tbuckley/cabot-search huggingface dataset:
Abstract 17250: Quantitative T Wave Morphology Analysis in Rett Syndrome Patients
Authors: Michael Collins, Hoang Nguyen, Mark Johnson, Robin Ryther, Judith Weisenberg
Journal: Circulation (2020)

Introduction: Rett syndrome (RTT) is a genetic neurologic disorder associated with a high incidence of sudden death. Abnormal cardiac repolarization is a potential risk factor for sudden death in this population. RTT patients may have prolonged corrected QT (QTc) on electrocardiogram (ECG) that is a sensitive marker of torsades des pointes. However, other repolarization markers such as T wave morphology, the time it takes the T wave to return to baseline from peak amplitude (Tpeak - Tend), and heart rate corrected JTpeak have not been studied. Hypothesis: Rett syndrome patients have abnormal cardiac repolarization. Methods: Retrospective T wave analysis was performed using QT Guard software. T wave morphology and heterogeneity parameters of RTT patients were compared to ECGs of age and sex matched healthy controls. A composite T wave morphology score was calculated from individual feature of flatness, notching, and asymmetry; a higher score means more abnormal morphology. Heterogeneity of repolarization was represented by the principal component analysis ratio 2 (PCA-2). Results: 57 Rett patients (260 ECG) and 121 controls (134 ECG) were studied. The RTT group had longer QTc (p = 0.001) along with more abnormal T-wave morphology scores and heterogeneity parameters when compared to controls (Tables 1, 2). RTT patients without long QTc also had more abnormal morphology scores than controls (p = 0.001). Conclusion: Cardiac repolarization is diffusely abnormal in RTT even in the absence of long QTc. T wave morphology analysis may be used to detect and monitor abnormal cardiac repolarization in RTT in clinical practice.
Abstract 16896: Electrogram Morphology Recurrence to Characterize Drivers of Persistent Atrial Fibrillation: Findings at Initial versus Redo Catheter Ablation
Authors: Ghaith Zaatari, Jorge Bohorquez, Raul Mitrani, Jason Ng, Justin Ng, Harold Rivner, Alex Velasquez, Litsa Lambrakos, Rishi Arora, Jeffrey J Goldberger
Journal: Circulation (2020)

Background: Electrogram (EGM) morphology recurrence (EMR) mapping of persistent atrial fibrillation (PeAF) quantifies consistency of activation at each site and is expected to be high and rapid near drivers of PeAF. Objective: To compare EMR in the left (LA) and right atrium (RA) in patients undergoing first- vs second-time PeAF catheter ablation (CA). Methods: Multisite bipolar EGM mapping of the LA (265±153 sites) and RA (224±148 sites) prior to CA for PeAF was performed in 40 patients (29 males, age 63±9 yrs, CHA2DS2-VASc 2.4±1.5, LVEF 48±12%) undergoing first (Group 1, n=31) or second-time (Group 2, n=9) CA. After cross-correlation of each automatically detected EGM with every other EGM in the recording, the most recurrent EGM morphology was identified and its frequency (Rec%) and cycle length of recurrence (CL R ) were computed (figure). The minimum CL R sites were identified. Results: In group 1, shortest CL R was in the LA in 26 patients (84%) and RA in 5 patients (16%). In the LA, there were 1 (n=23), 2 (n=2), or 3 (n=1) areas of shortest CL R , most commonly in the pulmonary veins (PV; n=19). In the RA, there was only 1 area of shortest CL R . Minimum CL R was 174.1±25.4 ms (LA-179.6±37.4 vs RA-207.9±34.5, p=0.0004), with Rec% 95±10%. In group 2, shortest CL R was in the LA in 5 patients and RA in 5 patients (56%)– one had both LA and RA. In the LA/RA, there were 1 (n=3/4) or 2 (n=2/1) areas of shortest CL R . The most common LA site was non-PV (6/7, 85.7%). The minimum CL R was 182.1±26.2ms (LA-190.8±36.2 vs RA-196.0±30.5, p=0.6), with Rec% 96±5%. Conclusion: In 61% of patients undergoing initial CA for PeAF, EMR identified LA drivers in the PVs which may explain why PV isolation has been reported to have 50-60% success rates in PeAF. In patients undergoing a 2 nd ablation for PeAF, EMR identified predominantly nonPV drivers with even distribution of shortest CL R between RA and LA and diminished CL R gradient between the LA and RA. EMR may be a useful mapping tool to characterize potential drivers of PeAF.
Abstract 16868: Conditional Renal Tubule Specific Deletion of <i>KDM6a</i> Gene Causes Hypertension in Mice
Authors: Xiaobin Han, Leah Akinseye, Kai Chen, Zhongjie Sun
Journal: Circulation (2020)

