tbuckley/cabot-search huggingface dataset:
Abstract 16691: Racial Differences in Heart Failure With Preserved Ejection Fraction: A Proteomic Analysis
Authors: Cynthia L Sanchez, Joyce Njoroge, Stan A Swat, Sanjiv J Shah
Journal: Circulation (2018)

Introduction: Heart failure with preserved ejection fraction (HFpEF) is common in African Americans (AAs). AAs with HFpEF tend to have lower natriuretic peptide levels, higher body mass index, worse hypertension, and higher risk for HF hospitalization than whites with HFpEF. Whether the underlying pathogenesis of HFpEF in AAs is different than whites is unclear. Hypothesis: Proteomic analysis could identify novel proteins that differ by race/ethnicity among HFpEF patients. Methods: 129 HFpEF patients (LVEF &gt;50% and elevated LV filling pressures by invasive hemodynamics, echocardiography, or BNP &gt; 100 pg/ml) were prospectively enrolled. Race/ethnicity was ascertained by self-report, and patients were stratified into 2 groups (AAs [n=23] and whites [n=94]), with the remaining patients (n=12) excluded. Biomarkers were quantified using the Olink antibody-based proximity extension assay technique (CVD2, CVD3, and inflammation panels). Each of the 276 biomarkers were compared between groups (AAs vs. whites) using multivariable logistic regression analysis adjusted for age, sex, BMI, hypertension, and creatinine. P-values were adjusted for multiple comparisons using false discovery rate (FDR). Principal component analyses (PCA) analyses were also used to analyze biomarker data. Results: Mean age was 70±12, 58% were female, and 20% were AA. History of HTN was more common in AAs compared to whites (96% vs. 72%, p=0.014); comorbidities were otherwise similar between the 2 groups. On multivariable analysis, 13/276 biomarkers were significantly different between groups after FDR correction: PSGL1, CXCL1, PRSS8, RAGE, CCL15, IL18, CPB1, CXCL5, BDNP, XCL1, THBS2, IL18, and CCL23. The top hit (PSGL1, P-selectin glycoprotein ligand 1), was significantly different between AAs and whites after multivariable adjustment (p=1.2 x 10 -9 ). PSGL1 is involved in the binding of cell adhesion molecules to the endothelium and white blood cells. Prior (non-HF) studies have found that RAGE (receptor for advanced glycation endproducts) levels are lower in AAs than whites, and low RAGE is associated with a number of chronic diseases. Of the top 10 principal components, 4 were significantly different between whites and AAs after multivariable adjustment, suggesting that groups of proteins differ between AAs and whites. Conclusions: On proteomic analyses, there are significant differences in circulating biomarkers between AAs and whites with HFpEF. If validated, these data may provide insight into racial differences in HFpEF pathogenesis and outcomes.
Abstract 16640: 2D Echocardiography Correlation Data Among Different Clinical Diseases
Authors: George M Yousef, Nader G Abraham, Ellen Thompson, Joseph I Shapiro
Journal: Circulation (2018)

Introduction: Different systemic disease affect the heart to varying degrees. However traditional echocardiographic parameters are somewhat limited with respect to sensitivity and specificity. Methods: Retrospective chart view of 98 patients in our Echo lab. Clinical and echocardiographic data were obtained. Correlation analysis was performed using the R programming language examining the impact of Diabetes Mellitus (DM), Coronary Artery Disease (CAD), Hypertension, and Chronic Kidney Disease (CKD) on correlations between variables. Results: 18.3% (N=18) patients have underlying CKD. In comparison between patients with and without CKD, there was a significant difference in in the correlation between measurements specifically involving those between blood pressure, ventricular architecture and diastolic function (see attached heatmaps). Conversely, there was no significant difference noted in patients with and without DM, CAD, or HTN. Conclusions: Certain correlations between clinical and echocardiographic data are significantly impacted in patients with chronic kidney disease. This suggests that comparing the ratio or product of these measurements might create new indices to track the development and/or progression of the cardiomyopathy associated with CKD.
Abstract 16590: The Association Between Long-Term Changes in Cardiorespiratory Fitness and Mortality Risk
Authors: Mary Imboden, Matthew P Harber, Mitchell H Whaley, W H Finch, Derron A Bishop, Leonard A Kaminsky
Journal: Circulation (2018)

