tbuckley/cabot-search huggingface dataset:
Abstract 14098: Epidemiology and Clinical Outcomes of Cardiac Arrhythmias in Pulmonary Arterial Hypertension
Authors: Thanaboon Yinadsawaphan, Mustafa Suppah, Srekar N Ravi, JUAN FARINA, Robert L Scott, Dan Sorajja
Journal: Circulation (2023)

Background: There is limited evidence regarding the impact of cardiac arrhythmias in patients with pulmonary arterial hypertension (PAH). We aim to comprehensively investigate the epidemiology and clinical outcomes of cardiac arrhythmias in patients with PAH. Methods: In a retrospective cohort study including 512 PAH patients from 2001-2021 at 3 Mayo Clinic sites, PAH patients were identified via echocardiogram, pulmonary function tests, and right heart catheterization. Demographic data at PAH diagnosis and clinical outcomes over a 10-year period were collected. The PAH patients were categorized into three groups based on arrhythmic onset: 1) patients with arrhythmia prior to PAH diagnosis, 2) patients diagnosed with arrhythmia during 10-year PAH follow-up, and 3) patients without arrhythmia during 10-year PAH follow-up. Survival outcomes were analyzed using multivariable Cox proportional hazards regression, adjusted with the REVEAL 2.0 score. Results: Among 512 PAH patients (mean age 56.1 years, 81.8% female), the prevalence of cardiac arrhythmias at PAH diagnosis was 10.5%. The cumulative incidences of new-onset arrhythmias at 1, 5, and 10 years were 6.6%, 18.4%, and 29.2%, respectively. Patients with arrhythmia diagnosed before and after PAH diagnosis showed significantly higher all-cause mortality rates with adjusted HR of 2.06 [95% CI 1.36-3.12] and 1.57 [95% CI 1.17-2.20] respectively (Figure 1). Similarly in both arrhythmic groups, there was a shorter median time to the first all-cause hospitalization (9.5 and 15.9 months vs. 21.2 months) and a higher number of all-cause hospitalizations (0.38 and 0.64 times per year vs. 0.10 times per year) compared to the non-arrhythmic group. Conclusions: Cardiac arrhythmias can develop in nearly one-third of PAH patients within 10 years of PAH diagnosis and independently contribute to increased mortality and hospitalization frequency.
Abstract 13321: Novel Regional Analysis of Left Atrial Strain From Computed Tomography Separates Patients With Persistent versus Paroxysmal Atrial Fibrillation
Authors: Charles Sillett, Orod Razeghi, Angela Lee, Jose Alonso Solis Lemus, Caroline Roney, Prasanth Ganesan, Ruibin Feng, Henry Chubb, Koen NIEMAN, Albert J Rogers, Ronak Rajani, Sanjiv M Narayan, Steven A Niederer
Journal: Circulation (2023)

Introduction: It is difficult to quantify progression of atrial fibrillation (AF). Atrial fibrosis is a hallmark of the AF substrate, increasing from paroxysmal to persistent AF, but is difficult to assess by voltage mapping or magnetic resonance imaging. It remains unclear if fibrosis could be revealed by atrial stiffness, which increases with regional fibrosis burden and can be measured by analysis of retrospective gated computed tomography (CT). Hypothesis: Differences in regional CT-derived atrial strain enable the identification and characterization of persistent versus paroxysmal AF. Methods: Fifty patients with paroxysmal (60%) and persistent (40%) AF (age 59.8 ± 12.8, 34% female) underwent CT coronary angiography which included a retrospective gated CT protocol prior to AF ablation. LA reservoir area strain was measured globally and regionally on the LA endocardium using an optimised feature tracking algorithm. The LA body was classified into five regions using Universal Atrial Coordinates (Fig A). Results: Global strain was significantly lower in patients with persistent versus paroxysmal AF (13.6 ± 8.2 % vs 24.5 ± 12.0 %, p = 0.0008). The posterior, septal, anterior and inferior wall strains were significantly lower in persistent AF patients (posterior: 16.6 ± 9.5 % vs 30.3 ± 15.9 %, p = 0.007; septum: 20.8 ± 11.8 % vs 39.6 ± 15.8 %, p = 0.00004; anterior: 17.5 ± 10.6 % vs 28.7 ± 15.7 %, p = 0.008, inferior: 16.6 ± 9.5 % vs 30.3 ± 15.9 %, p = 0.001, Fig B). Receiver operator curve analysis showed septal wall strain outperformed CHA2DS2-VASc score, LA volume and global strain for binary classification between groups (AUC: CHA2DS2-VASc: 0.67; LA volume: 0.79; global strain: 0.78; septal strain: 0.84, Fig C). Conclusions: Novel feature tracking of retrospective gated CT reveals abnormal atrial strain in patients with persistent versus paroxysmal AF. Future work could incorporate this tool into patient phenotyping or the identification of AF substrates to target ablation.
Abstract 18748: Prevention of Skeletal Muscle Atrophy and Fibrosis in Congestive Heart Failure by Skeletal Myoblast-Targeted Overexpression of Angiotensin II Type 2 Receptor
Authors: Tadashi Yoshida, C. S Lott, Patrice Delafontaine
Journal: Circulation (2023)

