tbuckley/cabot-search huggingface dataset:
Abstract 15072: Lipoprotein(a) Regulates Vascular Redox State and Predicts Adverse Cardiovascular Outcomes in Coronary Artery Disease
Authors: Murray D Polkinghorne, Cheng Xie, JAGAT SINGH CHAUHAN, Andrea Baragetti, Parijat Patel, Edmarcia de Araujo, Elizabeth Wahome, Christos Kotanidis, Ioannis Akoumianakis, George Krasopoulos, Nicholas Walcot, Ileana Badi, Keith M Channon, Tomasz J Guzik, Giuseppe Danilo D Norata, Charalambos Antoniades
Journal: Circulation (2023)

Introduction: Lipoprotein(a) [Lp(a)] has an established link with cardiovascular disease yet the underlying mechanisms are incompletely understood. Methods: In 1472 cardiac surgery patients, we compared patients with any alternative allele from ≥3 of 7 Lp(a)-increasing SNPs (alternative variant group) to those with no alternative alleles in any of these SNPs (reference variant group). Plasma Lp(a) was measured using the Randox assay. The arterial redox state was measured using lucigenin chemiluminescence, where the contribution of NADPH-oxidases (NOX) and uncoupled nitric oxide synthases (eNOS) to superoxide (O 2 .- ) production was quantified. Arterial biopsies were used to perform RNA-sequencing. Patients were followed up for a median of 7.8 years. Results: Alternative variant patients had significantly higher plasma Lp(a) (A), plasma apolipoprotein-B (ApoB) (p&lt;0.01), and arterial basal-O 2 .- (B). Patients with medium/high vs low plasma Lp(a) had significantly increased plasma ApoB (p&lt;0.0001) and arterial basal-O 2 .- (C) as well as reduced tetrahydrobiopterin bioavailability (p&lt;0.01). The association between Lp(a) and arterial basal-O 2 .- was ApoB-independent. Non-diabetic patients in the alternative variant group and those with medium/high plasma Lp(a) had significantly increased arterial basal and eNOS-derived (p&lt;0.05), but not NOX-derived, O 2 .- . The transcriptomic profile of patients with high vs low plasma Lp(a) showed significantly downregulated PI3K-Akt signalling (D). Genetic tools revealed that Lp(a) is causally associated with an increased risk of cardiovascular death in an ApoB-independent manner (E). Patients with medium/high plasma Lp(a) also had a significantly increased risk of cardiovascular death (adj. HR=4.274 [95%CI: 1.227, 14.925], p=0.022). Conclusions: We demonstrate that Lp(a) increases arterial O 2 .- through dysregulating vascular insulin signalling, mediating its association with cardiovascular disease.
Abstract 18062: Association of Leisure Time Physical Activity With Incidence of Heart Failure With Preserved and Reduced Ejection Fraction in the Million Veteran Program
Authors: Shamlan Sheikh, Michel Farah, Andrew Dey, Jacob Joseph, John M Gaziano, Luc Djousse
Journal: Circulation (2023)

Introduction: Heart failure (HF) continues to be the leading cause of hospitalization in older men in the United States. While previous studies have reported beneficial effects of leisure time physical activity (LTPA) on cardiovascular disease, it is unclear whether LTPA is associated with incidence of HF with reduced or preserved ejection fraction (EF). The current study examined the association of LTPA with incidence of HF in US Veterans in the Million Veteran program. Methods: The MVP is a nationally representative, prospective cohort study of Veterans which started in 2011 and has currently enrolled over 900,000 participants. Self-reported vigorous, moderate, and light activity was collected at baseline and converted into hours of metabolic equivalent of task per week (MET-h/week). HF was ascertained using ICD-9 code of 428.x or ICD-10 code of I50.x. We defined incident HFpEF using ejection fraction ≥ 50% and HFrEF using ejection fraction ≤ 40%. Cox proportional hazard model was used to compute multivariable adjusted hazard ratio (HR) and 95% confidence intervals (95%). Results: Among 461,267 Veterans analyzed, the mean age was 63.9 years (SD 12.7) and 95% were men. Participants were followed for 5 years, with 25,192 new cases of HF (12,226 HFrEF and 10,422 HFpEF) occurred. In a multivariable adjusted model, LPTA was inversely associated with incident HF with HR (95% CI) of 1.00 (ref), 0.82 (0.79-0.86); 0.67 (0.63-0.71); 0.65 (0.62-0.69); and 0.50 (0.48-0.53), from the lowest to the highest quintile of LTPA, respectively, p for linear trend &lt;0.00001. Similar inverse associations were observed for HFpEF as well as HFrEF (p&lt;0.0001 each). Conclusion: Our data are consistent with inverse association of LTPA with incidence of HF including HFpEF and HFrEF.
