tbuckley/cabot-search huggingface dataset:
Abstract 12000: A Novel Human Arterial Transcriptomic Signature Associated With Major Adverse Cardiovascular Events and Oxidative Stress
Authors: Christos Kotanidis, Helen Lockstone, Benjamin Wright, Nadia Akawi, Ioannis Akoumianakis, Ileana Badi, Murray Polkinghorne, Shakil Farid, Vivek Srivastava, George Krasopoulos, Keith M Channon, Charalambos Antoniades
Journal: Circulation (2021)

Introduction: The biology of human vascular wall is implicated in cardiovascular pathology. We applied discovery transcriptomics to internal mammary arteries (IMAs) obtained from cardiac surgery patients, to identify pathways that can be treated therapeutically. Methods: Weighted correlation network analysis was conducted in sequencing data from IMAs RNA in 205 patients (Arm 1). Association with future incidence of major adverse cardiovascular events [MACE: cardiovascular death (CVD), non-fatal myocardial infarction or stroke, or new-onset heart failure] was assessed with Cox regression models (adjusted for age, sex, hypertension, dyslipidaemia, diabetes mellitus, and plasma TNFa). Arm 2 included 497 patients in whom segments of IMA were used for ex-vivo quantification of NADPH-stimulated superoxide by lucigenin chemiluminescence. Results: We identified 10 coexpressed gene ‘modules’ in the human arterial wall, through unsupervised transcriptomic analysis. The “red” module was found to cluster with arterial NADPH oxidase activity, while its eigengene values had the most significant correlation ( a ). Patients with high eigengene values for the “red” module showed a 3-fold higher risk of MACE ( b ), and enrichment analysis revealed top pathways ( c ). The Study Arm 2 population was followed up for a median of 6.35 years [IQR: 3.97-8.38], with 50 CVD and 101 MACE. High NADPH oxidases activity was independently predictive of cardiovascular mortality ( d ) and MACE (adj. hazard ratio 1.58 [1.07-2.36], p=0.02). Conclusion: We demonstrate that arterial oxidative stress leads to high risk of MACE in patients with atherosclerosis. We also identify a novel, redox-related arterial transcriptomic signature that predicts long-term cardiovascular risk. Pathways related with oxidative stress, or glucose metabolism or Hypoxia-Inducible Factor-1 in the human arterial wall, may be rational therapeutic targets to reduce cardiovascular risk in secondary prevention.
Abstract 10247: Establishing a Therapeutically Modifiable ROS/RNS-Beta 1 Adrenergic Receptor Desensitization and Internalization Axis in Aging Coronary Microvessels
Authors: Evan P Tracy, Michaela Dukes, Gabrielle Rowe, Jason Beare, Amanda Leblanc
Journal: Circulation (2021)