Introduction: We have previously shown that angiotensin II (Ang II) type 2 receptor (AT2R) positively regulates skeletal myoblast differentiation. Systemic angiotensin II (Ang II) increase or congestive heart failure suppress AT2R expression, likely contributing to the development of skeletal muscle atrophy and fibrosis associated with these conditions. Hypothesis: We hypothesized that AT2R overexpression in skeletal myoblasts could prevent skeletal muscle atrophy and fibrosis associated with congestive heart failure (CHF). Approach: Two mouse models, systemic Ang II infusion and left anterior descending coronary artery (LAD) ligation were used in this study. Myoblast differentiation, muscle atrophy and muscle fibrosis were assessed by analyzing gene expressions (e.g. myogenin and atrogin-1), myofiber cross sectional area, and the collagen deposition (picrosirius red staining). Primary myoblasts were isolated from mouse hindlimb muscles. Myoblast-specific AT2R-overexpressing transgenic mice were generated by crossing Pax7 CreER/+ mice (tamoxifen-inducible cre recombinase is expressed under Pax7 promoter) and CAG-stop flox -AT2R mice (AT2R is expressed under CMV early enhancer element, chicken β-actin gene promoter upon cre-mediated excision of floxed stop codon). Results: AT2R expression was robustly increased during myoblast differentiation both in vitro and in vivo . siRNA-mediated AT2R knockdown significantly suppressed myoblast differentiation in vitro and skeletal muscle regeneration in vivo . In both Ang II infusion and LAD ligation models, AT2R induction during myoblast differentiation was significantly suppressed, associated with reduced muscle regeneration and increased atrophy and fibrosis. Myoblast-specific AT2R overexpression in vivo restored muscle regenerative capacity, and prevented muscle atrophy and fibrosis. Conclusions: AT2R induction in skeletal myoblast is suppressed in CHF, possibly via increased Ang II. Decreased AT2R expression and its downstream signaling in myoblast lead to lowered muscle regenerative capacity and increased muscle atrophy and fibrosis. Restoration of myoblast AT2R expression could lead to a novel therapy to prevent muscle atrophy and fibrosis in CHF condition.
Abstract 16252: A Survival Analysis in Patients With Tricuspid Regurgitation and Cardiac Resynchronization Therapy
Authors: Janelle Muuse, Hanad Bashir, Muhaimen Siddiqui, Santosh Menon
Journal: Circulation (2023)

Introduction: Cardiac resynchronization therapy (CRT) is a well established treatment in heart failure with reduced ejection fraction. It involves simultaneous pacing of the left and right ventricles to restore ventricular synchrony, leading to increased cardiac output and contractility. The impact of CRT on tricuspid regurgitation (TR) severity has not been evaluated. Studies have shown that up to 22% of CRT recipients have significant TR, and of these patients only 41% will improve to no or mild TR. For a majority of patients who have persistent significant TR despite CRT, long term outcomes are put into question. Hypothesis: Tricuspid regurgitation adversely affects the response and survival of CRT patients. Goals: To analyze the prevalence of TR in a cohort of patients admitted to The Christ Hospital who have undergone CRT. To assess the association between TR after CRT and long-term survivability. Methods: This is a retrospective cohort study conducted at The Christ Hospital in Cincinnati Ohio. 13292 patients diagnosed with tricuspid regurgitation (mild to severe) in total were included. 184 of these patients underwent CRT, and survival probability was measured against the no CRT group. Kaplan meier method was used for analysis. Results: Survival probabilities at 1 year, 2 years, and 3 years for patients with CRT = 0.769, 0.661, and 0.558 respectively. Patients without CRT = 0.911, 0.863, and 0.826 respectively. Hazard ratio = 2.84 (2.33, 3.47) compared to solely tricuspid regurgitation. Conclusions: Patients with TR without CRT had greater survival rates up to three years compared to TR with CRT. The risk of death in the TR with CRT was 2.84 times higher than the no CRT group. It can be further investigated why the no CRT group had a greater survival rate than CRT. Limitations include variable assessments of TR due to the subjective nature of grading TR. Future research could investigate the difference between primary (device-related) and secondary TR in this cohort.
Abstract 14239: Extracellular Matrix Disorganization Caused by ADAMTS16 Deficiency Leads to Bicuspid Aortic Valve
Authors: Ying Lin, Qifan Yang, Xiaoping Lin, Xianbao Liu, Xiangmin Kong, Lianlian Zhu, Bin Zhou, Yidong Wang, Jinrong Peng, Wei Zhu, Jianan Wang
Journal: Circulation (2023)