Objective: Aging-associated downregulation of Klotho is partly due to epigenetic upregulation of H3K27me3 in the kidney. The purpose of this study is to investigate the potential role of KDM6a, a demethylase of histone 3 lysine (K) 27 trimethylation (H3K27me3), in the regulation of blood pressure and explore the related molecular pathways that may influence the kidney function during aging. Methods and Results: Wild type and Ksp-Cre/KDM6a-floxed mice were divided into vehicle control and tamoxifen (10 mg/kg/mouse/7days) treated cohorts (WT mice: KDM6a floxed or Ksp-Cre only and Ksp-Cre/KDM6a -loxed mice). Blood pressure (BP) was measured by tail cuff method and confirmed by carotid artery cannulation at the end of study. Deletion of the KDM6a gene (KDM6a-cKO) significantly increased BP at day 7. BP remained elevated throughout the study. We found that the H3K27me3 level was significantly increased in the kidneys of KDM6a-cKO mice compared to control mice confirming that KDM6a is an important H3K27 demethylase in the control of methylation levels in the kidney. Elevation of BP was likely due to upregulation of the Na + :K + :2Cl - co-transporter (NKCC2) in the thick ascending limb of Henle's loop and NaCl co-transporter (NCC) in the distal convoluted tubule confirmed by qPCR and immunohistochemistry. Accordingly, we found that the urine sodium level was decreased in KDM6a-cKO mice compared to KDM6a-con mice. We showed that expression of aquaporin 2 (AQP2) was increased in the kidney of KDM6a-cKO mice, suggesting that AQP2 may also contribute to increased BP through modulation of body water homeostasis. Furthermore, we demonstrated that expression of Klotho was downregulated by 50%, which blocked FGFR1/Klotho/ERK signaling in the kidney of KDM6a-cKO mice. Notably, expression of aging markers including p53, p21, and p16 was significantly increased in the kidney of KDM6a-cKO mice, indicating that deletion of KDM6a in the renal tubule results in kidney aging. Conclusion: KDM6A is essential to the maintenance of normal kidney function and blood pressure. Renal-specific KDM6A knockout-induced hypertension is likely attributed to increased H3K27me3 levels and the resultant dowregulation of Klotho gene expression which impairs the FGFR1/Klotho/ERK signaling.
Abstract 16629: Endothelial Caveolin-1-trpv4 Regulation of Pulmonary Arterial Pressure and Impairment in Pulmonary Hypertension
Authors: Zdravka Daneva, Corina Marziano, Matteo Ottolini, YEN LIN CHEN, Kwangseok Hong, Aimee Zhang, Thomas Baker, Andrew Mihalek, Elena Goncharova, Richard D Minshall, Victor Laubach, Swapnil K SONKUSARE
Journal: Circulation (2020)

