tbuckley/cabot-search huggingface dataset:
Junctophilin-2 tethers T-tubules and recruits functional L-type calcium channels to lipid rafts in adult cardiomyocytes
Authors: Claire Poulet, Jose Sanchez-Alonso, Pamela Swiatlowska, Florence Mouy, Carla Lucarelli, Anita Alvarez-Laviada, Polina Gross, Cesare Terracciano, Steven Houser, Julia Gorelik
Journal: Cardiovascular Research (2020)

Abstract Aim In cardiomyocytes, transverse tubules (T-tubules) associate with the sarcoplasmic reticulum (SR), forming junctional membrane complexes (JMCs) where L-type calcium channels (LTCCs) are juxtaposed to Ryanodine receptors (RyR). Junctophilin-2 (JPH2) supports the assembly of JMCs by tethering T-tubules to the SR membrane. T-tubule remodelling in cardiac diseases is associated with downregulation of JPH2 expression suggesting that JPH2 plays a crucial role in T-tubule stability. Furthermore, increasing evidence indicate that JPH2 might additionally act as a modulator of calcium signalling by directly regulating RyR and LTCCs. This study aimed at determining whether JPH2 overexpression restores normal T-tubule structure and LTCC function in cultured cardiomyocytes. Methods and results Rat ventricular myocytes kept in culture for 4 days showed extensive T-tubule remodelling with impaired JPH2 localization and relocation of the scaffolding protein Caveolin3 (Cav3) from the T-tubules to the outer membrane. Overexpression of JPH2 restored T-tubule structure and Cav3 relocation. Depletion of membrane cholesterol by chronic treatment with methyl-β-cyclodextrin (MβCD) countered the stabilizing effect of JPH2 overexpression on T-tubules and Cav3. Super-resolution scanning patch-clamp showed that JPH2 overexpression greatly increased the number of functional LTCCs at the plasma membrane. Treatment with MβCD reduced LTCC open probability and activity. Proximity ligation assays showed that MβCD did not affect JPH2 interaction with RyR and the pore-forming LTCC subunit Cav1.2, but strongly impaired JPH2 association with Cav3 and the accessory LTCC subunit Cavβ2. Conclusions JPH2 promotes T-tubule structural stability and recruits functional LTCCs to the membrane, most likely by directly binding to the channel. Cholesterol is involved in the binding of JPH2 to T-tubules as well as in the modulation of LTCC activity. We propose a model where cholesterol and Cav3 support the assembly of lipid rafts which provide an anchor for JPH2 to form JMCs and a platform for signalling complexes to regulate LTCC activity.
White Blood Cells and Blood Pressure
Authors: Mateusz Siedlinski, Ewelina Jozefczuk, Xiaoguang Xu, Alexander Teumer, Evangelos Evangelou, Renate B. Schnabel, Paul Welsh, Pasquale Maffia, Jeanette Erdmann, Maciej Tomaszewski, Mark J. Caulfield, Naveed Sattar, Michael V. Holmes, Tomasz J. Guzik
Journal: Circulation (2020)

High blood pressure (BP) is a risk factor for cardiovascular morbidity and mortality. While BP is regulated by the function of kidney, vasculature, and sympathetic nervous system, recent experimental data suggest that immune cells may play a role in hypertension.We studied the relationship between major white blood cell types and blood pressure in the UK Biobank population and used Mendelian randomization (MR) analyses using the ≈750 000 UK-Biobank/International Consortium of Blood Pressure-Genome-Wide Association Studies to examine which leukocyte populations may be causally linked to BP.A positive association between quintiles of lymphocyte, monocyte, and neutrophil counts, and increased systolic BP, diastolic BP, and pulse pressure was observed (eg, adjusted systolic BP mean±SE for 1st versus 5th quintile respectively: 140.13±0.08 versus 141.62±0.07 mm Hg for lymphocyte, 139.51±0.08 versus 141.84±0.07 mm Hg for monocyte, and 137.96±0.08 versus 142.71±0.07 mm Hg for neutrophil counts; all P<10-50). Using 121 single nucleotide polymorphisms in MR, implemented through the inverse-variance weighted approach, we identified a potential causal relationship of lymphocyte count with systolic BP and diastolic BP (causal estimates: 0.69 [95% CI, 0.19-1.20] and 0.56 [95% CI, 0.23-0.90] of mm Hg per 1 SD genetically elevated lymphocyte count, respectively), which was directionally concordant to the observational findings. These inverse-variance weighted estimates were consistent with other robust MR methods. The exclusion of rs3184504 SNP in the SH2B3 locus attenuated the magnitude of the signal in some of the MR analyses. MR in the reverse direction found evidence of positive effects of BP indices on counts of monocytes, neutrophils, and eosinophils but not lymphocytes or basophils. Subsequent MR testing of lymphocyte count in the context of genetic correlation with renal function or resting and postexercise heart rate demonstrated a positive association of lymphocyte count with urine albumin-to-creatinine ratio.Observational and genetic analyses demonstrate a concordant, positive and potentially causal relationship of lymphocyte count with systolic BP and diastolic BP.
Dalcetrapib Reduces Risk of New-Onset Diabetes in Patients With Coronary Heart Disease
Authors: Gregory G. Schwartz, Lawrence A. Leiter, Christie M. Ballantyne, Philip J. Barter, Donald M. Black, David Kallend, Fouzia Laghrissi-Thode, Eran Leitersdorf, John J.V. McMurray, Stephen J. Nicholls, Anders G. Olsson, David Preiss, Prediman K. Shah, Jean-Claude Tardif, John Kittelson
Journal: Diabetes Care (2020)