Introduction: There is a strong inverse association between cardiorespiratory fitness (CRF) and mortality outcomes. This relationship has predominantly been assessed cross-sectionally, however low CRF is a modifiable risk factor, thus assessing this association using a single baseline measure may be sub-optimal. The primary purpose of this research was to examine the association of the long-term change in CRF, measured using cardiopulmonary exercise testing (CPX) with all-cause and disease-specific mortality. Methods: Participants included 833 apparently healthy men and women (42.9±10.8 y) who underwent two maximal CPXs, the second CPX being ≥ 1 year following the baseline assessment. Participants were followed for 17.7 ± 11.8 years for all-cause, cardiovascular disease (CVD), and cancer mortality. Cox-proportional hazard models were performed to determine the association between the change in CRF, computed as visit 1 (V1) peak oxygen consumption (VO 2peak (ml·kg -1· min -1 )) - visit 2 (V2) VO 2peak , and mortality outcomes. Results: During follow-up, 172 participants died. Overall, the change in CPX-derived CRF was inversely related to all-cause, CVD, and cancer mortality (p&lt;0.05). Each 1 ml·kg -1· min -1 increase was associated with a 10.8, 14.7, and 15.9% reductions in all-cause, CVD, and cancer mortality, respectively. The inverse relationship between CRF and all-cause mortality remained significant (p&lt;0.05) when men and women were examined independently, after adjusting for years since first CPX, baseline VO 2peak , and age. Conclusions: Long-term changes in CRF were inversely related to mortality outcomes, and mortality was better predicted by CRF measured at subsequent examination than baseline CRF. These findings support the recent American Heart Association scientific statement advocating CRF as a clinical vital sign that should be assessed routinely in clinical practice, as well as support regular participation in physical activity to maintain adequate CRF levels across the lifespan.
Abstract 16624: Association of Subclinical Atherosclerosis and Echocardiographic Indices of Cardiac Remodeling: The Framingham Study
Authors: Cecilia Castro-Diehl, Rebecca J Song, Vanessa Xanthakis, Gary F Mitchell, Susan Cheng, Ramachandran S Vasan
Journal: Circulation (2018)

Subclinical atherosclerosis, a marker of myocardial ischemia, may impact cardiac remodeling indices; yet this association has not been evaluated. We hypothesized that higher coronary artery calcium (CAC) burden is associated with alterations of cardiac remodeling in individuals free of congestive heart failure (CHF) and myocardial infarct (MI). We related CT-based CAC score to echocardiographic (echo) indices in 2,650 Framingham Study participants (mean age 52 yrs, 48% women; 39% had CAC&gt;0). We examined the following echo indices (log-transformed dependent variables): left ventricular (LV) mass index (LVMi), LV ejection fraction (LVEF), E/e’, global longitudinal strain (GLS), left atrial ejection fraction (LAEF) and aortic root diameter (AoR). Using multivariable-adjusted generalized linear models to account for relatedness, we modeled CAC score (independent variable) as a log-transformed continuous [ln(CAC+1)] or categorical (0, 1-100, and ≥101) variable. Adjusting for standard risk factors, higher CAC burden was associated with higher LVMi, E/e’ and AoR, and with lower LAEF. Those with CAC score≥101 had lower LAEF and higher E/e’ and AoR compared to those with CAC=0 ( P &lt;0.05 for all, Figure). We observed effect modification by sex and age (interaction P &lt;0.05) for the association of CAC score with LAEF and with AoR, respectively. In stratified analysis, higher CAC values were associated with lower LAEF values only in women ( P &lt;0.003), and with higher AoR in older participants (&gt;median age of 58 yrs; P &lt;0.007). Conclusions: Subclinical atherosclerosis is associated with cardiac remodeling indices, consistent with the potential adverse impact of subclinical ischemia on myocardial and aortic remodeling in individuals free of CHF and MI. The prognostic significance of these associations warrant evaluation in future studies.
Abstract 13939: Triiodothyronine and Dexamethasone Enhances Electrophysiological Maturation of Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes
Authors: Lili Wang, Yuko Wada, Nimer Ballan, Jeffrey Schmeckpeper, Lior Gepstein, Bjorn C Knollmann
Journal: Circulation (2021)