Background: Pulmonary hypertension (PH) is a degenerative disorder that is characterized by elevated vascular resistance and pulmonary arterial pressure (PAP). Endothelial transient receptor potential vanilloid 4 (TRPV4 EC ) ion channels represent an important Ca 2+ influx signaling mechanism that promotes vasodilation of small pulmonary arteries (PAs). Scaffolding protein caveolin-1 (Cav-1) has been shown to precipitate with TRPV4 channels in pulmonary endothelial cells in culture. Hypothesis: We hypothesized that the endothelial Cav-1-TRPV4 channel signaling in small PAs lowers PAP, and is impaired in PH. Methods: Inducible endothelium-specific KO mice for TRPV4 channel or Cav-1 were used to study the role of Cav-1-TRPV4 signaling in the regulation of resting PAP. Endothelium-specific P2Y2 receptor KO mice were used to test if Cav-1 provides a signaling scaffold for purinergic activation of TRPV4 EC channels. Endothelial Cav-1-TRPV4 signaling was assessed in PAs from two PH mouse models and PH patients. The role of NADPH oxidase (NOX1)- and inducible nitric oxide synthase (iNOS)-mediated peroxynitrite (PN), an oxidant molecule, in impairing Cav-1-TRPV4 signaling in PH was evaluated using NOX1-/- and iNOS-/- mice and pharmacological inhibitors. Results: We show that endothelial Cav-1-TRPV4 signaling in small PAs lowers resting PAP, and protects against the pathogenesis of PH. Endothelial Cav-1 provides a signaling scaffold for the activation of TRPV4 channels by endogenous purinergic receptor signaling. Moreover, TRPV4 EC channel activity and Cav-1-TRPV4 signaling are impaired in small PAs from two mouse models of PH and PH patients. Elevated levels of NOX1 and iNOS enzymes in caveolae resulted in PN formation close to Cav-1 in PH. Elevated PN targeted Cav-1 to lower Cav-1-TRPV4 signaling, thereby contributing to impaired vasodilation and increased PAP. Pharmacological inhibition of NOX1, iNOS, or PN rescued TRPV4 EC channel activity and vasodilation in PH. Conclusion: This study provides novel evidence that endothelial Cav-1-TRPV4 signaling lowers PAP and is impaired in PH. Inhibiting NOX1 or iNOS activity, or lowering endothelial PN levels may represent a novel strategy for restoring TRPV4 EC channel activity, vasodilation, and PAP.
Oxidative Stress in Stem / Progenitor Cells and Specific Antioxidant Response in Bone Marrow from Myelodysplastic Syndrome Patients
Authors: Frederic Picou, Christine Vignon, Joelle Hanna, Sebastien Lachot, Marie-Helene Estienne, Amelie Foucault, Frederic Mazurier, Florence Rouleux-Bonnin, Fabrice Gouilleux, Jorge Domenech, Emmanuel Gyan, Michaela Fontenay, Olivier Herault
Journal: Blood (2017)
Endovascular Therapy for Basilar-Artery Occlusion — Still Waiting for Answers
Authors: Marc Fisher
Journal: New England Journal of Medicine (2021)

The benefits of endovascular therapy provided soon after the onset of acute ischemic stroke due to large-vessel occlusion in the proximal anterior cerebral circulation were established by five clinical trials, the results of which were published in 2015.1 The DAWN (DWI or CTP Assessment with Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention with Trevo) trial2 and the DEFUSE 3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke) trial3 subsequently showed that endovascular therapy was beneficial up to 24 hours after the onset of stroke in patients who were selected on the basis of advanced . . .
Abstract P114: Sparse Partial Least Squares Regression: A Promising Technique To Identify Heart-healthy Dietary Patterns In The Multi-Ethnic Study Of Atherosclerosis (MESA)
Authors: Natalie Gasca, Robyn McClelland
Journal: Circulation (2021)

Most nutritional epidemiology studies investigating trends between diet and heart disease use outcome-independent dimension reduction methods, like principal component analysis, to create dietary patterns. While these methods construct patterns that describe important aspects of food consumption, these patterns are not inherently related to heart disease. Incorporating disease data into the pattern construction offers the possibility of more concisely summarizing the most disease-related foods. Sparse partial least squares (SPLS), one such method, was found to have favorable interpretation and prediction properties in the continuous outcome setting; while selecting a subset of relevant foods, it constructed a few dietary patterns that were correlated with BMI while also capturing variation in diet composition. These results were validated with simulated data. We propose incorporating SPLS into the Cox proportional hazards model to analyze a right-censored survival outcome. We hypothesized that this method would inherit the beneficial parsimony properties seen in the continuous setting, and we assessed whether this proposed method could use the most relevant covariates to create a few patterns that were associated with a survival outcome. While the proposed method targets covariate-level sparsity (i.e. variable selection), one competitor method exists that integrates pattern-level parsimony and partial least squares (PLS) in the Cox model, but it imposes more model parameters than the proposed method. We compared the variable selection, pattern selection, and predictive performance of four survival methods (Lasso, PLS, competitor sparse PLS, and proposed SPLS) via a simulation study. Simulation settings were informed in part by the Multi-Ethnic Study of Atherosclerosis (MESA), which has detailed food frequency questionnaire data on a large multi-ethnic population-based sample (6814 participants aged 45-84), as well as subsequent cardiovascular disease follow-up for over 15 years. In most studied simulation settings, the proposed method selected all 9 relevant predictors and the fewest number of irrelevant predictors (of 15) while creating a similar number of patterns and maintaining predictive ability of the outcome. In the setting most comparable to MESA, PLS chose all 24 predictors (by default) and 3.4 patterns (C-statistic=0.90), the competitor SPLS selected 21.1 predictors and 4.4 patterns (C-statistic=0.91), Lasso chose 16.4 predictors (C-statistic=0.91), and the proposed SPLS selected 11.7 predictors and 4.3 patterns (C-statistic=0.91), on average. We will also present an analysis of a coronary event in MESA using these four survival methods. In conclusion, we propose that using methods like SPLS to summarize food intake can create more heart disease-tailored dietary patterns that can complement the current nutritional epidemiology literature.
Acute Kidney Injury–Induced Systemic Inflammation and Risk of Kidney Cancer Formation
Authors: Sergei Kusmartsev
Journal: Cancer Research (2021)