Abstract 18465: Regulation of Collagen Synthesis and Fibrosis Development in Skeletal Muscle by La-Related Protein 6 (LaRP6)
Authors: Tadashi Yoshida, C. S Lott, Sergiy Sukhanov, Patrice Delafontaine
Journal: Circulation (2023)

Introduction: Excessive extracellular matrix (ECM) accumulation, especially collagens, impairs muscle function in muscular dystrophies, aging and muscle trauma (fibrosis). We have found increased skeletal muscle fibrosis in congestive heart failure (CHF) conditions, likely contributing to the impaired muscle functions. Hypothesis: We hypothesized that LARP6 (La Ribonucleoprotein Domain Family Member 6), an mRNA binding protein that coordinates efficient translation of Collagen I α chains, regulates collagen synthesis during skeletal muscle fibrosis in CHF conditions. Approach: Skeletal muscle fibrosis was analyzed in two mouse models, angiotensin II (Ang II) infusion and left anterior descending artery (LAD) ligation. Expression and subcellular localization of Collagen I, Larp6 and myogenic markers (myogenin and Myh3) were analyzed by qRT-PCR, western blotting, in situ hybridization (RNAScope) and immunostaining in hindlimb muscles in vivo and primary myoblasts and fibro/adipogenic progenitor (FAP) cells in vitro . Collagen I levels were also analyzed by picrosirius red staining (PSR). These analyses were performed in a newly-generated Larp6 knockout (Larp6 -/- ) mice. Results: In both Ang II and LAD ligation models, Collagen I mRNA and protein levels were increased together with LARP6, suggesting that LARP6 may regulate Collagen I synthesis in these conditions. In cultured myoblasts and FAPs, LARP6 protein was co-localized with Col1a1 mRNA at endoplasmic reticulum (ER). TGF-β treatment increased the LARP6 and Col1a1 mRNA co-localization, associated with increased pro-collagen I protein levels. Although Larp6 deficiency did not alter basal Collagen I levels, Collagen I induction in fibrotic conditions was decreased in Larp6 -/- mice. We found that thick collagen fibers were more significantly decreased compared to intermediate or loosely-packed thin collagen fibers (PSR signal analysis under the polarized microscope). Conclusions: These data suggest that LARP6 regulates Collagen I protein synthesis and its filament assembly likely in ER by binding to Col1a1 mRNA upon fibrosis induction. Suppression of LARP6 may be a therapeutic strategy to prevent pathophysiological fibrosis development in skeletal muscle.
