tbuckley/cabot-search huggingface dataset:
Abstract 16710: Racial Disparities in Outcomes in Women Undergoing Percutaneous Intervention
Authors: Micaela Iantorno, Rebecca Torguson, Deepakraj Gajanana, Paul Kolm, Toby Rogers, Itsik ben-dor, William O Suddath, Lowell Satler, Hector Garcia-garcia, William S weintraub, Ron Waksman
Journal: Circulation (2018)

Introduction: Cardiovascular disease is the leading cause of death in men and women, blacks and whites. Women are underrepresented in clinical studies. African-American women have a higher coronary heart disease mortality risk than their white counterparts. However, there exists limited outcomes data for black women (BW) compared to white women (WW) after percutaneous coronary intervention (PCI). Hypothesis: The aim of this retrospective analysis was to evaluate the 1 year major cardiovascular events (MACE) in patients undergoing PCI based on gender and race Methods: Within our PCI database we identified 4776 patients who underwent PCI from 2003 to 2016. Of those 1,916 were BW and 2,860 were WW. MACE/target vessel revascularization (TVR) at 30 days and 1 year were assessed and proportional Cox hazard model analyses was performed to assess outcomes after adjustment for confounding factors (i.e. age, BMI, presentation with acute M, diabetes, smoking, history of CAD, family history of CAD, hyperlipidemia, hypertension, prior coronary intervention, chronic kidney disease (CKD)). Results: Characteristics of the patient population is shown in the table. BW presented at younger age and had significantly higher rate of risk factors. BW were significantly sicker than WW. Periprocedural and in-hospital were similar between the 2 groups except for vascular complications more likely in WW (4.3% vs 2.6%; p=0.003). At 30 days and 1 year, the rate of MI, TVR and stent thrombosis (ST) was significantly higher in BW (Figure). There was a large difference in median income, $102,250 for WW vs. $80,150 for BW, but it had no effect on the outcome (HR = 1.00, p = 0.362). After adjusting for confounding factors BW were 1.6 times more likely to experience MI at 1 year than WW (HR 1.6, 05%CI 1.04-2.49, p= 0.03). Conclusions: In this large cohort of women with coronary artery disease undergoing PCI we observed significant race disparities in MI rate at 1 year even after adjustment for clinical presentation and cardiovascular risk factors
Abstract 16942: Reduced Gastrointestinal Bleeding in Patients With Improved Left Ventricular Function After Left Ventricular Assist Device Implantation
Authors: Aditya Mandawat, Anant Mandawat, Priya Vijayvargiya, Ravi Karra
Journal: Circulation (2018)

Introduction: Gastrointestinal bleeding (GIB) after continuous-flow left ventricular assist device (CF-LVAD) implantation is common, with an incidence estimated at 18-40% per year. While the pathophysiology of GIB in these patients is unclear, physiologic changes related to the absence of pulsatility may account for the high rates of GIB seen in these patients. Hypothesis: Improved left ventricular (LV) function (increased myocardial pulsatility) after LVAD implantation may be associated with decreased rates of GIB. Methods: We studied 119 consecutive patients with CF-LVADs implanted between March 2006-November 2016 who received serial transthoracic echocardiograms (TTE), including at least one pre-implant and one post-implant TTE. Left ventricular ejection fraction (LVEF) was assessed by experienced readers, with a kappa statistic between readers &gt;0.90. Improved LV function was defined as an improvement of at least 7% between the pre-implant LVEF and the best post-implant LVEF obtained with 9 months of the implantation date. Similarly, worsening LV function was defined as a decrease of at least 7%. Primary GIB was defined using INTERMACS adverse event criteria. Patients were followed until transplantation, device complication requiring explantation, or death. Results: The study sample was 58±12 years old, 72% male, and 63% Caucasian. Hemoglobin at implantation was 11±2 g/dL. Maximum LV recovery was seen a median of 103 (IQR 49-158) days after LVAD implantation. Improved LV function occurred in 25 (21%) patients, while LVEF remained stable or worsened in 94 (79%) of patients. When compared with patients whose LVEF remained stable or worsened, patients with improved LV function were more likely to be female (p=0.05). GIB occurred in 29 patients (24%). Improved LV function was associated with a significantly decreased risk of GIB (Figure; p=0.05). Conclusions: Improved LV function is seen in one-fourth of patients and is associated with a significantly decreased risk of GIB following CF-LVAD implantation.
