tbuckley/cabot-search huggingface dataset:
Abstract 4141151: Coronary Artery Disease Polygenic Risk Scores with Equivalent Performance Produce Discordant Estimates of Individual Risk
Authors: Sarah Abramowitz, Kristin Boulier, Karl Keat, Katie Cardone, Manu Shivakumar, John Depaolo, Renae Judy, Dokyoon Kim, Marylyn Ritchie, Benjamin Voight, Bogdan Pasaniuc, Michael Levin, Scott Damrauer
Journal: Circulation (2024)

Background: Dozens of polygenic risk scores (PRSs) have been developed to estimate coronary artery disease (CAD) risk. Some are available clinically. PRS performances are traditionally evaluated and compared at the population level. Whether they provide similar individual-level assessments of disease liability is a critical consideration for clinical implementation that remains uncharacterized. Research Question: How does individual-level risk prediction compare across CAD PRSs? Methods: Published CAD PRSs were curated from the PGS Catalog, and two novel PRSs were created from the results of a large GWAS meta-analysis. For each score, normalized individual risk scores were calculated for All of Us Research Program (AOU) participants. PRSs with equal population-level performance were identified by using Bayesian analysis of variance to compare calibration and discrimination (Brier score and AUROC) of generalized linear models of prevalent CAD. Among equivalently performing scores, the individual-level agreement between risk percentile estimates was tested with intraclass correlation (ICC) and Light’s Kappa. This approach was replicated in the Penn Medicine Biobank (PMBB) and UCLA ATLAS Biobank. Results: 50 PRSs were calculated for 171,095 AOU participants. When included in a model of prevalent CAD, 48 scores had practically equivalent Brier scores and AUROCs (region of practical equivalence = 0.02). Across these scores, 84% of AOU participants had at least one score in both the top and bottom risk quintile. Continuous agreement of individual risk predictions from the 48 scores was poor, with an ICC of 0.351 (95% CI; 0.349, 0.352). Agreement between two statistically equivalent scores was moderate, with an ICC of 0.646 (95% CI 0.643, 0.649). Light’s Kappa, used to evaluate consistency of assignment to high-risk percentile cutoffs, did not exceed 0.56 (interpreted as ‘fair’) across statistically and practically equivalent scores. Repeating the analysis among 41,193 PMBB and 50,748 UCLA participants yielded different sets of statistically and practically equivalent scores which also lacked strong individual agreement. Conclusions: When tested across three diverse biobanks, CAD PRSs that performed equivalently at the population level produced highly variable individual estimates of risk. Approaches to clinical implementation of CAD PRSs need to consider the potential for discordant individual risk estimates from otherwise indistinguishable scores.
Abstract 4141662: Study of Angiogenic Cell Therapy for Progressive Pulmonary Hypertension: Intervention with Repeat dosing of eNOS-enhanced EPCs: the SAPPHIRE Trial
Authors: Duncan Stewart, Sanjay Mehta, George Chandy, Naushad Hirani, John Granton, Nathan Hambly, John Swiston, Kim Danovitch, Monica Taljaard, Dean Fergusson, Antonio Giulivi, David Courtman
Journal: Circulation (2024)