Abstract In this issue of Cancer Research, Zhou and colleagues investigate the role of acute kidney injury (AKI) and AKI-associated systemic inflammation in the development of kidney cancer. They demonstrate a positive association between the formation of clear-cell renal cell carcinoma and AKI induced by ischemia-reperfusion injury in genetically modified mice. In parallel with the emergence of kidney tumors, mice with ischemic injury develop systemic inflammation associated with tissue infiltration by neutrophils and fibroblasts and upregulated expression of several inflammatory factors, with CXCL1 displaying the highest levels of upregulation. Accordingly, blockade of CXCL1-mediated signaling inhibited the emergence of kidney tumors in mice subjected to ischemic kidney injury. The study provides evidence for a new experimental approach to prevent the formation of clear-cell renal cell carcinoma and reduce kidney cancer incidence through modulation of the AKI-induced inflammatory response using inhibitors of CXC/CXCR2 axis. As the incidence of kidney cancer continues to increase, new treatment strategies for this devastating disease are urgently needed. Zhou and colleagues provide preclinical proof of concept for a new therapeutic strategy and address an unmet need for this difficult to prevent and treat cancer disease. See related article by Zhou et al., p. 2690
Dabigatran Plasma Concentration Correlates Well with Activated Partial Thromboplastin Time (aPTT) in Patients with Non-valvular Atrial Fibrillation
Authors: Kondo Hirokazu, Yoshikawa Yusuke, Takahashi Yusuke, Amano Masashi, Hayama Yukiko, Onishi Naoaki, Tamaki Yodo, Enomoto Soichiro, Miyake Makoto, Tamura Toshihiro, Motooka Makoto, Kaitani Kazuaki, Izumi Chisato, Nakagawa Yoshihisa
Journal: Circulation (2014)
The integrated information theory of consciousness: A case of mistaken identity
Authors: Bjorn Merker, Kenneth Williford, David Rudrauf
Journal: Behavioral and Brain Sciences (2021)

Abstract Giulio Tononi's integrated information theory (IIT) proposes explaining consciousness by directly identifying it with integrated information. We examine the construct validity of IIT's measure of consciousness, phi (Φ), by analyzing its formal properties, its relation to key aspects of consciousness, and its co-variation with relevant empirical circumstances. Our analysis shows that IIT's identification of consciousness with the causal efficacy with which differentiated networks accomplish global information transfer (which is what Φ in fact measures) is mistaken. This misidentification has the consequence of requiring the attribution of consciousness to a range of natural systems and artifacts that include, but are not limited to, large-scale electrical power grids, gene-regulation networks, some electronic circuit boards, and social networks. Instead of treating this consequence of the theory as a disconfirmation, IIT embraces it. By regarding these systems as bearers of consciousness ex hypothesi , IIT is led toward the orbit of panpsychist ideation. This departure from science as we know it can be avoided by recognizing the functional misattribution at the heart of IIT's identity claim. We show, for example, what function is actually performed, at least in the human case, by the cortical combination of differentiation with integration that IIT identifies with consciousness. Finally, we examine what lessons may be drawn from IIT's failure to provide a credible account of consciousness for progress in the very active field of research concerned with exploring the phenomenon from formal and neural points of view.
Abstract 16842: Cost-Effectiveness of Antibiotic-Eluting Envelopes for Prevention of Infections Associated With Cardiac Implantable Electronic Devices
Authors: Ronuk Modi, Peter Zimetbaum, Nicolas Isaza, Paola Calvachi, Inbar Raber, Brandon Bellows, Daniel B Kramer, Dhruv Kazi
Journal: Circulation (2020)