Background: Human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) technology opens new avenues for disease modeling and drug development. However, hiPSC-CMs remain functionally immature, which hinders their utility as a model of human cardiomyocytes. Objective: To improve the electrophysiological maturation of hiPSC-CMs. Methods and Results: Day 16 th hiPSC-CMs were treated with vehicle or 100 nmol/L triiodothyronine (T3) and 1 μmol/L Dexamethasone (Dex) for 14 days. On day 30 th , hiPSC-CMs were dissociated and replated as cell sheets or single cells. Optical mapping and patch-clamp technique were used to examine the electrophysiological properties of vehicle- and T3+Dex-treated hiPSC-CMs. T3+Dex-treated hiPSC-CMs had a slower spontaneous beating rate (vehicle 17 ± 0.8 vs . T3+Dex 12 ± 0.8 beats/min, P &lt; 0.01), more hyperpolarized resting membrane potential (vehicle -65.04 ± 1.20 vs. T3+Dex -72.00 ± 1.10 mV, P &lt; 0.01), faster maximal upstroke velocity (vehicle 86.08 ± 8.12 vs. T3+Dex 131.78 ± 8.49 mV/ms, P &lt; 0.01), and shorter action potential duration at 90% repolarization (APD 90 , vehicle 550.44 ± 39.54 vs. T3+Dex 418.59 ± 21.58 ms, P &lt; 0.01) compared to the vehicle. Changes in spontaneous activity and AP were mediated by decreasing the funny current (I f , vehicle -12.20 ± 2.15 vs. T3+Dex -6.98 ± 0.89 pA/pF at -120 mV, P &lt; 0.05) and increasing the inward rectifier potassium current (I K1 , vehicle -4.62 ± 0.59 pA/pF vs . T3+Dex -18.79 ± 1.98 pA/pF at -120 mV, P &lt; 0.01), the sodium current (I Na , vehicle -9.8 ± 1.86 vs. T3+Dex -44.9 ± 7.10 pA/pF at -30 mV, P &lt; 0.01), and the rapidly and slowly activating delayed rectifier potassium currents (I Kr , 0.81 ± 0.07 vs. T3+Dex: 1.35 ± 0.19 pA/pF at 20 mV, P &lt; 0.01; I Ks , vehicle 0.38 ± 0.06 vs. T3+Dex 0.72 ± 0.17 pA/pF at 40 mV, P &lt; 0.05). Furthermore, T3+Dex-treated hiPSC-CM cell sheets (hiPSC-CCSs) exhibited a faster conduction velocity and shorter APD than the vehicle. Inhibition of I K1 by 100 μM BaCl 2 significantly slowed conduction velocity and prolonged APD in T3+Dex-treated hiPSC-CCSs but had no effect in the vehicle group, demonstrating the important role of I K1 for conduction velocity and APD. Conclusion: T3+Dex treatment is an effective approach to rapidly enhance electrophysiological maturation of hiPSC-CMs.
Abstract 16683: Subcellular Changes in NF-κB p50-Dependent iNOS Regulation in Doxorubicin-Induced Cardiomyopathy (DIC)
Authors: Ashim K Bagchi, Alexsandra Zimmer, Gauri Akolkar, Ana R Ludke, Pawan K Singal
Journal: Circulation (2018)

A repeat use of doxorubicin (Dox), an anti-cancer drug, can cause heart failure in cancer patients. Dox-induced cardiac mitochondrial as well as ER damage due to oxidative and nitrosative stress (O/NS) has been widely studied. However, mechanism by which Dox exerts iNOS changes via mitochondrial damage and/or ER stress is yet to be elucidated. We investigated whether iNOS induced inflammatory changes in Dox exposed hearts involve mitochondrial and/or endoplasmic reticulum (ER) damage. A cumulative dose of Dox (15mg/kg B.W., ip) was given to Male Wistar rats. We noted an increase in cytC release in the cytoplasm due to O/NS indicating mitochondrial injury. Dox induced linking of chaperone binding immunoglobulin protein (Bip) to activating transcription factor 6 (ATF6) suggested an increased unfolded protein response (UPR) contributing to ER stress which was independent of upstream transcription factors inositol requiring enzyme 1 (IRE1) and protein kinase RNA-like ER kinase (PERK). ATF6-induced ER stress promoted NFκBp105/p50-induced expression of iNOS and NO production in the myocardium. The latter was associated with increased expression of TLR2 and TRAF2 together with NFκB105/50 expression suggesting that ER-stress promoted the inflammatory response in the myocardium. Co-localization of iNOS or TLR2 together with calnexin/grp78 (ER markers) but not with Tom20 (mitochondria marker) suggested that only ER stress promoted inflammatory response. The study suggests that inhibition of Bip binding to ATF6 may modulate ER-stress-mediated inflammation in DIC and presents a novel avenue for a development of the therapeutics for treatment of DIC.
Abstract 16629: Empagliflozin Directly Stimulates PGC-1α-Dependent Mitochondrial Biogenesis in Cardiac Cells; A Potential Mechanism Associated With Its Cardiovascular Benefits
Authors: Allen M Andres, Yang Song, Roberta A Gottlieb, Robert M Mentzer
Journal: Circulation (2018)