Introduction: Coronary Microvascular Disease (CMD) causes hyperconstriction, reduced perfusion, and chronic angina in aging. We previously showed increased coronary microvascular ROS and reduced NO/glutathione in aging rats correlating with reduced β1 Adrenergic receptor (β1ADR) dilation. Adipose Stromal Vascular Fraction (SVF) therapy reverses oxidative stress in CMD to improve β1ADR function. Our objective is to elucidate a mechanism for SVF’s recovery of β1ADR function in pursuit of a cell therapy to treat CMD. Hypothesis: β1ADR dilation is reduced in aging due to ROS-mediated receptor desensitization &amp; internalization, reversible by inhibition of GRK2/dynamin &amp; SVF antioxidation. Methods: Rat coronary microvessels were isolated from young (YC, 3-6 months), old (OC, 24 months), and old + SVF injection (OSVF, 24 months). RNAseq (n = 3 per group) and immunofluorescence (n ≥ 5 per group) were used to analyze pro/antioxidant gene &amp; protein expression. Using pressure myography, dilation to isoproterenol was evaluated at baseline and with ROS (hydrogen peroxide and menadione) or RNS (sodium nitroprusside, SNP) +/- inhibitors of receptor desensitization (GRK2 via paroxetine) and internalization (dynamin via dynasore). Significance was set at p &lt; .05 utilizing Two-Way Repeated Measures ANOVA with Holm-Sidak post-hoc analysis. Results: Aging (n = 16) reduced dilation to isoproterenol, reversed to youthful (n = 17) levels by SVF (n = 16). In YC/OSVF, ROS (n = 10 &amp; 6) attenuated dilation reversed by dynasore (n = 8) and paroxetine (n = 7). In OC, SNP (n = 7), dynasore (n = 10), and paroxetine (n = 5) restored dilation. Aging increased prooxidant genetic (xanthine oxidase) and protein (NOX4) expression and increased antioxidant genetic (catalase) but not protein expression. SVF reduced prooxidant genetic (dynamin related protein 1) and protein (NOX4) expression with increased antioxidant genetic (glutathione synthetase) and protein (SOD2) expression. Conclusion: ROS in aging causes β1ADR dysfunction via desensitization &amp; internalization, as their inhibition preserves β1ADR function. We name this interaction the ROS/RNS- β1ADR Desensitization &amp; Internalization Axis , which was therapeutically modulated by SVF antioxidation to restore β1ADR function.
Abstract 6984: Cost Effectiveness of a 1-Hour High-Sensitivity Troponin-t Protocol in Suspected Acute Coronary Syndrome: A Trial-Based Analysis of the Rapid-tnt Randomised Trial
Authors: Anthony Chuang, Emmanuel Gnanamanickam, Kristina Lambrakis, Matthew Horsfall, Jonathan Karnon, Andrew Blyth, Anil Seshadri, Mau Nguyen, Tom G Briffa, Louise Cullen, Stephen Quinn, John K French, Derek P Chew
Journal: Circulation (2021)