Abstract 16598: Carnosine Synthetase Overexpression in Skeletal Muscle Promotes Functional Recovery of Ischemic Limb
Authors: Daniel Conklin, Luping Guo, Aruni Bhatnagar, Shahid P Baba
Journal: Circulation (2018)

Carnosine synthetase (ATPGD1) is an ATP grasp enzyme that catalyzes formation of histidyl dipeptides such as carnosine (β-alanine-histidine) and anserine (β-alanine-methyl histidine). These dipeptides are food constituents found in a high concentration in the skeletal muscle (10-20 mM) that have the abilities to chelate metals, scavenge lipid peroxidation products and buffer intracellular pH. These dipeptides are regarded as protective against injury and stress. Despite this knowledge, whether carnosine regulates angiogenesis is unknown. To assess this potential, a model of hindlimb ischemia (HLI) was surgically induced by femoral artery and vein ligation in the C57BL/6J (wild type, WT) mice provided drinking water without or with carnosine (1g/L) for 21 days post-surgery. C57BL/6J WT mice subjected to HLI and supplemented with carnosine had increased skeletal muscle expression of the dipeptide/histidine transporter (PHT1), carnosine transport, improved blood flow recovery, re-vascularization and regeneration of myocytes in the ischemic limb compared with mice without carnosine. To support that elevated skeletal muscle carnosine was beneficial in HLI, transgenic mice overexpressing ATPGD1 in the skeletal muscle were constructed. Transgenic (α-HSA-ATPGD1TG) mice had ~2-2.5-fold increase in carnosine (WT: 2.71±0.54 vs 7.40±0.54 nmoles/mg protein α-HSA-ATPGD1TG; p &lt;0.05) and anserine levels (WT: 3.65±1.12 vs 8.04±0.23 nmoles/mg protein α-HSA-ATPGD1TG p &lt;0.05) in the skeletal muscle than WT mice. At 2 and 3 weeks post-HLI surgery, α-HSA-ATPGD1TG mice had significantly improved blood flow recovery compared with the WT mice (2 weeks: α-HSA-ATPGD1TG: 59±3% vs 45±3% WT; p &lt;0.05; 3 weeks: α-HSA-ATPGD1TG: 65±4% vs 46±2% WT; p &lt;0.05). Because faster recovery of blood flow in the carnosine-supplemented mice was accompanied with increased expression of hypoxia inducible factor (HIF-1α) and vascular endothelial factor (VEGF) in the ischemic limb, we further investigated the mechanistic connection. Skeletal muscle myoblasts C2C12 cells pretreated with octyl-D-carnosine and subjected to 1 h of hypoxia, replacing oxygen with 95% N 2 and 5% CO 2 , had enhanced HIF-1α translocation, VEGF mRNA and secretion compared with untreated hypoxic and normoxic cells. Collectively, our results demonstrate that carnosine improves ischemia-stimulated angiogenesis potentially by stabilizing HIF1-α and promoting VEGF formation suggesting that carnosine may be a useful therapy in critical limb ischemia.