In pulmonary arterial hypertension (PAH), widespread pruning of the lung distal arterial bed leads to increased vascular resistance, right heart failure and death. Currently, there are no available therapies designed to revascularize the lung. We assessed the effects of autologous, angiogenic endothelial progenitor cells (EPCs) transfected with endothelial NO synthase (eNOS) in PAH patients receiving available standard-of-care therapies in a 12-month randomized, controlled trial (RCT; NCT03001414). Patients were randomized to receive a course of 4 monthly infusions over the first 6 months consisting of placebo (Arm 1) or eNOS-EPCs (20M cells; Arms 2 and 3) at 0, 1, 2 and 3 months, for a total 80M cells. After 6 months, Arm 1 crossed over to cell infusions, Arm 2 to placebo, whereas Arm 3 received a second course of eNOS-EPCs (total 160M cells). The primary endpoint was change in 6MWD (baseline to 6 months) between patients receiving eNOS-EPCs vs. placebo. However, due to the COVID-19 pandemic the trial was stopped after only 12 of the planned 45 patients were enrolled (5 placebo, 7 cells). While small sample size precluded appropriately powered analyses, a qualitative difference was seen between the eNOS-EPC and placebo groups over the first 6 months (Figure), with a 2-fold greater proportion of patients achieving a 35-meter increase in 6MWD in the cell therapy group (40% vs. 20%, resp). As well, these improvements coincided with cell delivery in all 3 Arms, with a sustained increase in 6MWD over 12 months after a single course of cells in the first 6 months (Arm 2). Treatment with eNOS-EPCs was well tolerated; however, an isolated decrease in 6MWD was apparent 1 month after the first infusion of the second course of cell therapy in Arm 3 patients, with full recovery by the end of the course. This raises the possibility of an immune response to rechallenging patients with this autologous cell product, despite the absence of any clinical indicators, which will be explored by analysis of immune biomarkers. Therefore, the results of the SAPPHIRE trial suggest possible clinical benefit of a single course of 4 infusions of eNOS-EPCs in PAH patients receiving cell therapy and support the performance of a larger RCT.
Abstract 4141605: Genetic Determinant for Prognosis of Dilated Cardiomyopathy: The role of NAV3 in Cardiac Fibrosis
Authors: Min Wang, Li Wang, Rachad Ghazal, Mayah Seal, Thanh Thanh Nguyen, Dennis McNamara, Simona Barlera, Silvana Pileggi, Luisa Mestroni, Marco Merlo, Gianfranco sinagra, Florence Pinet, Jan Krejci, Duan Liu, Richard Weinshilboum, Naveen Pereira
Journal: Circulation (2024)

Background: Dilated Cardiomyopathy (DCM) is a major cause of heart failure (HF) and carries a high mortality rate. Drug treatment response for DCM-related HF patients is highly variable, with some patients having no response. A pharmacogenomic approach, genome-wide association study (GWAS) followed by biologically functional validation, can potentially identify genetic determinants of prognosis in DCM and might provide insight into novel biology of DCM pharmacotherapy. Methods: A GWAS was performed using DNA from 686 patients with recent onset DCM who were on standard HF therapy using change in left ventricular ejection fraction (LVEF) at a median of 6 months after initial diagnosis. Cultured human cardiac fibroblasts (HCFs) were used to functionally validate the GWAS findings in vitro . RNA-seq followed by pathway analysis after NAV3 knock-down (KD) using siRNA in HCFs were performed to explore potential biological mechanisms. Results: A genetic variant, rs11105445(G&gt;A), identified from the GWAS, mapping to the neuron navigator 3 (NAV3) gene (rs11105445, p=2.37E-07; beta 2.74 ± 0.53) was associated with improvement in LVEF. Functional genomic experiments demonstrated that, both in LV tissue and in cultured fibroblasts, the minor allele A was associated with decreased transcription of NAV3 (pvalue: 0.0335 and 0.0432) suggesting that ↓NAV3 expression might be associated with improvement in LVEF. TGF-β1 can induce HCF transdifferentiation into myofibroblasts and we demonstrate that it also increases NAV3 expression. NAV3 KD which mimics the GWAS variant significantly suppressed TGF-β1 induced HCF transdifferentiation demonstrated by decreased expression of α-smooth muscle actin (ACTA2) and collagen I (COL1A1). RNA-seq after NAV3 KD followed by pathway analysis suggested that NAV3 exerted its effect by regulating ECM and cell cycle processes, especially G1/S transition. We demonstrate that NAV3 KD suppressed TGF-β1 induced G1/S arrest by regulating CDK4, CDK6 and INK4B (cyclin-dependent kinase inhibitor 2B/P15, CDK4 inhibitor). Conclusion: Decreased expression of NAV3 is associated with myocardial recovery in DCM, most likely due to its role in suppressing HCF differentiation by regulating TGF-β1 induced G1/S arrest. The role of NAV3 as a novel therapeutic target in DCM needs to be explored.
Abstract 4141543: Exercise-induced cardiomyopathy in the absence of coronary artery disease: Clinical characteristics and outcomes.
Authors: Luca Fazzini, Scott Hubers, Jenny Jia Ling Cao, Christopher Scott, Robert McCully, Matteo Castrichini, Marta Figueiral, Akanksha Mohananey, Rachad Ghazal, Min Wang, Li Wang, Rajiv Gulati, Roberta Montisci, Patricia Pellikka, Naveen Pereira
Journal: Circulation (2024)