OBJECTIVE Incident type 2 diabetes is common among patients with recent acute coronary syndrome and is associated with an adverse prognosis. Some data suggest that cholesteryl ester transfer protein (CETP) inhibitors reduce incident type 2 diabetes. We compared the effect of treatment with the CETP inhibitor dalcetrapib or placebo on incident diabetes in patients with recent acute coronary syndrome. RESEARCH DESIGN AND METHODS In the dal-OUTCOMES trial, 15,871 patients were randomly assigned to treatment with dalcetrapib 600 mg daily or placebo, beginning 4–12 weeks after an acute coronary syndrome. Absence of diabetes at baseline was based on medical history, no use of antihyperglycemic medication, and hemoglobin A1c and serum glucose levels below diagnostic thresholds. Among these patients, incident diabetes after randomization was defined by any diabetes-related adverse event, new use of antihyperglycemic medication, hemoglobin A1c ≥6.5%, or a combination of at least two measurements of serum glucose ≥7.0 mmol/L (fasting) or ≥11.1 mmol/L (random). RESULTS At baseline, 10,645 patients (67% of the trial cohort) did not have diabetes. During a median follow-up of 30 months, incident diabetes was identified in 403 of 5,326 patients (7.6%) assigned to dalcetrapib and in 516 of 5,319 (9.7%) assigned to placebo, corresponding to absolute risk reduction of 2.1%, hazard ratio of 0.77 (95% CI 0.68–0.88; P &amp;lt; 0.001), and a need to treat 40 patients for 3 years to prevent 1 incident case of diabetes. Considering only those with prediabetes at baseline, the number needed to treat for 3 years to prevent 1 incident case of diabetes was 25. Dalcetrapib also decreased the number of patients who progressed from normoglycemia to prediabetes and increased the number who regressed from diabetes to no diabetes. CONCLUSIONS In patients with a recent acute coronary syndrome, incident diabetes is common and is reduced substantially by treatment with dalcetrapib.
Abstract P346: Cohort Identification to Harness the Electronic Health Record for Cardiovascular Disease Prediction
Authors: Sheila M Manemann, Jennifer St Sauver, Janet E Olson, Nicholas B Larson, Paul Y Takahashi, Veronique L Roger, Paul A Decker, Jill M Killian, Suzette J Bielinski
Journal: Circulation (2020)

Background: Current cardiovascular disease (CVD) risk scores are derived from research cohorts and are particularly inaccurate in women, older adults, and those with missing data. To overcome these limitations, we aimed to develop a cohort to capitalize on the depth and breadth of clinical data within electronic health record (EHR) systems in order to develop next-generation sex-specific risk prediction scores for incident CVD. Methods: All individuals 30 years of age or older residing in Olmsted County, Minnesota on 1/1/2006 were identified. We developed and validated algorithms to define a variety of risk factors, thus building a comprehensive risk profile for each patient. Outcomes including myocardial infarction (MI), percutaneous intervention (PCI), coronary artery bypass graft (CABG), and CVD death were ascertained through 9/30/2017. Results: We identified 73,069 individuals without CVD (Table). We retrieved a total of 14,962,762 lab results; 14,534,466 diagnoses; 17,062,601 services/procedures; 1,236,998 outpatient prescriptions; 1,079,065 heart rate measurements; and 1,320,115 blood pressure measurements. The median number of blood pressure and heart rate measurements ascertained per individuals were 11 and 9, respectively. The five most prevalent conditions were: hypertension, hyperlipidemia, arthritis, depression, and cardiac arrhythmias. During follow-up 1,455 MIs, 1,581 PCI, 652 CABG, and 2,161 CVD-related deaths occurred. Conclusions: We developed a cohort with comprehensive risk profiles and follow-up for each patient. Using sophisticated machine learning approaches, this electronic cohort will be utilized to develop next-generation sex-specific CVD risk prediction scores. These approaches will allow us to address several challenges with use of EHR data including the ability to 1) deal with missing values, 2) assess and utilize a large number of variables without over-fitting, 3) allow non-linear relationships, and 4) use time-to-event data.
Abstract P338: Cardiovascular And Cerebrovascular Events Associated With Cancer Surgery In The United States
Authors: Anshul Saxena, Muni Rubens, Venkataraghavan Ramamoorthy, Sankalp Das, Chintan B Bhatt, Joseph A Salami, Peter McGranaghan, Nancy Shehadeh, Emir Veledar
Journal: Circulation (2020)