Empagliflozin (EMP) is a member of the gliflozin class of drugs used to treat type 2 diabetes mellitus (T2DM). These drugs inhibit the sodium glucose co-transporter 2 (SGLT-2) and facilitate glucose disposal via the kidneys. There is considerable interest in the growing evidence that select anti-diabetic drugs such as empagliflozin may have a cardioprotective effect independent of glycemic control manifested as a reduction in the risk of developing a major adverse cardiovascular event (MACE). The mechanism(s) underlying this effect are unknown. To test the hypothesis that the beneficial cardiac effects of EMP may be mediated by enhancing mitochondrial turnover, specifically enhanced mitophagy and mitochondrial biogenesis, we treated 5 day differentiated H9C2 rat ventricular cardiomyocytes with 100nM EMP for 24h. As shown below, we found that EMP increases several markers of mitochondrial mass assessed by western blot. Seahorse respirometry confirmed that this translates to increased basal and maximal respiratory capacity of the cardiomyocyte. Moreover, these findings were associated with increased translocation of PGC-1α to the nucleus suggesting that EMP-mediated mitochondrial biogenesis is PGC-1α-dependent. To determine if increased mitochondrial biogenesis was SGLT-2 receptor mediated we interrogated the protein expression in our differentiated H9C2 cardiomyocytes and in several tissues of the mouse. We detected protein expression in our differentiated H9C2 cardiomyocytes and in mouse heart, liver, adipose, kidney, lung, and spleen. Whether EMP-mediated stimulation of mitochondrial biogenesis is related to SGLT-2 receptor inhibition, or if this process is linked to its ability to improve cardiac function has yet to be determined. Our findings suggest however that a possible mechanism underlying the reduction in MACE associated with EMP treatment may be due in part to its effect on mitochondrial turnover.
Abstract 16839: The Outer Mitochondrial Membrane Protein, mitoNEET, Sustains Structure of Mitochondrial Cristae
Authors: Takaaki Furihata, Shintaro Kinugawa, Shingo Takada, Satoshi Maekawa, Takashi Katayama, Ryosuke Shirakawa, Hideo Nambu, Yoshikuni Obata, Katsuma Yamanashi, Naoya Kakutani, Akimichi Saito, Arata Fukushima, Takashi Yokota, Toshihisa Anzai
Journal: Circulation (2018)

Background: Mitochondria are essential organelles with various functions, and change its network dynamically. The inner mitochondrial membrane (IMM) contains the cristae membrane (CM), which extends into mitochondrial matrix space. A loss of mitofilin, one of the main component of mitochondrial contact site and cristae organizing system (MICOS) complex in the IMM, has known to be unable to preserve CM structure, accompanied with lower membrane potential. And a disruption of mitoNEET, novel protein located in the outer mitochondrial membrane, has been shown to decrease mitochondrial membrane potential, however, the role of mitoNEET in structure of the CM has not been elucidated. Methods and Results: mitoNEET flox/flox mice were generated with lox-P and homologous recombination strategies. Cardiac-specific deletion of mitoNEET (mitoNEET-knockout) was achieved using αMHC-Cre. Transmission electron microscopy showed the mitochondria isolated from mitoNEET-knockout mice reduced number of cristae, loss of the cristae junctions, and accumulation of cristae stack. These mitochondria also exhibited a swollen morphology. ROS production from the mitochondria were higher in mitoNEET-knockout mice. Mitochondrial state 3 respirations were comparable between the groups, however, mitochondrial maximal capacity and reserve capacity in mitoNEET-knockout mice. Mitochondrial membrane potential measured by using cultured cells transfected with CISD1 , encoding mitoNEET, siRNA was decreased in this condition compared to scramble. Mass spectrometry analysis revealed that endogenous mitoNEET coprecipitated with endogenous mitofilin, which is known to be localized in the IMM and involved in CM structure. Echocardiography showed cardiac dysfunction in mitoNEET-knockout mice. Conclusions: The protein-protein interaction between mitoNEET and mitofilin may regulate CM structure through the maintenance of MICOS complex including mitofilin. The lack of this interaction could induce mitochondrial dysfunction, suggesting that mitoNEET play an important role in the regulation of mitochondrial function via mitochondrial morphology.
Abstract 16991: Relationship Between Restenosis After Percutaneous Transluminal Renal Angioplasty for Atherosclerotic Renal Artery Disease and the Preprocedural Renal Resistance Index in the Contralateral Kidney
Authors: Nobuyasu Ito, Kan Zen, Osami Kawarada, Satoshi Yasuda, Satoaki Matoba
Journal: Circulation (2018)