Abstract 18837: Association of Urinary Catecholamines and Their Metabolites With the Use of Electronic and Combustible Cigarettes
Authors: Remy Poudel, Shen Li, ROSE MARIE O ROBERTSON, Jessica L Fetterman, Sanjay Srivastava, Haoyun Hong, Juan Zhao, Naomi M Hamburg, Aruni Bhatnagar, Rachel J Keith
Journal: Circulation (2023)

Nicotine, present in combustible cigarettes, is a strong sympathomimetic drug, and many of the cardiovascular and metabolic effects of smoking have been linked to increases in catecholamine production. However, it is not known whether vaping also leads to an increased catecholamine formation. Therefore, we measured the urinary catecholamines and their metabolites associated with vaping and smoking, or no tobacco use. Healthy adults 18-45 yoa who use tobacco products were asked to vape for every 30sec for 10min, smoke 1 cigarette, or inhale through a straw (sham) prior to providing urine samples three times: before tobacco use (T0), one hour (T1), and two hours (T2) after tobacco exposure. Catecholamines and their metabolites were measured in urine samples containing internal standards analyzed on a LC/MS/MS. Participants were categorized by the product used at the study visit: combustible cigarettes (n=70), e-cigarette (n=171), or sham use of a straw (n=82). Log transformed catecholamines and metabolites, normalized to urinary creatinine, were compared among each tobacco use group. Generalized linear models were used to estimate the associations between the outcomes and tobacco product use at each time point, adjusting for age, race and sex seen in table 1. At T0, smoking was associated with lower metanephrine, 5-hydroxindole-3-acetic acid, and vanillymandelic acid. At T1, after vaping normetanephrine and 3-methoxytyramine, epinephrine and homovanillic acid were higher. After smoking, norepinephrine, dopamine, normetnephrine, epinephrine and homovanillic acid were higher at T1. Whereas at T2 there was lower 5-hydroxindole-3-acetic acid in e-cigarette users. Our findings that both vaping and smoking are associated with increased urinary catecholamines or their metabolites, suggesting that the use of either product could elevate CVD risk due to repeated sympathetic stimulation. Catecholamines could be useful as a biomarker of harm for tobacco use.
Abstract 15750: Impact of Acute Heart Failure on COVID -19 Patients: An Insight From Nationwide Inpatient Sample
Authors: Nouraldeen Manasrah, Lalitsiri Atti, Sanchit Duhan, Shafaqat Ali, Tarec Micho, Anoop Titus, Krutarth K Pandya, Neel N Patel, yasar sattar, Wael AlJaroudi, M Chadi C Alraies
Journal: Circulation (2023)

Introduction: Patients with COVID-19 had experienced adverse cardiovascular outcomes, such as myocarditis, MI, and Heart Failure (HF). Among them, HF has emerged as the most common critical complication during COVID-19 exacerbations, potentially leading to increased mortality rates and poorer clinical outcomes. However, there is a lack of available data to thoroughly investigate the consequences of acute HF in patients admitted with COVID-19. Methods: We analyzed the Nationwide Inpatient Sample (NIS) dataset to select COVID-19 patients over 18 years old who were hospitalized during 2020, in the United States (US) using ICD-10. Based on the presence of acute HF, patients were divided into two cohorts. Propensity score was used to match patients across various factors including age, race, sex, and comorbidities. Results: A total of 1,666,960 COVID-19 patients were hospitalized in 2020, of which 156,755 (9.4%) had associated HF. COVID-19 patients with HF had a mean age of (72.38±13.50) years compared to (62.3 ± 17.67) years for patients without HF. HF patients had a higher prevalence of HTN, hyperlipidemia, type 2 diabetes, smoking, and preexisting cardiovascular disease. After propensity matching, HF patients had higher rates of in-hospital mortality (23.86% vs 17.63%, p&lt;0.001), acute MI (18.83% vs 10.91%, p&lt;0.001), acute stroke (0.78% vs 0.58%, p=0.004), cardiogenic shock (2.56% vs 0.69%, p&lt;0.001), and sudden cardiac arrest (5.54% vs 3.41%, p&lt;0.001) compared to those without HF. Conclusions: COVID-19 patients admitted with acute HF had worse clinical outcomes and higher mortality rates. In addition to a higher length of stay and healthcare compared with patients without HF.