Background: Major adverse cardiovascular and cerebrovascular events (MACCE) are significant causes of perioperative morbidity and mortality but, the incidence and effects following cancer surgeries are unknown. The aims of this study were to evaluate national trends in MACCE after major cancer surgeries and to identify cancer types associated with cardiovascular events using a large national database. Methods: Patients who had major cancer surgeries from 2005 to 2014 were identified from the National Inpatient Sample database. Hospitalizations for surgeries for cancer of prostate, bladder, esophagus, pancreas, lung, liver, breast, colon and rectum were identified by ICD9 diagnosis and procedure codes. The main outcome was perioperative MACCE, defined as in-hospital, all-cause death, acute myocardial infarction (AMI), or acute ischemic stroke, and was evaluated over time. Results: Among 2,854,810 hospitalizations for major cancer surgeries, perioperative MACCE occurred in 67,316 hospitalizations (2.4%). Mean (SE) age of patients was 65.4 (0.07) years and 54.2% were male patients. MACCE occurred most frequently in patients undergoing surgeries for lung (6.8%), pancreatic (4.5%), and colorectal (3.3%) cancers. Between 2005 and 2014, the frequency of MACCE declined from 2.7% to 2.2% ( P &lt;0.001) and was driven by a decline in the frequency of perioperative death ( P &lt;0.001) and AMI ( P = 0.002). However, no significant changes were observed for acute ischemic stroke ( P = 0.6) during the study period. Conclusion: Perioperative MACCE occurs in 1 out of every 42 hospitalizations for major cancer surgeries. Despite reductions in the rate of death and AMI among patients undergoing major cardiac surgeries, perioperative ischemic stroke remained constant over time. The lack of improvements in perioperative ischemic stroke rate is concerning and requires additional interventions. Significant efforts should be directed towards improving cardiovascular care during the perioperative period of cancer surgeries.
Abstract P296: Investigation Of Geographic Disparities Of Pre-diabetes And Diabetes And Associated County-level Risk Factors In Florida, 2016
Authors: Jennifer E Lord, Shamarial L Roberson, Agricola Odoi
Journal: Circulation (2020)

Background: Diabetes and its complications represent a significant public health burden in the United States, with evidence of geographic disparities. Identifying these disparities and their determinants is useful for guiding control programs. Therefore, this study investigated geographic disparities of pre-diabetes and diabetes prevalence in Florida in 2016, and identified predictors of the observed spatial patterns. Additionally, we investigated changes in geographic distribution of the two conditions between 2013 and 2016. Methods: The 2013 and 2016 Behavioral Risk Factor Surveillance System data were obtained from the Florida Department of Health. Flexible scan statistics were used to identify significant high prevalence geographic clusters. Global ordinary least squares regression and local Poisson geographically weighted generalized linear models were used to investigate predictors of the identified spatial patterns. Counties with significant changes in prevalence of the two conditions between 2013 and 2016 were identified using tests for equality of proportions adjusted for multiple comparisons using Simes method. Results: The state-wide diabetes prevalence was 11.2% in 2013, and 11.8% in 2016. Statistically significant ( p ≤0.05) increases in prevalence were identified in 73% (49/67) of the counties. Similarly, the state-wide prevalence of pre-diabetes was 7.1% in 2013 and 9.2% in 2016 with 76% (51/67) of the counties reporting statistically significant increases. Significant local hotspots were identified for both conditions. Predictors of county-level diabetes prevalence were: proportion of the obese population, number of physicians per 1000 persons, proportion of the population living below the poverty level, and proportion of the population with arthritis. Predictors of pre-diabetes prevalence included proportion of the population with arthritis and proportion of the population that identified as non-Hispanic black. There was evidence of geographical variability of all regression coefficients for both the pre-diabetes and diabetes models indicating that the strength of association of the relationships between the predictors and outcomes varied by geographic area. Conclusions: Geographic disparities of both conditions continue to exist in Florida. Moreover, there was a state-wide increase in the burden of both conditions between 2013 and 2016. The fact that the strength of association of the relationships between the predictors and outcomes varied across the counties implies that some predictors may be more important in some counties than others. These findings imply that local models provide useful information to guide public health decision-making and resource allocation. Identifying high-risk geographic areas and location-specific determinants of chronic disease prevalence should be used to inform targeted intervention programs.
Abstract 28: Regular Aerobic Exercise Counteracts Endothelial Vasomotor Dysfunction Associated With Insufficient Sleep
Authors: Kelly A Stockelman, Anthony R Bain, Caitlin A Dow, Jared J Greiner, Brian L Stauffer, Christopher A Desouza
Journal: Circulation (2020)