Introduction: To better understand the economic impact of an accelerated 0/1-hour high-sensitivity troponin-T (hs-cTnT) protocol compared to conventional 0/3-hour protocol, we conducted a patient-level economic analysis of the RAPID-TnT randomised trial with a 12-month follow-up in patients presenting to emergency department (ED) with suspected acute coronary syndrome (ACS). Methods: An economic evaluation was conducted with 3265 patients randomised to either the 0/1-hour hs-cTnT protocol (n=1634) or the conventional 0/3-hour protocol (n=1631). The primary outcome measure was a composite of all-cause mortality and new/recurrent myocardial infarction (MI). Results: Mean per patients costs were numerically higher in the 0/1-hour arm compared to the conventional 0/3-hour arm (by $1830.56/patient, 95% confidence interval [95%CI]: $-1610.83 - 5271.96, P=0.30) with no statistically significant difference in primary outcome (0/1-hour: 62/1634 [3.8%], 0/3-hour: 82/1631 [5.0%], HR: 1.32 [95%CI: 095-1.83], P=0.1). The mean ED length of stay (LOS) was significantly lower in the 0/1-hour arm (by 0.63 hours/patient, 95%CI: 0.34-0.92, P&lt;0.001), but the cost saving was offset but the higher cumulative emergency-related inpatient costs (by $2247.31/patient, 95%CI: -656.55 - 5151.18, P=0.12). Restricting the analysis to patients with hs-cTnT≤29ng/L, the mean per patients cost remained numerically higher in the 0/1-hour arm (by $1480.24/patient, 95%CI:$-1097.62 - 2058.10, P=0.26), but the reduction in ED LOS was more pronounced (by 0.75 hours/patient, 95%CI: 0.46-1.05, P&lt;0.001). Conclusions: This economic evaluation suggest that there were no differences in costs and outcomes between the 0/1-hour hs-cTnT protocol and the conventional 0/3-hour protocol for the assessment of suspected ACS in ED after 1 year of follow-up from the Australian healthcare system perspective. Our observations suggest that the 0/1-hour hs-cTnT protocol improves initial ED efficiency with more rapid exclusion of ACS and discharge. However, the associated cost savings were offset by the subsequent emergency inpatient costs. Further refinements in cost-effective strategies to improve clinical outcomes whilst efficiently utilising healthcare resources is needed.
RADT-34. OLFACTORY PERCEPTION DURING PROTON RADIATION AND DIFFERENCES IN FREQUENCY OF OLFACTORY PERCEPTIONS BASED ON PROTON CRANIOSPINAL IRRADIATION TECHNIQUE FOR PEDIATRIC BRAIN TUMOR PATIENTS
Authors: Myrsini Ioakeim-Ioannidou, Parsa Erfani, Tobias Urell, Juliane Daartz, julia Berv, Shannon leahy, Barbara Fullerton, Rachel Bolton, Torunn Yock, Nancy Tarbell, Beow Yeap, Shannon MacDonald
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Unusual olfactory perception has been reported during brain radiation treatments but is infrequent and does not typically interfere with the ability to deliver treatment or cause notable distress. METHODS We performed a retrospective review of 127 pediatric patients treated with proton radiation therapy (PRT) for primary brain tumors in a single institution between 2016-2021. Patients received PRT to the brain as part of craniospinal irradiation (CSI) followed by a boost to the brain. Proton CSI was delivered with 3D-CRT protons (n=53) or pencil beam scanning technique (PBS) (n=74). Within the PBS group, treatment delivery to the CSI utilized a single PA field (n=24) or two posterior oblique fields (n=50). We collected data on abnormal olfactory sensations, nausea/vomiting, and the use of medical intervention for those symptoms. RESULTS Our cohort included 80 males and 47 females. The median age of patients was 10 years old (range, 3 – 21). Seventy-one patients received concurrent chemotherapy. Prior to PRT, 31 patients were nauseous. During the radiation course, 104 patients developed worsening nausea while 63 patients reported episodes of emesis. Four patients vomited while receiving radiation. Seventeen patients reported olfactory perceptions during CSI. We found a higher rate of olfactory perception in patients treated with PBS (n=16, 22%) than 3D-CRT (n=1, 2%) (p=0.001) and, within the PBS group, patients treated with a single PA field (n=11, 46%) than two oblique fields (n=5, 10%) (p=0.002). Seventy-eight patients required intervention including addition of anti-emetic or anti-anxiety medication. Two patients required sedation due to the malodorous smell during CSI. We did not find any significant difference in nausea/vomiting based on treatment technique. CONCLUSIONS PBS and PBS technique influence olfactory perceptions but not the occurrence of the rate of nausea/vomiting. Further studies should be performed to validate these findings and determine techniques to minimize unpleasant olfactory perceptions.
Abstract 12443: Predictors of Long-Term Adherence to Exercise in Adults With Heart Failure Enrolled in an Exercise Clinical Trial
Authors: Windy W Alonso, Kevin Kupzyk, Joseph F Norman, Scott Lundgren, Kenneth Faulkner, Steven J KETEYIAN, Sara Bills, Bunny J Pozehl
Journal: Circulation (2021)