Abstract 16712: Cardiovascular Event Rates Among Patients With Peripheral Arterial Disease in a United States Administrative Insurance Claims Database
Authors: Katherine E Mues, Kiran Philip, Brian D Bradbury, Sebastian S Schneeweiss, Keri L Monda
Journal: Circulation (2018)

Introduction: A sub-analysis of the cardiovascular (CV) outcomes trial, FOURIER, showed that among patients with peripheral arterial disease (PAD), the PCSK9 inhibitor evolocumab reduced the risk of myocardial infarction (MI), stroke, and cardiovascular death by 27% over 2.2 years compared to those on moderate- or high-intensity statins. To contextualize the impact of these findings, we estimated rates of CV events and treatment utilization among a population with PAD in the real world. Methods: We identified patients with a first diagnosis of PAD between January 1, 2008 and October 1, 2016 in the Truven MarketScan claims database. Patient were required to have continuous enrollment 365 days prior to and 1 day following the index date. Medication use was evaluated in the one year prior; comorbidities were evaluated using all available data prior to index. Patients were followed until the occurrence of a CV hospitalization, disenrollment, death, or October 1, 2016. Event rates and corresponding 95% confidence intervals were calculated. Analyses were conducted in the Aetion platform. Results: We identified 565,942 subjects with PAD; mean age was 71 years, 49% were female, 67% had Medicare supplemental insurance, 37% had Type 2 diabetes (T2DM), 13% a prior MI or ischemic stroke (IS), and 10% critical limb ischemia (CLI). During baseline, 45% of patients filled an anti-hypertensive, 43% a statin, 18% an anti-platelet, and 11% an anti-coagulant. Patients were followed for a median of 1.4 years. Incident event rates were 42.7, 24.6, 12.9, 8.9, and 1.1 per 1000 person-years (py) for the composite, MI, coronary revascularization (CABG/PCI), IS, and unstable angina (UA) respectively. Rates were higher among those with history of MI or IS, T2DM, and CLI (Table). Conclusions: These findings suggest that among a real world population of PAD patients there is underutilization of effective therapies prior to diagnosis and substantial burden in terms of cardiovascular residual risk.
Abstract 16758: The Role of Estrogen Receptor Alpha in Preserving Right Ventricular Mitochondrial Respiration in Pressure Overload
Authors: Tik-Chee Cheng, Jennifer L Philip, Santosh Kumari, Diana M Tabima, Timothy A Hacker, Rongbo Li, Xin Sun, Kara Goss, Tim Lahm, Naomi C Chesler
Journal: Circulation (2018)

Background: Pulmonary arterial hypertension (PAH) occurs more often in women, but women exhibit better survival. Rodent models of PAH suggest a right ventricular (RV) protective effect of estrogen signaling through estrogen receptor alpha (ERα). While estrogen regulates mitochondrial biogenesis and function, the role of ERα in preserving RV mitochondrial function in the setting of pressure overload is unknown. Methods: Estrogen receptor alpha knockout (ERKO) rats were created using a CRISPR/Cas9 system. Male and female ERKO and littermate control (WT) rats underwent pulmonary artery banding (PAB) or sham surgery. After 10 weeks, RV systolic pressure (RVSP) and contractility as measured by dP/dt max were recorded by open-chest right heart catheterization. RV hypertrophy was measured by normalizing RV free wall weight to tibia length (TL). Permeabilized muscle fibers from the RV were placed in a high-resolution respirometer in the presence of substrates and inhibitors to measure mitochondrial respiration. Results: PAB caused a greater increase in RVSP (Fig. A) and contractility (Fig. B) in the ERKO compared to WT rats. WT and ERKO had comparable degrees of RV hypertrophy (Fig. C). RV muscle fiber respiratory control ratio (RCR) demonstrated a significant positive correlation with RVSP in ERKO rats (Fig. D) not found in WT rats, suggesting that pressure overload is associated with enhanced mitochondrial coupling in the absence of ERα. A decrease in State 4 ADP-depleted respiration in ERKO rats (Fig. E) accounts for the decrease in RCR. PAB did not alter Complex II or Complex IV respiration in either ERKO or WT rats. Conclusions: Whereas in the presence of ERα RV adaptation to pressure overload is independent of mitochondrial respiration changes, in the absence of ERα, pressure overload decreased State 4 ADP-depleted respiration, suggesting that ERα regulates RV mechanoenergetic remodeling due to pressure overload.