Abstract 17143: Lorundrostat for Treatment of Obesity-Related, Aldosterone-Dependent Hypertension - An Endotype-Specific, Targeted Approach to the Treatment of Uncontrolled Hypertension
Authors: David Rodman, Borut Cizman
Journal: Circulation (2023)

Hyperaldosteronism manifests as low renin hypertension (HTN) with endothelial dysfunction and vascular fibrosis. In the aging vasculature, these pathological changes may be exacerbated by non-genomic aldosterone signaling via GPER (GPR30), which is not inhibited by mineralocorticoid receptor antagonists (MRA). In trials with healthy subjects and patients with uncontrolled HTN, the novel, highly selective aldosterone synthase inhibitor, lorundrostat, reduced median morning plasma aldosterone concentration (PAC) by approximately 70%. PAC reduction was dose-dependent and associated with a mean placebo-adjusted reduction in systolic blood pressure (BP) of -16.7 mmHg (N=15, p&lt;0.01, 90% CI: -25.5 to -7.9 mmHg) and -12.3 mmHg (N=12, p&lt;0.03, 90% CI: -21.6 to -3.1 mmHg) in subjects with body mass index (BMI) &gt; 30 kg/m 2 receiving 50mg or 100mg QD of lorundrostat, respectively. In contrast, in non-obese individuals, BP reductions were modest and not statistically significant. Salutary BP effects of 100mg QD lorundrostat at week 8 were observed in individuals with normal to high renin (N=30, -11.4 ± 2.5 mmHg) and low renin (N=25, -11.9 ± 2.8 mmHg). Linkage between obesity, HTN and increased aldosterone has been suggested by studies in a mouse model of obesity, hyperleptinemia and HTN. In this model, both leptin receptor blockade and lorundrostat restored normal BP. As anticipated, in the Phase 2 trial, mean serum leptin was elevated at baseline in obese (N=103, 37.8 ± 2.4 ng/mL) v. non-obese (N=88, 21.6 ± 1.9 ng/mL, p&lt;0.001) individuals with uncontrolled HTN and could be a useful biomarker to identify lorundrostat-responsive HTN. MRAs are recommended as fourth-line therapy for resistant HTN. However, MRAs can be associated with hormonal side-effects and stimulate excess aldosterone production that may increase non-genomic signaling, endothelial dysfunction and vessel wall remodeling. Lorundrostat has neither of these liabilities and may be an important new antihypertensive. Renin-independent, leptin- and aldosterone-dependent HTN defines a unique endotype in obese hypertensive individuals. Endotype-targeted therapy may allow early identification, intervention and improved BP control in obese individuals.
Abstract 13917: Predictors of Ventricular Arrhythmias in Patients With Left Ventricular Ejection Fraction Improvement to &gt;35% Following Cardiac Resynchronization Therapy
Authors: Saadia Sherazi, Ilan Goldenberg, Scott McNitt, Nikhila Rao, Nilesh Rao, Ahmed A Shah, Mehmet K Aktas, Valentina Kutyifa, Wojciech Zareba, Krishna Rao
Journal: Circulation (2023)

Introduction: Patients undergoing cardiac resynchronization therapy with a defibrillator (CRT-D) show significant improvement in LVEF. We designed this study to identify predictors of ventricular arrhythmic (VA) events among patient with LVEF improvement &gt; 35% after one year of treatment with CRT-D. Hypothesis: We hypothesized that LVEF improvement &gt; 35% is associated with a decreased risk of VA events. Methods: Patients randomized to CRT-defibrillator from the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) trial with LVEF &gt; 35% at 12 months were included in this analysis (N=651). Predictors of an appropriate ICD therapy for VA subsequent to one year were evaluated by cox regression model. Cumulative probability of first event was analyzed by Kaplan Meier Method with time for follow-up beginning at 1 year after device implantation. Results: The average follow-up was 2.04 ± 0.83 years. We identified 3 independent predictors of VA among patients treated with CRT-D subsequent to LVEF improvement to &gt; 35%: (1) baseline non-LBBB morphology (HR=1.93; 95% CI,1.23-3.04; p= 0.004); (2) the occurrence of VA during first year post CRT-D implant (HR=4.91 [95% CI, 2.99-8.07]; p&lt;0.001); and (3) lower range improvement in LVEF (36-40% vs. &gt;40%; HR =1.97 [95% CI 1.21-3.20]; p= 0.006). When compared with patients with 0 risk factors, having one and 2 or more risk factors had significantly higher risk of VTA (2-year rate of VT/VF = 4%, 11% and 32% respectively; HRs = 2.9 [p=0.002]and 7.9 [p=&lt;0.001], respectively [Figure]). Conclusions: We identify a sub-group of patients who remain at high risk of VTA despite improvement in LVEF &gt; 35% with CRT-D. Having a baseline non-LBBB morphology, experiencing VA during the first year post CRT-D, and lower-range LVEF improvement are associated with high risk of future arrhythmias, with a cumulative effect.