Background: Patients with normal resting left ventricular ejection fraction (LVEF) without either coronary artery disease (CAD) or a hypertensive response can paradoxically develop reduced LVEF during exercise stress echocardiography (ESE). The clinical phenotype and outcomes of these patients is unknown. Hypothesis: Patients who paradoxically develop reduced LVEF during exercise may represent a sub-phenotype of heart failure with preserved LVEF (HFpEF). Aims: To describe the baseline characteristics and clinical outcomes of this unique patient population. Methods: Among all ESE performed between January 2003 and December 2022, patients without a hypertensive response to exercise and without CAD by angiogram within 90 days of ESE, who had a resting LVEF ≥50% with a ≥5% LVEF decrease during ESE were identified. All-cause mortality, HF hospitalization, and atrial fibrillation (AF) outcomes were assessed. Kaplan-Meier and Cox regression methods were used to analyze time-to-event outcomes. Results: Among 213,643 stress echocardiograms performed, 134 patients met eligibility criteria (Table 1). The mean age of the population was 66±10 years, 76% were women, and 16% had AF at baseline. Mean LVEF was 58±4% at rest and 43±4% at peak stress. Stress electrocardiogram met criteria for ischemia in 14%. The 10-year all-cause mortality risk was 12.9% (95% CI 5.5-20.3) with 10 (37%) of 27 deaths due to cancer (Figure 1, Panel A). The 10-year estimated risk of HF hospitalization was 17.6% (95% CI 9.0-26.2) (Figure 1, Panel B). Among 112 patients without AF at baseline, the 10-year risk of developing AF was 23.4% (95% CI 13.4-33.4). Conclusions: Patients with exercise-induced reduced LVEF in the absence of obstructive CAD have a high incidence of HF hospitalizations and AF. Given the preponderance of women, risk for AF, HF hospitalizations, and cancer-related deaths, the possibility that this condition is an early sub-phenotype of HFpEF should be investigated.
Abstract 4141589: Race, neighborhood poverty, and all-cause mortality in heart failure with preserved ejection fraction
Authors: Yulia Khodneva, Pankaj Arora, Megan Nordberg, Larry Hearld, Andrea Cherrington
Journal: Circulation (2024)

Background: Race and neighborhood socioeconomic disadvantage are linked to worse health outcomes in heart failure, but studies have not specifically focused on patients with heart failure with preserved ejection fraction (HFpEF). Research Question: Is race associated with all-cause mortality among patients with HFpEF and does the area-level poverty moderate this association? Methods: ICD diagnostic codes for HFpEF were used to identify patients with first hospitalizations for HFpEF in University of Alabama in Birmingham (UAB) Medicine EHR data from 2017-2023. Demographics, comorbidities, and laboratory data were extracted at admission. Patient zip codes were merged with Census zip code poverty data. All-cause mortality was ascertained in the EHR. Multivariable-adjusted Cox proportional hazard models examined the association between race and all-cause mortality and interaction between race and zip-level poverty ratio, dichotomized at the median. Results: Between 2017-2023, 14,043 adults had a first hospitalization for HFpEF at UAB; 37% were African American (AA), 58% white, 4.5% from other race/ethnicities. Half resided in high poverty areas (19% of area residents with income below the median poverty level). Compared to whites, AA adults with HFpEF were more likely to be younger, women, reside in high-poverty areas, and have hypertension, diabetes, obesity, worse kidney function and higher brain-natriuretic peptide at admission (Table). Over a median follow-up of 2.7 years [IQR: 0.9-4.9 years], there were 3,747 deaths; 2146 (26.2%) among whites, 1447 (27.8%) among AAs, and 154 (24.3%) among other ethnicities. AA adults had increased all-cause mortality compared to whites, with an adjusted HR 1.14 [95% CI: 1.06-1.23, p=0.001]. The race* poverty interaction p-value was 0.02, indicating that the association between race and all-cause mortality was significantly more pronounced among those residing in higher poverty areas (Table). This was not observed for AA adults in lower poverty areas or for other ethnicities. Conclusion: In this study, AA patients with HFpEF, residing in high poverty areas, had higher all-cause mortality rates compared to white patients. No racial differences in mortality were observed in lower poverty areas.
Abstract 4141399: Chronic Moderate Alcohol Consumption In ApoE <sup>-/-</sup> Mice Impaires Vascular Endothelial Function Through Redox Dysregulation of Rac1
Authors: Kerstin Seidel, Catherine Ha, Rebecca Johnson, Yanru Wang, Jingyan Han
Journal: Circulation (2024)