Background: Extracellular matrix (ECM) is involved in aortic valve development and aortic valve anomaly. ADAMTS gene mediated ECM dysfunction was reported to be related to aortic valve diseases. Hypothesis: The ADAMTS gene family members can contribute to aortic valve diseases. Methods: Morpholino based adamts gene-targeted phenotype-screening of outflow tract anomaly in zebrafish and the 19 ADAMTS family gene-targeted exon sequencing on a cohort BAV patients (304 BAV and 301 normal controls) were performed. Accordingly, both specific genetic tracing and different gene modified mouse models were generated to evaluate the role of specific genes in the aortic valve formation process. Movat’s pentachrome staining was used to describe the altered ECM maturation process. Bulk RNA-seq was performed on both mouse heart tissue and human iPSC-induced ECs to explore the potential molecular pathways, which was further confirmed in ex vivo embryonic outflow tract tissue culture studies. Results: We identified some novel adamts genes that resulted in cardiac outflow valve defects in zebrafish, while exon sequencing identified ADAMTS16 p.H357Q variant in an inherited BAV family. The generated Ad amts16-Cre; Rosa26-tdTomato mice showed Adamts16 -expressing cells were primarily restricted to valvular endothelial cells (VECs) at E12.5 and then expressed in valvular mesenchymal cells (VICs) at E13.5. Both Adamts16 +/- and Adamts16 +/H355Q mice exhibited an R-NC-type BAV phenotype, with progressive aortic valve thickening. Conditional Adamts16 mutant mouse models demonstrated that endothelial lineage cell deficiency in Adamts16 recapitulated the BAV phenotype, which was associated with worse ECM deposition without ECM trilaminar structure. Bulk RNA sequencing unveiled enhanced FAK signaling, which was accompanied by elevated fibronectin levels. Both in vitro iPSC-ECs culture and ex vivo embryonic tissue explant studies validated the altered FAK signaling resulted in exaggerated cell proliferation. Conclusions: Our present study identified a novel BAV-causing ADAMTS16 p. H357Q variant. ADAMTS16 deficiency led to BAV formation.
Abstract 13284: New Elastic Fiber Formation by Non-Smooth Muscle Lineage Cells During the Progression of Aortic Dissections
Authors: Hisashi Sawada, Sohei Ito, Hong S Lu, Alan Daugherty
Journal: Circulation (2023)

Introduction: Aortic dissection (AD) is a life-threatening vascular disease displaying the disruption of the extracellular matrix (ECM). Elastic fibers are a major component of ECM and confer structural integrity to the aortic wall. Normally, elastic fibers are minimally synthesized in adulthood. However, it remains unknown whether and how elastic fibers are synthesized following ADs. Methods and Results: AD was induced by administration of β-aminopropionitrile (BAPN, 0.5% wt/vol) to male C57BL/6J mice at 4 weeks of age. Thoracic aortas were collected after 4 or 12 weeks of BAPN administration. False lumen formation with fresh hematomas was observed at 4 weeks of BAPN administration, indicating development of acute ADs. The false lumen developed striking remodeling at 12 weeks, suggesting progression to the chronic phase. RT-qPCR revealed that mRNA abundance of tropoelastin, a precursor of elastic fibers, was increased significantly at the chronic phase of ADs, but not at the acute phase. Tropoelastin mRNA was observed primarily in the vascular wall of the false lumen, as evidenced by in situ hybridization. Of interest, elastic fibers were formed in the wall of the false lumen in chronic ADs. These data suggest that elastic fibers were newly synthesized during the progression of ADs. Immunostaining revealed that the walls of true and false lumens of chronic ADs were mainly composed of cells expressing both αSMA (encoding by Acta2 ) and MYH11, common markers for smooth muscle cells (SMCs). However, in a lineage tracing study, the walls of the false lumen of chronic ADs were negative for the Acta2 lineage, suggesting that cells in the wall of the false lumen were derived from a non-SMC lineage but acquired SMC properties during AD progression. Bulk RNA sequencing identified the increased abundance of 2,799 genes in chronic ADs and 102 transcription factors were predicted to regulate these genes. Among them, JunB was the most abundant molecule that can be aligned in the promotor region of tropoelastin. Of note, JunB was expressed adjacent to both αSMA-positive cells and new elastic fibers in the dissected aortas. Conclusion: ADs exhibit vascular remodeling with newly elastic fiber formation by non-SMC lineage cells during the disease progression.
Abstract 14420: Role of Thromboprophylaxis in Outpatients With COVID-19: A Meta-Analysis of Randomized Controlled Trials
Authors: Sahib Singh, Udaya Tantry, Kevin Bliden, Aakash Garg, Paul Gurbel
Journal: Circulation (2023)