Abstract 13607: The Lipoprotein(a)-Induced Soluble CD36/Interleukin-6/RAS Homolog Family Member A-GTP Signaling Axis Promotes M1 Macrophage Polarization in Coronary Artery Spasm
Authors: Ming-Yow Hung, Chi-tai Yeh, Vijesh Kumar Yadav, Iat-Hang Fong
Journal: Circulation (2023)

Background: We previously demonstrated that lipoprotein(a) (Lp(a)) mediated coronary artery spasm (CAS) through α7-nAChR/p38 MAPK/IL-6/RhoA-GTP signaling stimulation, macrophage M1 polarization and activation of human coronary artery smooth muscle cells (HCASMCs). While CD36, as a scavenger receptor for oxidized low-density lipoprotein, was correlated with coronary vasoconstriction in an in-vivo study, whether Lp(a) effects are related to soluble CD36 (sCD36) dependent/IL-6/RhoA-GTP inflammatory signalling remain unknown. Methods: In patient monocyte-derived macrophages (PMDMs) and HCASMCs the relevance of Lp(a)/sCD36/IL-6/RhoA-GTP signaling axis were investigated through computational biology and experimental approaches. Results: Plasma sCD36 levels in 25 CAS patients were significantly higher than that in 10 controls (p &lt; 0.01). Serum Lp(a) level was positively correlated with sCD36 (r 2 =0.41, p &lt; 0.01) in patients with CAS rather than without CAS. The RNA-sequencing revealed a significant and strong co-overexpression between the CD36 and RhoA in PMDMs and HCASMCs. Compared with untreated or low-density lipoprotein (LDL)-treated macrophages, Lp(a)-treated macrophages exhibited markedly enhanced CD36 mRNA expression (p &lt; 0.01) and activity (p &lt;0.01), in vitro and ex vivo . Lp(a), but not LDL, preferentially stimulated CD80+ macrophage (M1) polarization. While shRNA- mediated or Amentoflavone-, a natural CD36 suppressor, mediated functional loss of CD36 lowered Lp(a)-induced CD80+ macrophage pool, shCD36 and Overexpressed-CD-CD36 suppressed and activated Lp(a)-upregulated sCD36, TNF-α, NFκB, IL-6 and RhoA-GTP protein expression levels, respectively, in HCASMCs. Conclusion: Lp(a) stimulated sCD36/IL-6/RhoA-GTP signaling in macrophages from CAS patients and HCASMCs, suggesting the contribution of Lp(a)-induced sCD36/IL-6/RhoA-GTP signaling, macrophage M1 polarization, and inflammation of HCASMCs in CAS development.
Abstract 13951: Change in Albuminuria Measured by Urine Albumin-to-Creatinine Ratio (UACR) and Associated Clinical Outcomes in Patients With Chronic Kidney Disease (CKD) Associated With Type 2 Diabetes (T2D)
Authors: Navdeep Tangri, Qixin Li, Yan Chen, Rakesh Singh, Keith A Betts, Youssef M Farag, Scott Beeman, Yuxian Du, Sheldon X Kong, Todd Williamson, Aozhou Wu, Manasvi Sundar, Kevin M Pantalone
Journal: Circulation (2023)

Introduction: The impact of change in albuminuria measured by UACR on key clinical outcomes (overall survival [OS], a composite cardiovascular [CV] outcome, and kidney disease progression) in patients (pts) with CKD associated with T2D is understudied. Hypothesis: A decreased UACR is associated with a lower risk of clinical outcomes, while an increased UACR is associated with a higher risk of clinical outcomes. Methods: Adult pts with an elevated UACR ≥30 mg/g (initial test) after T2D and CKD diagnosis were identified from the Optum EHR database (1/2007-9/2021). UACR change was categorized as increased (&gt;30% change), stable (-30% to 30%), or decreased (&lt;-30%) based on the percentage change between the initial test and the last test (between 6 to 24 months after the initial test). Clinical outcomes, including OS, a composite CV outcome (CV death, myocardial infarction, stroke, or heart failure hospitalization), and kidney disease progression (≥40% eGFR decline or kidney failure) were evaluated after the last UACR test using Kaplan-Meier analysis. Hazard ratios (HR) of clinical outcomes for UACR change were estimated using Cox proportional hazard models adjusting for baseline characteristics. Results: Among 160,382 pts (median follow-up: 2.9 years), 89,562 had decreased UACR, 35,117 had stable UACR, and 35,703 had increased UACR. Compared with pts with stable UACR, pts with decreased UACR had significantly lower risks for all clinical outcomes (Figure) with adjusted HR of 0.93 for OS, 0.93 for the composite CV outcome, and 0.84 for kidney disease progression, while pts with increased UACR had significantly higher risks for OS (HR=1.24), the composite CV outcome (HR=1.24), and kidney disease progression (HR=1.41). Conclusions: In pts with CKD associated with T2D, &gt;30% UACR decrease was associated with a lower long-term risk of overall mortality, CV events, and kidney disease progression. These findings highlight the importance of albuminuria monitoring in these pts.