Introduction: Exercise is recommended for adults with heart failure (HF), but long-term adherence to exercise is poor. The purpose of this analysis is to determine predictors of long-term adherence to exercise in adults with HF enrolled in a RCT testing effects of a behavioral intervention compared to enhanced usual care (EUC) on long-term adherence to exercise. Hypothesis: Unmodifiable (e.g. gender, race, age) and modifiable (e.g. physical function, self-regulation, attitudes) variables predict long-term adherence to exercise in adults with HF. Methods: All subjects (n=204) in this 2-group RCT received paid access to a fitness center for 18 months. Subjects in the intervention group (n=102) also received weekly coaching for 12 months. Adherence was defined as 120 minutes of moderate-intensity exercise weekly. Logistic regression models to examine predictors by group included baseline variables that significantly related to adherence at 12 or 18 months: gender, BMI, 6-minute walk test distance, attitudes, self-regulation, and health status. Results: The sample was 55% men, 47% non-white, and 71% HF with reduced ejection fraction. Mean age was 60.4 years. In the intervention group, gender predicted adherence at both 12 (B=-1.36, p=.01) and 18 months (B=-2.48, p=.003) with men achieving greater adherence at both time points. In the EUC group, no variables in the final model predicted adherence at 12 months and at 18 months, adherence was predicted by baseline scores on the Physical Activity Self-Regulation Scale (B=.084, p=.007) with higher self-regulation associated with a greater likelihood of adherence. Conclusions: To our knowledge, this is the first study to report predictors of long-term adherence to exercise in adults with HF. Men with HF achieved greater adherence to exercise than women following a behavioral coaching intervention. Future studies are necessary to identify behavioral strategies that will promote long-term adherence to exercise in women with HF. Adults with HF that can self-regulate at baseline adhere better to long-term exercise if given guidance to exercise and paid access to a fitness center. These findings are important as we move toward a precision health approach to improve long-term exercise adherence in adults with HF.
Abstract 9838: Genetic Architecture and Clinical Outcomes of the Fredrickson-Levy-Lees Dyslipoproteinemias
Authors: Thomas C Gilliland, Mark Trinder, Kaavya Paruchuri, Sarah M Urbut, Sara Haidermota, Rachel Bernardo, Md Mesbah Uddin, Michael Honigberg, Gina Peloso, Pradeep Natarajan
Journal: Circulation (2021)

Introduction: In 1967, Fredrickson, Levy, and Lees (FLL) proposed a classification scheme for dyslipidemias based on lipoprotein particle patterns. However, the genetic basis and clinical relevance of the FLL classification has not been evaluated in general population-based cohorts. Methods: Among UK Biobank participants free of prevalent coronary artery disease (CAD), we used statin-adjusted triglycerides, total cholesterol, and apolipoprotein-B to infer FLL classes (Types I, IIa, IIb, III, IV, and V). We performed Cox proportional hazards regression to quantify risk of incident CAD comparing each FLL class to unaffected individuals, adjusting for age, sex, statin use, BMI, smoking status, hypertension, diabetes mellitus, principal components 1-5, and genotyping array. Genome-wide association studies (GWAS) were performed for each of the FLL classes. Results: Of 412,502 participants without prevalent CAD, 237,570 (57.6%) had a FLL dyslipoproteinemia: Type I 30 (&lt;0.01%); Type IIa 36,629 (8.9%); Type IIb 86,682 (21%); Type III 12,957 (3.1%); Type IV 101,226 (24.5%); Type V 46 (&lt;0.01%). Over a median of 7.0 years of follow-up, Type IIb individuals were at highest risk of incident CAD (HR 1.97, 95% CI 1.83-2.13) followed by IIa (HR 1.68, 95% CI 1.52-1.86) and IV (HR 1.25, 95% CI 1.16-1.36). Across strata of non-HDL cholesterol, Type IIb pattern was still associated with greater incident CAD risk compared with other dyslipoproteinemias ( Figure ). GWAS revealed 316 total loci contributing to any of the FLL phenotypes, of which 12 were shared; 145 loci were unique to Type IIb. SNP heritability ranged from 23.5% to 53.9% across FLL types. Conclusions: Type IIb dyslipoproteinemia pattern is associated with incident CAD independent of non-HDL cholesterol. GWAS revealed the distinct genetic signatures for atherogenic dyslipoproteinemias.
Abstract 17795: Study of Inter-Vendor Variability of 3D Echo Based Strain Measurements: Role of Vendor Specific and Vendor Independent Analysis Tools
Authors: Muhammad Ashraf, Thuan Nguyen, Ijaz Mahmood, Cole Streiff, Meihua Zhu, Eriko Shimada, David J Sahn
Journal: Circulation (2013)

Background: We studied the inter-vendor variability of 3D echo derived strain measurements. Methods: Ten freshly harvested pig hearts were studied. Each pig heart was driven passively in a water ta...
Abstract 10126: Lifetime Cardiovascular Risk Model to Identify Individuals with Low 10-Year Risk but High Lifetime Risk
Authors: Hokyou Lee, Yuichiro Yano, Norrina Allen, Yu Rang Park, Dong Wook Kim, Sungha Park, Eun Jig Lee, Don Lloyd-jones, Hyeon Chang Kim
Journal: Circulation (2021)