Insufficient sleep, defined as chronic short sleep duration (&lt;7 h/night), is an independent risk factor for cardiovascular disease (CVD). We have previously demonstrated that insufficient sleep is associated with reduced endothelium-dependent vasodilation and enhanced endothelin (ET)-1-mediated vasoconstrictor tone. Impaired endothelial vasomotor regulation is thought to contribute mechanistically to the increased risk of atherosclerotic vascular disease incurred with chronic insufficient sleep. Regular aerobic exercise is an effective lifestyle strategy for improving endothelial function and, in turn reducing cardiovascular risk. It is currently unknown if regular aerobic exercise can counteract the negative impact of insufficient sleep on endothelial vasomotor regulation. We tested the hypotheses that regular aerobic exercise would: 1) improve endothelial vasodilation; and 2) decrease ET-1-mediated vasoconstrictor tone in middle-aged adults who chronically sleep less than 7 h/night. We studied 36 healthy, middle-aged adults: 16 with normal sleep duration (10M/6F; age: 57±2 yr; sleep duration: 7.4±0.1 h/night) and 20 with short sleep duration (11M/9F; 56±1 yr; sleep duration: 6.2±0.1 h/night). The 20 short sleepers completed a 3-month aerobic exercise training intervention. Forearm blood flow (FBF; plethysmography) was determined in response to intra-arterial doses of acetylcholine (ACh), sodium nitroprusside (SNP), BQ-123 (ET A receptor antagonist) and ACh + BQ-123 in both groups and after the exercise intervention in the short sleepers. As expected, forearm vasodilator responses to ACh were lower (20%; P&lt;0.05) in the short (from 4.2±0.2 to 10.5±0.6 mL/100 mL tissue/min) vs normal (4.2±0.2 to 12.7±0.6 mL/100 mL tissue/min) sleepers. FBF responses to SNP were comparable between the groups. In response to BQ-123, short sleep group had a greater increase in resting FBF than normal sleep group (~25% vs ~8%; P&lt; 0.05). ACh+BQ-123 resulted in an ~25% increase in the ACh-vasodilation in the short sleep group only. After exercise training, although nightly sleep duration was not affected (6.4±0.1 h/night), ACh-mediated vasodilation was ~20% higher (P&lt;0.05), ET-1-mediated vasoconstriction was ~90% lower (P&lt;0.05) and vasodilator response to ACh was not significantly increased with ET A receptor blockade. These results indicate that regular aerobic exercise can reverse the negative influence of insufficient sleep on endothelial vasomotor function, independent of changes in nightly sleep duration.
Dupilumab reduces need for systemic corticosteroid use, sinonasal surgery in patients with severe chronic rhinosinusitis with nasal polyps : pooled results from the SINUS- 24, SINUS- 52 phase 3 studies
Authors: M Desrosiers, Claus Bachert, Peter Hellings, C Hopkins, H Olze, JK Han, Se Lee, M Zhang, X Lu, N Amin, N Patel, Nmh Graham, M Ruddy, H Staudinger, LP Mannent
Journal: Allergy (2019)
Abstract P245: Impact of Depressive and Anxiety Symptoms on All Cause Mortality Among Andean Hispanics: Result From the PREVENCION Study
Authors: Diana Chirinos, Liliana Aguayo, Emily Vargas, Mercedes R Carnethon, Josefina Medina Lezama
Journal: Circulation (2020)