Abstract 11958: Incidence and Predictors of In-Hospital Complications After Myocardial Infraction in Contemporary Clinical Practice: Findings From the FRENCHIE Myocardial Infarction Cohort
Authors: Gilles Lemesle, Guillaume Cayla, Romain Gallet de Saint-Aurin, Celia Nekrouf, Alexandra Rousseau, Gregory DUCROCQ, Denis Angoulvant, Pierre COSTE, Franck Boccara, Thibault Lhermusier, Gilles Baronne Rochette, Olivier Dubreuil, Philippe G Steg, Nicolas Danchin, Tabassome Simon
Journal: Circulation (2023)

Introduction: It is important to identify patients presenting with myocardial infarction eligible for early hospital discharge in order to avoid prolonged hospitalizations and reduce costs. Hypothesis: From a contemporary French nationwide MI cohort, we aimed to analyze incidence and correlates of in-hospital MI complications. Methods: French Cohort of Myocardial Infarction Evaluation (FRENCHIE) is a large ongoing MI registry, which collects data from all patients admitted for MI &lt; 48h of symptom onset in 21 French centers. In-hospital complications were collected and patients who experienced complications were compared to those who did not. Results: Overall, 9692 patients presenting with MI were enrolled (5325 STEMI (55%) and 4367 NSTEMI). Among these, 2755 (28%) presented at least one complication during hospitalization. The median length of stay was 4 days [3-7]. The complications were: high degree AV block (2.4%), atrial arrhythmias (7.7%), ventricular arrhythmias (5%), reinfarction (including stent thrombosis) (0.9%), stroke (0.6%), mitral valve and chordae rupture/tear (1.4%), ventricular free wall rupture (0.1%), ventricular septal defect (0.2%), tamponade (0.2%), heart failure (Killip class &gt;1) (15.4%) including cardiogenic shock (3.2%) and need for assistance (1.3%), LV thrombus (1.5%), acute renal failure (4.2%), major bleeding (0.7%) and in-hospital death (2.9%). Independent predictors of the absence of any complications were: younger age (OR=0.97 and 95%CI=[0.96-0.97]), absence of PAD (1.4 [1.2-1.8]), absence of AF (2 [1.6-2.5], absence of HF (2.3 [1.7-3.1]), presentation as NSTEMI (as compared to STEMI) (1.6 [1.4-1.8]), successful PCI (0.6 [0.5-0.7]), heart rate (0.98 [0.98-0.99]), systolic blood pressure (1.01 [1.00-1.01]), creatinine (0.98 [0.97-0.99]), hemoglobin (1.06 [1.03-1.10]), leucocytes (0.94 [0.93-0.96]) and CRP (0.99 [0.99-1.00]). Conclusions: In-hospital complications after MI are still frequent (more than 1/4 of patients) and driven by atrial arrhythmias and heart failure. Patients presenting with inaugural NSTEMI successfully revascularized, with no history of cardiovascular disease, and normal heart rate, systolic blood pressure and biology parameters may be targeted for early discharge.