Abstract 16815: GJA1-20k, a Truncated Isoform of Connexin 43, Nucleates <i>De Novo</i> Actin Clusters
Authors: Rachel Baum, TingTing Hong, Andre G Kleber, Robin M Shaw
Journal: Circulation (2018)

Introduction: Connexin 43 (Cx43) gap junctions allow rapid communication of signals between cardiomyocytes. Loss of Cx43 gap junction coupling contributes to arrhythmogenesis. GJA1-20k, a truncated internally translated isoform of the Cx43 gene GJA1 , is necessary for full length Cx43 trafficking to intercalated discs for gap junction formation. GJA1-20k stabilizes actin filaments, necessary for the Cx43 delivery highway. The mechanism of GJA1-20k interaction with actin, while essential for gap junction formation, is still not known. Methods: Cell free individual actin dynamics were observed by TIRF microscopy. For real time imaging of actin nucleation and polymerization, glass bottom chamber slides were pre-incubated with 100nM N-ethylmaleimide myosin and loaded with Alexa Fluor 488-conjugated actin (Thermo Fisher) with GJA1-20k in ATP containing buffer. Actin binding assays were performed using a spin-down assay kit (Cytoskeleton, Inc.). Actin polymerization was studied by using pyrene labeled actin (Cytoskeleton, Inc.). Results: Cell free biochemical binding assays show that GJA1-20k binds to G-actin molecules, nucleating de novo actin clusters yet also surprisingly preventing G-actin polymerization. Pyrene actin assays further confirm that GJA1-20k alone does not promote polymerization. Cell free TIRF imaging also reveals that GJA1-20k promotes the formation of de novo G-actin clusters (Figure 1). Once a critical degree of nucleation is present however, polymerization occurs at a rate that promotes the formation of thicker actin fibers. Because GJA1-20k preferentially supports nucleation over polymerization, GJA1-20k introduces novel foci of new actin growth that, when a critical mass is present, rapidly overflows to polymerization. Conclusions: GJA1-20k nucleates de novo actin clusters, and thus is able to seed novel cytoskeleton growth patterns, dictating the direction of gap junction delivery.
Abstract 16756: Coxsackievirus Infection During Early Pregnancy Leads to Congenital Heart Defects
Authors: Vipul Sharma, Lisa Goessling, Anoop Brar, Pirooz Eghtesady
Journal: Circulation (2018)

Introduction: Coxsackievirus B (CVB), the most common cause of myocarditis, targets cardiomyocytes through the Coxsackie and Adenovirus Receptor which is highly expressed in the fetal heart. Association between maternal CVB infection and fetal cardiac malformations has not been studied. Hypothesis: CVB infection during early pregnancy may play a role in the pathogenesis of congenital heart disease (CHD). Methods: Pregnant C57Bl/6J mice were infected between embryonic days (E) 5-11 with CVB3 (Nancy strain) at doses 1x10 6 , 2.5x10 6 , and 5x10 6 TCID50. Presence of the virus was confirmed by RT-PCR and infectivity assay and quantified by qPCR. Fetal heart phenotype was assessed by histology and to determine changes at the molecular level after infection, RNA was collected from fetal hearts using laser microdissection and analyzed by RNA-Seq. The results were confirmed by immunohistochemistry and qPCR. To assess the potential clinical relevance of our observations in mice, we analyzed the sera from pregnant women for presence of antibody titers against of CVB. Results: Offspring of pregnant mice infected with CVB3 at different time points developed a spectrum of CHD (38.2%, n=78/204): ventricular septal defect, double outlet right ventricle, and non-compaction of the ventricular myocardium, along with fetal death. Infection at E9 led to the highest incidence of VSD compared to infection earlier (E5, E7 or E8) or later (E11) in gestation. Transcripts found to be differentially expressed between infected fetal hearts with VSDs compared with controls were mediators of the Transforming growth factor β and Extracellular matrix signaling pathways. Consistent with the former, expression levels of BMP2 and Smad1/5/9 mRNA were elevated. Simultaneously suppressed proliferation of cardiomyocytes in these fetuses was observed. Serum analysis from 66 pregnant women who had babies with heart defects showed elevated titers of antibodies against CVB underlining the clinical significance of CVB infection during pregnancy. Conclusions: In mice, there is a critical window during pregnancy where CVB infection leads to abnormal cardiac development, likely through reduction of cardiomyocyte proliferation mediated by elevated levels of BMP2 and Smad1/5/9. Collectively, the data confirm a link between CVB infection and CHD development in mouse and human.