Introduction: COVID-19 has been known to cause a hypercoagulable state, leading to venous and arterial thromboembolism. While thromboprophylaxis with anticoagulation (AC) agents is beneficial in hospitalized patients, their role is unclear in outpatients with COVID-19. We conducted a meta-analysis to assess the potential role of AC in outpatients with COVID-19. Methods: Multiple online databases were searched for randomized clinical trials (RCTs) comparing prophylactic AC to placebo in patients presenting in the outpatient setting with COVID-19. The primary outcomes of interest were hospitalization, death, venous thromboembolism (VTE) and bleeding at the longest available follow up. A random-effects model was used to estimate pooled risk ratios (RR) and 95% confidence intervals (CI). Results: Four RCTs with a total of 1,464 patients (AC group n=726, placebo group n=738) were included. The mean age was 55 years, 48% of patients were men and the mean duration of follow up was 65 days. Both groups had similar risk of hospitalization (RR 0.93, 95% CI 0.56-1.53, p = 0.76) (Figure 1), death (RR 1.09, 95% CI 0.07-17.14, p = 0.95), VTE (RR 0.35, 95% CI 0.08-1.49, p = 0.16) (Figure 2), and bleeding (RR 1.99, 95% CI 0.73-5.40, p = 0.18). Conclusions: Thromboprophylaxis with AC in outpatients with COVID-19 is not associated with reduction in the risk of hospitalization, death or VTE when compared with placebo.
Abstract 14945: Left Bundle Branch Area Pacing Improves Right Ventricular Function in Heart Failure With Preserved Ejection Fraction: Evidence From PROPHET Trial
Authors: Yang Su, Dongdong Zhao
Journal: Circulation (2023)

Introduction: Left bundle branch area pacing (LBBAP) has emerged as a promising pacing strategy, especially for patients with heart failure. However, the impact of LBBAP on hemodynamics and cardiac function in heart failure with preserved ejection fraction (HFpEF) has not been investigated yet. Hypothesis: LBBAP could improve cardiac function of patients with HFpEF. Methods: This prospective cohort study enrolled patients with preserved left ventricular ejection fraction who were receiving LBBAP, and two cohorts (non-HFpEF cohort and HFpEF cohort) were built based on diagnosis of HFpEF. Hemodynamics before and after LBBAP were measured using right heart catheterization (RHC). And the changes of cardiac function were evaluated by transthoracic speckle tracking echocardiography (STE) Results: 30 consecutive patients were included in the study, with 17 patients in the non-HFpEF group and 13 patients in the HFpEF group. Preprocedural STE showed worsened right ventricular function in the HFpEF group indicated by global longitudinal strain rate, free-wall strain rate, fractional area change, Tricuspid annular plane systolic excursion and Tei index. And RHC showed elevated right ventricular stroke work index (RVSWI, 8.6±4.1 non-HFpEF vs 15.0±5.6 HFpEF, P=0.170). While post-LBBAP evaluation showed a more significant reduction in RVSWI in the HFpEF group (6.7±2.5 (reduction 22.1%) non-HFpEF vs 8.0±1.0 (reduction 46.7%) HFpEF, P=0.043). Besides, post-LBBAP STE showed improvement of right ventricular function, despite no significant difference in the extent of improvement was found between groups. Conclusions: LBBAP might be more beneficial to patients with HFpEF as it could improve right ventricular function by alleviating the workload of right ventricle. Long-term benefit of LBBAP in HFpEF requires further investigation.
Abstract 11317: Comprehensive Plasma Proteomics Profiling Identifies Signaling Pathways Dysregulated in Genotype-Positive versus Genotype-Negative Patients With Hypertrophic Cardiomyopathy
Authors: Keitaro Akita, Kohei Hasegawa, mathew S Maurer, Albree Tower Rader, Michael A Fifer, Veli K Topkara, Muredach P Reilly, Yuichi Shimada
Journal: Circulation (2023)