Introduction: Percutaneous transluminal renal angioplasty (PTRA) is an established treatment for atherosclerotic renal artery disease. Renal resistive index (RRI) is known as an indicator of renovascular atherosclerosis, and several studies reported that high preoperative RRI in the target kidney predicts poor response in hemodynamics and renal function after PTRA. However, RRI is elevated not as a sequence of proximal renal artery stenosis, and relationship between the patency after PTRA and RRI still has not been clarified. Methods: The CARMEL study (Cardiac Benefits of Renal Artery Stenting: A Prospective Multicenter Observational study) is a study of patients with de novo symptomatic ARAD who underwent PTRA between September 2012 and December 2015 at 14 institutions in Japan. Of the 76 patients who included in the final analysis of the CARMEL study, 46 patients (71.8±9.9 years) whose bilateral RRI were recorded before PTRA procedure were retrospectively analyzed. We evaluated renal ultrasonographic data collected before PTRA, and at 1-day, 1-month and 6-month follow-up. Results: 55 lesions of the 46 patients were treated, and preprocedural RRI in the target kidney (tRRI) were higher than 0.8 in 16 lesions (High-tRRI group) and preprocedural RRI in the contralateral kidney (cRRI) were higher than 0.8 in 18 lesions (High-cRRI group). Preprocedural peak systolic velocity (PSV) and renal/aorta ratio (RAR) of the lesions were comparable between High-tRRI group and the rest, and also between High-cRRI group and the rest. However, in High-cRRI group, PSV of the target lesion is significantly higher than the rest at every follow up exam (at 6-month follow up: PSV 224.4±126.5 cm/s vs 113.7±53.7 cm/s, p&amp;lt;0.001; RAR 3.91±2.68 vs 1.99±1.07, p=0.009). (Table 1, Table 2) Conclusion: High preprocedural RRI in the contralateral kidney could be a predictor of restenosis after PTRA.
Abstract 16978: Use of 2-D Speckle Tracking Strain to Predict Onset of Cardiomyopathy in Chagas Disease
Authors: Monica Miranda Schaeubinger, Sithu Win, Lola Camila Telleria, Freddy Tinajeros, Jorge Flores, Paula Carballo Jimenez, Caryn Bern, Ronald Gustavo Durán Saucedo, Robert H Gilman, Monica Mukherjee
Journal: Circulation (2018)

Introduction: Chagas disease is a major cause of morbidity in Latin America where it affects approximately 8 million people, with highest prevalence in Bolivia. An estimated 20-30% of those infected develop Chagas cardiomyopathy (CC) and clinical heart failure. There is currently a lack of reliable predictors of CC, hindering early identification and treatment of patients at highest risk of progression. Methods: This prospective observational study was conducted at the Hospital San Juan de Dios in Santa Cruz, Bolivia. Between 2016 and 2018, participants with Chagas disease underwent a focused history and physical exam, 12-lead ECG and echocardiogram at baseline and at 1-year follow-up. Participants were assigned cardiac disease severity stages according to ECG findings and systolic function as done by Okamoto et al. Those classified as stage A or B at baseline were selected from the overall cohort, and considered to have developed cardiomyopathy (stage C or D) by structural abnormalities on their follow-up echo. Echocardiograms were analyzed for peak averaged and regional left ventricular global longitudinal systolic strain (GLS) using TomTec Image-Arena software. Baseline GLS was compared between those who progressed and those who did not using two-sample t-tests. Results: Of the 113 participants with stage A or B at baseline, 10 had progressed to stage C or D at follow-up 1 year later. Mean age was similar in the two groups, however those who progressed were more likely to be male (see table). At baseline, mean LVEF was lower and peak GLS was less negative among those who progressed compared to those who did not. These differences were similar at the follow-up visit. Conclusion: Mild abnormalities in GLS identify patients with Chagas disease with a higher risk of developing cardiomyopathy within 1 year. Screening for these changes may provide a non-invasive and cost-effective approach to identify patients who could benefit from timely management.