Abstract 16925: KLF and AP1 Having Opposing Roles in Regulating Chromatin Accessibility and the Endothelial Enhancer Landscape Under Laminar vs. Disturbed Shear Stress
Authors: Jan-Renier Moonen, James Chappell, Li Dan, Minyi Shi, Aiqin Cao, Shalina Taylor, Zhixin Zhao, Lingli Wang, Michael P Snyder, Marlene Rabinovitch
Journal: Circulation (2018)

Background: Laminar shear stress (LSS) is associated with a vasculoprotective endothelial phenotype, while exposure to disturbed shear stress (DSS) is linked to endothelial dysfunction and vascular disease. Epigenetic changes in chromatin accessibility and enhancer dynamics are important regulators of gene expression. We hypothesized that LSS and DSS induce distinct transcription factors that recruit chromatin remodelers to change the chromatin landscape, making it permissive for either protective or disease-related gene expression profiles. Methods &amp; Results: Human pulmonary arterial endothelial cells were exposed to LSS (15 dyne/cm2) or DSS (±3 dyne/cm2, 0.8 Hz; and static) for 24h and analyzed by ATAC-Seq and RNA-Seq. Exposure to LSS resulted in increased chromatin accessibility, predominantly in regions within 100 kb of transcription start sites. These changes correlated with induction of protective, and suppression of disease-related genes. Many differentially accessible regions were also differentially marked by H3K27ac and H3K4me1 enhancer marks, as identified by ChIP-Seq. Motif analyses found enrichment for KLF binding sites in enhancers that are open under LSS vs. enrichment for AP1 at enhancers that are open under DSS. ChIP-Seq for KLF and AP1 confirmed differential binding at those sites. Gain-and-loss of function studies using a constitutive active mutant of MEK5, which induces KLF akin to LSS, and RNAi for KLF and AP1 confirmed that these factors were required to differentially mediate accessibility changes under LSS and DSS. We then used IP-MS to identify the chromatin remodelers recruited by KLF, and uncovered several components of the SWI/SNF nucleosome remodeling complex. Co-IP assays confirmed interaction of SWI/SNF with KLF under LSS. This was further documented by in situ proximity ligation assays. Under conditions of DSS we observed nuclear translocation of AP1 member ATF2 that interacts with c-Jun, which is enriched at enhancers that are open under DSS. Conclusions: KLF and AP1 differentially regulate the endothelial enhancer landscape under laminar vs. disturbed shear stress, which culminates in protective or disease-related gene expression profiles.