Background: Chronic alcohol consumption is known to impair endothelial function and contribute to cardiovascular disease. However, the effects of moderate alcohol consumption on vascular function, especially in the presence of atherogenic risk factors like hypercholesterolemia, remain inconsistent and unclear. Methods and Results: To simulate chronic moderate and heavy drinking in hypercholesterolemic conditions, ApoE deficient (ApoE−/−) mice were fed a Lieber-DeCarli liquid diet with ethanol (2g/kg/day for moderate and 5g/kg/day for heavy drinking) or isocaloric maltose (5g/kg/day as control) for 12 weeks. In vivo flow-mediated vasodilation (FMD) of the femoral artery was assessed at 6 and 10 weeks. Both moderate and heavy alcohol consumption significantly impaired endothelium-dependent FMD, while endothelium-independent FMD increased after 10 weeks, indicated by higher FMD values in the presence of L-NAME, an eNOS inhibitor. Moderate and heavy drinking also promoted aortic endothelial permeability (measured by Evan’s blue dye infiltration) and atherosclerotic lesions at the aortic root. In aorta and endothelium-rich lung tissues, protein S-glutathionylation levels were elevated in both drinking groups, coinciding with eNOS inactivation (reduced dimer to monomer ratio), impaired Rac1 RhoGTPase activity, and increased Rac1 glutathionylation. In human aortic endothelial cells, ethanol exposure dose-dependently promoted protein S-glutathionylation and lowered glutaredoxin-1 (Grx1) levels. Moderate ethanol treatment (25mM) alone had negligible impact on eNOS and Rac1 activities but caused endothelial dysfunction under metabolic stress or Grx1 knockdown, mirroring animal study findings. Conclusions: This study provides evidence that moderate alcohol consumption can cause vascular endothelial dysfunction in the presence of hypercholesterolemia. The underlying mechanism involves S-glutathionylation-centered redox dysregulation of Rac1 and eNOS.
Abstract 4140901: Compression-Only or Standard Cardiopulmonary Resuscitation for Out-of-Hospital Cardiac Arrest: A Systematic Review and Meta-analysis of Randomized Controlled Trials
Authors: Muhammad Ehsan, Arshbeer Singh Sandhu, Muhammad Arslan Arif Maan, OGECHUKWU OBI, Oliver Hervir, Mark Abdelnour, Mansoureh fattahi, Nayan Gandhi, Abuelgasim Mohamed, Ratan Pal Yadav, Jassim Shah
Journal: Circulation (2024)

Background: This meta-analysis aims to compare chest compression-only cardiopulmonary resuscitation (CO-CPR) with standard CPR (sCPR), which includes mouth-to-mouth ventilation, as potential strategies for managing out-of-hospital cardiac arrest (OHCA). Methods: We systematically searched various databases and registries such as MEDLINE, Embase, The Cochrane Library, and Clinicaltrials.gov to retrieve relevant studies. We used the revised Cochrane “Risk of bias” tool for randomized trials (RoB 2.0) to assess the risk of bias in included studies. Revman 5.4 was used to pool dichotomous outcomes under a random effects model. Results: A total of 4 RCTs were included in our meta-analysis. Our results indicate that CO-CPR was associated with a significantly increased survival to hospital discharge compared to sCPR (RR 1.22, 95% CI: 1.01 to 1.46) with minimal heterogeneity (I 2 = 0%). No significant difference was observed between the two groups regarding 1-day survival (RR 1.07, 95% CI: 0.94 to 1.23), survival to hospital admission with a good neurological outcome (CPC 1 or 2) (RR 1.10, 95% CI: 0.80 to 1.51), return of spontaneous circulation (RR 1.05, 95% CI: 0.95 to 1.17), and survival to hospital admission (RR 1.08, 95% CI: 0.93 to 1.25). Conclusion: This meta-analysis found that chest compression-only CPR (CO-CPR) significantly improves survival to hospital discharge compared to standard CPR for managing OHCA while yielding comparable results for other resuscitation outcomes.
Abstract 4141616: The Prognostic Role of Dynamic Cardiopulmonary Exercise Testing Variables: Assessing for Myocardial Reserve to Improve Risk Stratification
Authors: Stephan Olaya, Matthew Cochran, Mary Acosta, Justin Sipiora, Maria Poonawalla, Umar Siddiqi, Ryan Hoang, Anthony Kanelidis, Leo Gozdecki, Sara Kalantari, Stanley Swat, Mark Belkin, Jonathan Grinstein
Journal: Circulation (2024)