Introduction: Young adults with poor lifestyle and multiple risk factors (RF) still have low predicted 10-y cardiovascular (CV) risks as existing models are largely age-driven. This is exaggerated in low-risk populations (eg, Asians), often understudied for similar reasons. Using the Korean National Health Insurance (NHI) data, we developed CV risk models to identify individuals with low 10-y risk but high lifetime risk. Methods: Models were derived from a 50% sample of 2004-2005 NHI health examinees of age 20-89 free of CV disease. We built sex-specific Cox models with age as time scale and age-varying coefficients for CV events (myocardial infarction, stroke, or CV death) and competing non-CV death. We defined 10-y and lifetime CV risks as the cumulative risks at baseline age+10 and 90 years of age, respectively. We examined distributions of predicted risks and identified individuals with low 10-y/high lifetime risks using nationwide complex-survey data. Results: The derivation set included 4 894 098 participants (median age, 44 y; 56.9% male; median follow-up, 15.1 y), in whom 238 292 new CV events occurred before age 90. Age-varying coefficients were introduced to account for differential relative hazard contributions from high RF burden by age (Fig A and B). Models were validated in the 50% holdout set (age, 20-80; C-index, 0.821-0.854) and the 3 external prospective cohorts (age, 40-80; C-index, 0.701-0.763); calibration plots showed good agreement between predicted vs observed risks. Examples of calculated 10-y/lifetime risks are in Fig C. At the population-level, lifetime risks remained stable across age, whereas 10-y risks exponentially increased with age (Fig D). People with low 10-y risk but high lifetime risk had high RF burden despite young age (Fig E). Conclusions: The lifetime CV risk model can be used to guide preventive strategies in young, low-risk population, whose 10-y risk may not fully reflect potential lifetime benefit from CV disease prevention.
Abstract 11478: Epicardial Adipose Tissue Volume - Relationship with Coronary Artery Plaque Vulnerability and Myocardial Ischemia in Non-Obstructive Coronary Artery Disease
Authors: Ingela Khan, Ingeborg Eskerud, Terje H Larsen, Caroline Berge, Eva R Pedersen, Mai Tone Lønnebakken
Journal: Circulation (2021)

Introduction: Myocardial ischemia is common among patients with chest pain and non-obstructive coronary artery disease (CAD). Epicardial adipose tissue (EAT) accumulation has been associated with inflammation, atherosclerosis and microvascular dysfunction. Accordingly, we hypothesised that EAT volume is associated with coronary plaque vulnerability and myocardial ischemia in patients with non-obstructive CAD. Methods: We included 125 patients with chest pain and non-obstructive CAD by coronary computed tomography angiography (CCTA). EAT volume was quantified on non-contrast cardiac computed tomography images by a semiautomatic analysis software. CCTA images were analysed with respect to plaque volume and composition. Plaque vulnerability was assessed as total coronary non-calcified plaque volume and positive remodelling index &gt;1.10. Myocardial ischemia was detected by contrast dobutamine stress echocardiography. Patients were grouped in tertiles of EAT volume and high EAT volume was defined as volumes in the highest tertile (≥125 ml). Results: In the total study population (median age 63(58, 69) years and 58% women), the median EAT volume was 104 (77, 141) ml. High EAT volume was more common in men and associated with higher BMI, hypertension and positive remodelling (all p&lt;0.05). There was no difference in age, prevalence of diabetes, total non-calcified plaque volume or presence of myocardial ischemia between groups (all p≥0.34). This was confirmed in univariable logistic regression analyses (Table). After adjusting for covariables in a multivariable model, the association between positive remodelling and high EAT volume was attenuated (Table). Conclusion: High EAT volume was associated with positive remodelling, but not with total non-calcified plaque volume or myocardial ischemia, and the association was attenuated after multivariable adjustments.
Impact of Direct-Acting Antivirals on the Outcome of HIV/HCV Coinfected Patients with Non-Hodgkin Lymphomas in the Modern Anti-Retroviral Therapy Era: A Retrospective Multicenter Study of 74 Cases
Authors: Michele Merli, Alessandro Re, Michele Bibas, Davide Dalu, Emanuele Ravano, Guido Gini, Carlo Visco, Maria Chiara Tisi, Emanuele Cencini, Dario Marino, Massimo Gentile, Roberta Sciarra, Cristina Rovelli, Valentina Zuccaro, Valentina Mazzotta, Cinzia Fasola, Vittorio Ruggero Zilioli, Costanza Fraenza, Benedetta Bianchi, Rosa Daffini, Carmela Pinnetti, Benedetta Lombardi Stocchetti, Barbara Mora, Caterina Cristinelli, Paolo Grossi, Francesco Passamonti, Michele Spina, Luca Arcaini
Journal: Blood (2021)
Not All Electrocardiographic ST-Elevations Are Acute Coronary Occlusions
Authors: Jane Belyavskaya, Ian S. deSouza
Journal: JAMA Internal Medicine (2021)