Introduction: Infections of cardiac implantable electronic devices result in substantial morbidity and healthcare costs. Using an antibiotic-eluting envelope (AEE) during implantation may reduce the incidence of device-related infection. We examined the cost-effectiveness of an AEE in patients receiving CRT-D devices. Methods: This analysis was conducted independent of the trial sponsor. We developed a state-transition Markov model to compare the use of an AEE with usual care during CRT-D initial implantation or reimplantation. Effectiveness of the AEE (unit cost $1000) was estimated from the Worldwide Randomized Antibiotic Envelope Infection Prevention Trial. Other inputs were derived from prior trials, registries, vital statistics, and nationally representative datasets. Long-term survival was projected using a non-parametric approach. The model reported incidence of infections, mortality, quality-adjusted life years (QALYs), and direct healthcare costs. Future costs and QALYs were discounted by 3% annually. The primary outcome was the incremental cost-effectiveness ratio (ICER) of AEE use from the US healthcare sector perspective over a lifetime analytic horizon. We assumed a cost-effectiveness threshold of $100,000 per QALY gained. Results: Use of an AEE at initial CRT-D implantation added 0.008 QALYs per patient at an incremental cost of $918 (ICER $118,000/QALY). Due to higher infection rates, the use of AEE in reimplantation procedures was more economically attractive (ICER $55,900/QALY). One-way sensitivity analyses showed an inverse relationship between ICER and rate of infection. The ICER was less than $100,000/QALY with infection rate greater than 2.42% in the first year after new CRT-D (Figure 1). Conclusions: At current prices, use of AEE is cost-effective for CRT-D reimplantation procedures but not for initial CRT-D implants. Cost-effectiveness of AEEs may be improved by restricting use to patients at increased risk of infection.
Abstract 15771: Recovery of Left Ventricular Function on Lvad Support is Associated With Improved Outcomes
Authors: Cameron Olsen, Aditya Mandawat, Taylor Triana, Marc D Samsky, Karen Chiswell, Ravi - Karra
Journal: Circulation (2020)

Introduction: For select patients, support with a left ventricular assist device (LVAD) can be used as a bridge to recovery of ventricular function. While rates of explant are low, improvement of left ventricular ejection fraction (LVEF) on LVAD support is more common. Hypothesis: We hypothesize that LVAD recipients whose LVEF recovers have better outcomes compared to those whose LVEF does not recover. Methods: Data from INTERMACS was merged with the Duke Echo Lab Database for all patients who underwent LVAD implantation between March 2006 and June 2017 at Duke Hospital. 286 patients with a continuous flow LVAD also had serial echocardiograms performed. Based on our prior work in HFrEF, we defined recovery as an LVEF &gt;= 40%. INTERMACS data and manual chart review was used to identify hospitalizations for recurrent heart failure (HF), gastrointestinal bleeding (GIB), and pump thrombosis along with mortality. Results: 9.8% of patients had an LVEF &gt;= 40% within 2 years of implant. LVEF recovery was associated with female gender [53.6% vs 21.7%. p &lt; 0.001], lower serum Cr prior to implant [1.30 mg/dL (IQR 1.00-1.60) vs 1.40 mg/dL (IQR 1.10-1.90), p = 0.05], and absence of an ICD [53.6% vs 79.8%, p = 0.002]. Within 1-year of the follow-up echo with the highest reported LVEF, patients whose LVEF was &gt;= 40% had a reduced incidence for a composite of hospitalizations for HF, GIB, pump thrombosis, and mortality [12.8% vs 39.8%, p = 0.013] as well as reduced rate of recurrent composite endpoint events [4.7 vs. 49 events per 100 person years, p = 0.020]. Of the individual endpoints, subjects with an LVEF &gt;= 40% had a lower, but non-significant, incidence of hospitalizations for HF [0% vs 10%, p = 0.122] and GIB [4.8% vs 18.2% p = 0.081]. Importantly, those who went on to recover their LVEF did not have a lower rate of recurrent composite endpoint events between the time of implant and time to follow-up echo (88 events per 100 person years in the recovery group vs 53 per 100 person years in the non-recovery group, p =0.052), suggesting that recovery of LVEF is temporally related to the improvement in outcomes. Conclusions: Recovery of LVEF on LVAD support in not uncommon. Strategies to facilitate recovery have the potential to improve outcomes of LVAD recipients beyond pump explant.