablation for Ventricular Tachycardia: A Single Center Experience
Authors: Abdelghani El Rafei, Amneet Sandhu, Lukasz Cerbin, Ryan Aleong, Matthew Zipse, Alexis Tumolo, Syed Rafay Ali Sabzwari, Lohit Garg, Christopher Barrett, Paul Varosy, Johannes von, Carmel Ashur, Joseph Adewumi, Kishan Padalia, Alex Grubb, Daniel Varela, Michael Rosenberg, Wendy Tzou
Journal: Circulation (2024)

Background: Catheter ablation (CA) is an established treatment for ventricular arrhythmias (VAs). Vasoactive drugs are used to manage intraprocedural acute hemodynamic decompensation (AHD). To date, there is limited data on the association between intra-procedural vasoactive drug choice and outcomes in patients undergoing VA CA. Objective: Evaluate if the use of certain vasoactive agents interprocedurally is associated with worse outcomes in patients undergoing VA CA. Methods: This was a single center retrospective analysis of patients undergoing VA CA 2018-2023. Patients were risk-stratified using the PAAINESD score (calculated by: presence of lung disease, age &gt;60, anesthesia use, New York Heart Association classification III/IV, left ventricular ejection fraction (LVEF) &lt;25%, electrical storm, and diabetes mellitus) and divided into low- (&lt;10), medium- (10-16), and high-risk (&gt;16) tertiles. Use of vasoactive drugs between tertiles was compared, as were outcomes when pure afterload agents (-INO), versus agents with positive inotropy (+INO) were used. Results: Two hundred and three patients undergoing 233 procedures were included. Mean (±SD) age was 62±13years, LVEF was 37±15%; 1/3 had LVEF&lt;25%, and 99 (39%) were NYHA III/IV. Median (range) PAAINESD was 17 (5-36). Use of -INO (ephedrine, phenylephrine, or vasopressin) occurred in 179 patients (77%); 63(27%) received 2 -INO, and 10 (4%) received 3 -INO agents. Twelve (5%) died within 90 days, all with PAAINESD &gt;16, and all with 1 -INO used interprocedurally (Fig., A). After adjustment for LVEF and +INO, increasing number of -INO was significantly associated with 90-day mortality (OR 2.67, 95%CI 1.24 – 5.76, P=0.012; Fig., B), as was the cumulative dose of -INO (OR 1.43, 95%CI 1.03 – 1.98, P=0.031, Fig., C). Discussion: Among patients with depressed LV function undergoing VAs ablation, the use of pure afterload agents is associated with increased 90-day mortality, especially among patients with high baseline risk of AHD.