Background: Cardiopulmonary exercise testing (CPET) remains an important test for risk assessment in ambulatory heart failure patients to identify those who may benefit from advanced therapies, such as left ventricular assist device (LVAD) or heart transplantation (HT). The prognostic strength of cardiac performance variables at peak exercise, including oxygen consumption (VO 2 ), oxygen pulse (O 2 pulse) and circulatory power (CP) is known. We explored the prognostic utility of augmentation of these parameters between resting and peak stress conditions. Methods: We performed a retrospective analysis of ambulatory heart failure patients from the National Heart, Lung, Blood Institute funded REVIVAL and our institutional PREDICT-HF databases. Patients with heart failure that underwent CPET and ≥ 1-year of follow-up were included. The primary outcome was a composite of death, HT, or LVAD at 1-year following CPET. The absolute change (Δ) in CPET variables was defined as the difference between resting and peak values. Results: A total of 351 patients from PREDICT-HF (n=110) and REVIVAL (n=241) were included; mean age 58, 70% male, 31% Black, 59% non-ischemic, median NYHA functional class 3, median INTERMACS profile 6, and mean LVEF 26%. At 1-year, there were 61 events (17%), which included 20 deaths, 19 HTs, and 22 LVAD implants. The ΔVO 2 , ΔO 2 pulse, and ΔCP were all higher in the non-event group (all p&lt;0.001). The ΔVO 2 (odds ratio [OR]) 0.92; 95% CI 0.87-0.97; p = 0.006), ΔO 2 pulse (OR 0.85; 95% CI 0.76-0.93; p = 0.001), and ΔCP (OR 0.48; 95% CI 0.31-0.70; p&lt;0.001) were significant predictors of the primary outcome on univariate analysis. Only ΔO 2 pulse (OR 0.85 vs. 0.89) performed better on univariate analysis when compared to its peak counterpart. Peak CP (OR 0.37) remained the strongest predictor overall. Conclusions: The absolute change between resting and peak VO 2 , O 2 pulse, and CP were predictive of death, HT, or LVAD at 1-year. Further multivariate analysis and comparative statistics assessing the prognostic utility of augmentation of these parameters compared to isolated peak values are needed to determine clinical utility.
Abstract 4141279: Catch me if you flow slow: The temporal filter slow flow fact
Authors: Munehiro Kanegawa, Eisuke Kagawa
Journal: Circulation (2024)

Background: Slow flow phenomenon is impaired coronary flow during percutaneous coronary intervention (PCI) in absence of mechanical obstruction, and it is associated with deteriorated outcome. Filter device may prevent final slow flow; however, the impact of slow flow phenomenon with an intra-coronary filter device for STEMI is unclear. Objectives: We assessed the hypothesis that temporal filter slow flow (FSF) during procedures of reperfusion therapy end in Thrombolysis in Myocardial Infarction flow grade 3 (TIMI-3) in STEMI is not associated with myocardial infraction size, using cardiac magnetic resonance (CMR). Methods: STEMI patients who underwent coronary revascularization therapy and cardiac magnetic resonance (CMR) at about 4 days and 6 months between 2017 and 2023 were included. The patients were divided into groups (Group 1, FSF (-) during procedures with final TIMI-3; Group 2, FSF (+) with TIMI-3; Group 3, final angiogram was non-TIMI-3). Myocardial salvage index was calculated with area at risk using acute phase T2 high volume and chronic phase late gadolinium enhancement volume. Results: The age (Group 1 (n=31): median 70 y [interquartile range 43 -84] vs. Group 2 (n=23): 68 [35 - 81] vs. Group 3 (n=9): 72 [61 - 79], P = 0.386), prevalence of male (81% vs. 96% vs. 89%, P = 0.258), and door-to-balloon time (58 min [20 -218] vs. 65 [30 - 157], vs. 59 [25 - 111], P = 0.491) were similar between the groups. The relationship between salvage index and FSF was shown in figure1. The relationship between salvage index and myocardial blush grade was shown in figure 2. In the multivariate regressive analysis of the salvage index, chronic kidney disease (CKD), myocardial blush grade 3, door to balloon time and filter slow flow groups, CKD and myocardial blush grade 3 were found to be independently and significantly correlated. Conclusions: Non-myocardial blush grade 3, as a part of slow flow observed in the final angiogram, is associated with impaired myocardial salvage. However, temporal filter slow flow may not diminish myocardial salvage.