Abstract 16745: Incremental Prognostic Value of Get With the Guidelines Heart Failure Risk Score and Comorbidity in Patients Admitted for Acute Decompensated Heart Failure: Insights From Osaka Prefectural Acute Heart Failure Registry (OPAR)
Authors: Kiyomi Kayama, Takahisa Yamada, Takashi Morita, Yoshiro Furukawa, Syunsuke Tamaki, Yusuke Iwasaki, Masato Kawasaki, Atsushi Kikuchi, Tsutomu Kawai, Masahiro Seo, Makoto Abe, Jun Nakamura, Kyoko Yamamoto, Masatugu Kawahira, Kazuya Tanabe, Masatake Fukunami
Journal: Circulation (2018)

Background: The Get With the Guidelines-Heart Failure (GWTG-HF) risk score was recently developed to predict in-hospital mortality in patients (pts) admitted with acute decompensated heart failure (ADHF). On the other hand, comorbidity is also associated with poor clinical outcome in HF patients. However, there is no information available on the prognostic value of combining GWTG-HF risk score and comorbidity in patients admitted for ADHF. Methods: We prospectively studied 396 ADHF patients with survival discharge. GWTG risk score consists of 7 admission variables (blood urea nitrogen, systolic blood pressure, age, sodium, heart rate, race, and lung disease). Comorbidity was measured with the Age-adjusted Charlson comorbidity index (ACCI) which is commonly used for the evaluation of the comorbid condition which is weighted and scored, with additional points added for age. The endpoint was all-cause death (ACD). Results: During a follow-up period of 2.2±1.4 years, 114 patients had ACD. At multivariate Cox analysis, GWTG-HF risk score (p&lt;0.0001) and ACCI (p=0.0077) were significantly and independently associated with ACD, after the adjustment with sex, NYHA class, history of worsening heart failure hospitalization, LVEF, eGFR and plasma BNP level at the discharge. Patients with both higher GWTG-HF risk score (&gt;39 by ROC analysis, AUC 0.714 [95%CI 0.667-0.758]) and higher CCI (&gt;5 by ROC analysis, AUC 0.653 [95%CI 0.604-0.700]) had a significantly increased risk of ACD than either or none of them (46% vs 28% vs 7%, p&lt;0.0001). Adjusted hazard ratio in patients with both higher GWTG-HF risk score and ACCI was 9.4 (95%CI 4.3-20.6), which was two-fold of that in patients with either of them (4.5[95%CI 2.0-10.1]). Conclusions: GWTG-HF risk score and comorbidity had an prognostic incremental value in patients admitted for ADHF.
Abstract 16918: Non-Invasive Diagnosis of Pulmonary Vascular Disease Using Inhaled 129-XenonMRI
Authors: Aparna Swaminathan, Elianna Bier, John Nouls, Karla Kennedy, Samantha Womack, Susana Almeida-Peters, Bastiaan Driehuys, Sudarshan Rajagopal
Journal: Circulation (2018)

Introduction: Pulmonary arterial hypertension (PAH) carries significant morbidity and mortality. Its diagnosis requires meeting specific hemodynamic and clinical criteria and can be particularly challenging in patients with concomitant heart or lung disease. Hyperpolarized 129 Xenon ( 129 Xe) magnetic resonance imaging and dynamic spectroscopy may overcome these challenges, providing a non-invasive new tool to diagnose and monitor PAH. This is based on its unique cardiogenic oscillations reflected in the 129 Xe spectrum as it transfers to red blood cells (RBCs, Figure). Hypothesis: We hypothesized that changes in the RBC 129 Xe spectroscopic parameters will discriminate PAH from healthy volunteers, patients with left heart failure, idiopathic pulmonary fibrosis (IPF) or chronic obstructive pulmonary disease (COPD). Methods: 129 Xe spectra were dynamically acquired every 20 milliseconds in all subjects. At each time point, the amplitude, chemical shift, linewidth, and phase of the 129 Xe-RBC resonance was calculated. Cardiogenic oscillations in these spectral parameters were compared using the Kruskal-Wallis test, followed by pairwise comparisons with the Wilcoxon rank sum test. Results: A total of 14 healthy volunteers, 10 subjects with PAH, 5 subjects with left heart failure, 9 subjects with IPF, and 7 subjects with COPD underwent 129 Xe spectroscopy. In patients with PAH, RBC amplitude oscillations were significantly reduced compared to those with IPF (p &lt; 0.001) or healthy subjects (p = 0.0064, Figure). Oscillations in chemical shift and phase were only observed in IPF patients. Conclusions: 129 Xenon dynamic spectroscopy produces different RBC signatures in patients with PAH, IPF, and healthy volunteers. 129 Xe uniquely probes the alveolar-capillary interface and can thus detect the effect of arterial lesions on capillary blood volume oscillations.