This case report discusses a patient who presented to the emergency department with complaints of nausea, vomiting, and malaise for 5 days, and an initial electrocardiogram showed an ectopic atrial rhythm with no other abnormality.
Abstract 11821: Telomerase Therapy Reverses Vascular Senescence and Extends Lifespan in Progeria Mice
Authors: Anahita Mojiri, Brandon Walther, Chongming Jiang, Gianfranco Matrone, Rhonda Holgate, Qiu Xu, Elisa Morales, Guangyu Wang, jianhua gu, Rongfu Wang, John P Cooke
Journal: Circulation (2021)

Background: Hutchinson-Gilford Progeria Syndrome (HGPS) is an accelerated aging syndrome associated with premature vascular disease and death due to heart attack and stroke. In HGPS a mutation in lamin A (progerin), alters nuclear morphology and gene expression. Current therapy increases the lifespan of these children only modestly. Thus, greater understanding of the underlying mechanisms of HGPS is required to improve therapy. Endothelial cells (ECs) differentiated from induced pluripotent stem cells (iPSCs) derived from these patients exhibit hallmarks of senescence including replication arrest, DNA damage, increased expression of inflammatory markers and telomere erosion. We hypothesized that correction of shortened telomeres may reverse these measures of vascular aging. Methods: We generated ECs from iPSCs belong to children with HGPS and their unaffected parents. Telomerase mRNA (hTERT) was used to treat HGPS ECs. Endothelial morphology and functions were assessed, as well as proteomic and transcriptional profiles with attention to inflammatory markers, DNA damage and EC identity genes. In a mouse model of HGPS, we assessed the effects of lentiviral transfection of mTERT on measures of senescence, focusing on the EC phenotype in various organs. Results: hTERT treatment of human HGPS ECs improved replicative capacity; restored endothelial functions such as nitric oxide generation, acLDL uptake and angiogenesis; and reduced the elaboration of inflammatory cytokines. In addition, hTERT treatment improved cellular and nuclear morphology, in association with a normalization of the transcriptional profile, effects which may be mediated in part by a reduction in progerin expression and an increase in SIRT1. Progeria mice treated with mTERT Lentivirus manifested similar improvements, with a reduction in inflammatory and DNA damage markers and increased SIRT1 in their vasculature and other organs. Furthermore, mTERT therapy increased the lifespan of HGPS mice. Conclusion: Vascular rejuvenation using telomerase mRNA is a promising approach for progeria and other age-related diseases.
Abstract 12465: Simultaneous Assessment of Coronary Flow Reserve and Contractile Functional Reserve During Vasodilator Stress Evaluated by 13N-ammonia PET/MRI
Authors: Takatoyo Kiko, Atsuro Masuda, Yasuchika Takeishi
Journal: Circulation (2018)

Introduction: Cardiac MRI is a gold standard for evaluating left ventricular (LV) function. 13N-ammonia PET has been used to evaluate myocardial blood flow (MBF) quantitatively. Therefore, 13N-ammo...