Introduction: Only a subset of patients with hypertrophic cardiomyopathy (HCM) have positive genotype. Although genotype-positive patients with HCM are known to have worse prognosis than genotype-negative patients, the underlying mechanism is unclear. Hypothesis/Aims: To test the hypothesis that plasma proteomics profiling identifies signaling pathways that are dysregulated in genotype-positive patients with HCM compared with those with negative genotype. Methods: In this multi-center study, we conducted plasma proteomics profiling of 4986 proteins in patients with HCM who underwent genetic testing. The outcome measure was positive genotype, defined as having a mutation that is pathogenic or likely pathogenic for HCM. We identified plasma proteins with significant (univariable P&lt;0.05) differences in concentration between patients with positive and negative genotype in HCM using the Mann-Whitney-Wilcoxon test. Using these proteins, we performed pathway analysis to determine dysregulated pathways with false discovery rate &lt;0.05. Results: A total of 340 patients with HCM underwent genotyping and 103 patients (30%) had positive genotype for HCM. Among the 4986 proteins, 844 (17%) had significant differences between patients with positive and negative genotypes - a larger percentage than what is expected by chance. Pathway analysis exhibited that both pathways known to be associated with poor prognosis (e.g., TGF-β, metabolic, and inflammation) and novel pathways (e.g., Ras-MAPK and associated pathways such as Pl3K-Akt and JAK-STAT) were dysregulated in genotype-positive patients with HCM compared to those who were genotype-negative ( Figure ). Conclusions: This study serves as the first to apply comprehensive proteomics profiling to identify signaling pathways that are differentially regulated in patients with positive genotype in the HCM population, elucidating dysregulation of both known (e.g., TGF-β) and novel (e.g., Ras-MAPK) pathways.
Abstract 14444: Sex-Mismatch in Heart Transplantation Confers No Additional Risk of Postoperative Outcomes Established via Two One-Sided Equivalence Testing on a Propensity-Matched Cohort
Authors: Reid Dale, Matt Leipzig, Nataliya Bahatyrevich, Katharine C Pines, Maria E Currie
Journal: Circulation (2023)

Introduction: Donor-recipient sex-mismatch in heart transplantation (HTx) has decreased since the 1990s, possibly due to conflicting findings regarding its risk. Size mismatch is known to confer risk. Hypothesis: Previously observed differences in outcomes between the arms of sex-matched and sex-mismatched patients were due to underlying size mismatch. Sex-mismatch confers no postoperative risks beyond that due to risk beyond those due to size mismatch. Methods: Patients from the UNOS database between October 1, 1987 and December 31, 2022 were analyzed; under 18 years old, multiorgan transplants, and retransplants were excluded. Cohorts were separated into male and female recipients. Propensity score matching on age, transplant year, waitlist status, donor/recipient PHM ratio, preoperative diagnosis, creatinine clearance, total bilirubin, and mechanical circulatory support was performed. Two One-Sided Testing (TOST) was performed to assess between-arm equivalence in postoperative outcomes. Survival differences were measured by the between-arm ratio of Restricted Mean Survival Time (RMST) and binary outcome differences by the Odds Ratio (OR). We set the equivalence bounds per Wellek’s strict a priori bounds of (0.66, 1.50) for OR and (0.95, 1.05) for the between-arm RMST ratio. Results: In the non-propensity matched cohort, there were significant differences in survival at temporal endpoints up to five years for male recipients (p&lt;0.001) but no significant differences in the female recipients at temporal endpoints up to five years (p=0.3). In the propensity matched cohort, we found significant equivalence between arms in both male and female recipients for all outcomes (Table 1). Conclusions: Sex-mismatch in HTx confers no additional risk to postoperative outcomes beyond those present due to size mismatch. Increasing the acceptance of sex-mismatched donors could potentially expand the donor pool and increase female donor utilization.