Introduction: Depressive/anxiety symptoms are associated with mortality among patients with established cardiovascular disease (CVD). These symptoms are also associated with higher burden of CVD risk factors. Few studies have examined whether the association between psychological symptoms and mortality is independent of CVD risk factors in community-based samples, and no study to date has focused on Andean Hispanic adults. In this study, we examined the association between depressive/anxiety symptoms and 10-year all-cause mortality among community-based Andean Hispanic adults, after adjusting for demographic and CVD risk factors. Hypothesis: Depressive/anxiety symptoms are independently associated with 10-year all-cause mortality among Andean Hispanic adults. Methods: Participants included 551 adults (57.7% female, mean baseline age=50.9 years [SD=16.8]) enrolled in the Peruvian Study of Cardiovascular Disease (PREVENCION). Depressive/anxiety symptoms were assessed with the Hospital Anxiety and Depression Scale. Cox proportional-hazards models were used to examine associations between depressive/anxiety symptoms and all-cause mortality. Results: Mean depressive and anxiety symptom scores were 5.7 (SD=3.5) and 7.6 (3.6), respectively. There were 42 events (7.6%) reported at the 10-year follow-up. In unadjusted models, depressive symptoms were significantly associated with all-cause mortality (HR=1.25, 95% Confidence Intervals [CI]=1.14-1.37). After controlling for demographic factors and CVD risk factors (Figure 1), depressive symptoms remained significantly associated with all-cause mortality (HR=1.18, 95% CI=1.06-1.31). No associations were found between anxiety symptoms and all-cause mortality in unadjusted or adjusted models. Conclusion: Depressive symptoms were associated with 10-year all-cause mortality among Andean Hispanic adults even after adjusting for demographic and CVD risk factors. Future studies should examine associations with cause-specific mortality.
The Long-term Effects of Metformin on Patients With Type 2 Diabetic Kidney Disease
Authors: Soie Kwon, Yong Chul Kim, Jae Yoon Park, Jeonghwan Lee, Jung Nam An, Clara Tammy Kim, Sohee Oh, Seokwoo Park, Dong Ki Kim, Yun Kyu Oh, Yon Su Kim, Chun Soo Lim, Jung Pyo Lee
Journal: Diabetes Care (2020)

Metformin is the first pharmacological option for treating type 2 diabetes. However, the use of this drug is not recommended in individuals with impaired kidney function because of the perceived risk of lactic acidosis. We aimed to assess the efficacy and safety of metformin in patients with type 2 diabetic kidney disease (DKD).We conducted a retrospective observational cohort study of 10,426 patients with type 2 DKD from two tertiary hospitals. The primary outcomes were all-cause mortality and end-stage renal disease (ESRD) progression. The secondary outcome was metformin-associated lactic acidosis. Taking into account the possibility that patients with less severe disease were prescribed metformin, propensity score matching (PSM) was conducted.All-cause mortality and incident ESRD were lower in the metformin group according to the multivariate Cox analysis. Because the two groups had significantly different baseline characteristics, PSM was performed. After matching, metformin usage was still associated with lower all-cause mortality (adjusted hazard ratio [aHR] 0.65; 95% CI 0.57-0.73; P < 0.001) and ESRD progression (aHR 0.67; 95% CI 0.58-0.77; P < 0.001). Only one event of metformin-associated lactic acidosis was recorded. In both the original and PSM groups, metformin usage did not increase the risk of lactic acidosis events from all causes (aHR 0.92; 95% CI 0.668-1.276; P = 0.629).In the present retrospective study, metformin usage in advanced chronic kidney disease (CKD) patients, especially those with CKD 3B, decreased the risk of all-cause mortality and incident ESRD. Additionally, metformin did not increase the risk of lactic acidosis. However, considering the remaining biases even after PSM, further randomized controlled trials are needed to change real-world practice.
Abstract 15453: Are High Intensity Statins Beneficial in Patients With “High Intensity Like” LDL-C Reduction on Low Dose Statin: Insights From the TNT Trial
Authors: Sripal Bangalore, Rana Fayyad, David A DeMicco, David D Waters
Journal: Circulation (2019)

Introduction: High intensity statins (LDL-C reduction of >=50%) are recommended for patients with atherosclerotic cardiovascular disease. However, it is not known if high-intensity statins provide ...
Topoisomerase 2β mutation impairs early B-cell development
Authors: Olivier Papapietro, Anita Chandra, Davide Eletto, Sarah Inglott, Vincent Plagnol, James Curtis, Mailis Maes, Ali Alisaac, Adriana S. Albuquerque, Eugenie Basseres, Olivier Hermine, Capucine Picard, Alain Fischer, Anne Durandy, Sven Kracker, Siobhan O. Burns, Delphine Cuchet-Lourenco, Klaus Okkenhaug, Sergey Nejentsev
Journal: Blood (2020)