1,236 results on '"Paul M. Ridker"'
Search Results
52. Data from Plasma C-Reactive Protein and Risk of Breast Cancer in Two Prospective Studies and a Meta-analysis
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Susan E. Hankinson, Bernard Rosner, Paul M. Ridker, Julie E. Buring, Shelley S. Tworoger, I-Min Lee, and Jun Wang
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Background: C-reactive protein (CRP) has been evaluated as a risk factor for breast cancer in epidemiologic studies. However, results from prospective studies are inconsistent.Methods: We evaluated the association using prediagnostic blood samples in a case–control study nested within the Nurses' Health Study (NHS) and the full cohort of the Women's Health Study (WHS). A total of 943 cases in the NHS and 1,919 cases in the WHS contributed to the analysis. Conditional logistic regression and Cox proportional hazards model were used in the NHS and WHS, respectively. We pooled our results with prior prospective studies using random effect meta-analysis.Results: In the NHS, higher CRP levels were associated with a suggestively increased risk of breast cancer [quintile 5 vs. 1: relative risk (RR), 1.27; 95% confidence interval (CI), 0.93–1.73; Ptrend = 0.02]; results did not vary significantly by tumor invasiveness or hormone receptor status. However, no association was observed in the WHS for overall risk (quintile 5 vs. 1: RR, 0.89; 95% CI, 0.76–1.06; Ptrend = 0.38) or by tumor invasiveness or hormone receptor status. The meta-analysis (including 5,371 cases from 11 studies) showed a modestly increased risk among women in the highest versus lowest categories of CRP (RR, 1.26; 95% CI, 1.07–1.49).Conclusions: Existing data from prospective studies suggest that CRP, a nonspecific marker of inflammation, is modestly positively associated with breast cancer risk.Impact: Our findings provide support to the concept that inflammation can influence breast cancer development. Cancer Epidemiol Biomarkers Prev; 24(8); 1199–206. ©2015 AACR.
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- 2023
53. Supplementary Tables 1-3 from Plasma C-Reactive Protein and Risk of Breast Cancer in Two Prospective Studies and a Meta-analysis
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Susan E. Hankinson, Bernard Rosner, Paul M. Ridker, Julie E. Buring, Shelley S. Tworoger, I-Min Lee, and Jun Wang
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Supplementary Tables 1-3. Supplementary Table 1. Summary of Previously Published Prospective Cohort Studies of Circulating CRP and Breast Cancer Risk. Supplementary Table 2. Plasma CRP Levels and Risk of Breast Cancer Overall by Menopausal Status, BMI, Aspirin Use in the NHS and WHS Respectively and the Combined Analysis. Supplementary Table 3. Plasma CRP Levels and Risk of Breast Cancer Overall by Years of Follow-up in the NHS and WHS Respectively.
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- 2023
54. Interactions Between Genetic Risk and Diet Influencing Risk of Incident Female Gout: Discovery and Replication Analysis of Four Prospective Cohorts
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Kehuan Lin, Natalie McCormick, Chio Yokose, Amit D. Joshi, Na Lu, Gary C. Curhan, Tony R. Merriman, Kenneth G. Saag, Paul M. Ridker, Julie E. Buring, Daniel I. Chasman, Frank B. Hu, and Hyon K. Choi
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Rheumatology ,Immunology ,Immunology and Allergy - Abstract
To examine whether the cross-sectional gene-diet interaction for prevalent hyperuricemia among women translates prospectively to risk of incident female gout.We analyzed the interaction between genetic predisposition and adherence to a healthy dietary pattern (i.e., Dietary Approaches to Stop Hypertension [DASH] score) on risk of incident female gout in 18,244 women from Nurses' Health Study (NHS; discovery) and 136,786 women from 3 additional prospective female cohorts from US and UK (replication). Genetic risk score (GRS) was calculated from 114 urate-associated loci.In the NHS and replication cohorts, association between diet and gout risk was larger and stronger among women with higher genetic risk. In all cohorts combined, compared with women with unhealthy DASH score (mean), multivariable relative risk (mRR) for incident female gout among women with healthy DASH score (≥mean) was 0.67 (95% CI 0.60-0.76) among higher GRS (≥mean) and 0.91 (0.78-1.05) among lower GRS (P multiplicative interaction=0.001); mRR for higher vs. lower GRS was 2.03 (1.80-2.29) and 1.50 (1.31-1.71) among unhealthy and healthy DASH score groups, respectively. Additive interaction was also significant, in both the discovery and replication cohorts (P0.001), with 51% of the excess risk attributable to the additive gene-diet interaction in all cohorts combined.The deleterious effect of genetic predisposition on risk of incident female gout was more pronounced among women with unhealthy diet, with nearly half the excess risk attributable to this gene-diet interaction. These data elucidate the important synergy of genetics and diet for female gout development. This article is protected by copyright. All rights reserved.
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- 2023
55. Abstract P330: Effect of Randomized Omega-3 Treatment on Downstream Bioactive Lipids and Their Association With Incident Cardiovascular Disease Events: Metabolomic Studies of the Vital and Jupiter Trials
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Olga Demler, Yanyan Liu, Mona Alotaibi, Rosangela Hoshi, Franco Giulianini, Heike Gibson, Jeramie Watrous, Nancy R Cook, Karen Costenbader, Olivia Okereke, Robert Glynn, Paul M Ridker, Joann E Manson, Susan Cheng, Daniel Chasman, Mohit Jain, and Samia Mora
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Physiology (medical) ,Cardiology and Cardiovascular Medicine - Abstract
Background: The effect of omega-3 (n-3) treatment on cardiovascular disease (CVD) outcomes in randomized controlled trials remains inconsistent. We hypothesize that the downstream products of n-3 metabolism, including bioactive lipids (BALs), have a heterogeneous relationship with CVD, which may provide insight into response heterogeneity. Methods: Using state of the art LC-MS, we assayed the plasma bioactive lipidome (>10K BALs) across 3,512 individuals at baseline and Y1 or -2, in the VITAL substudies (CVD case control N=1540; CTSC subcohort N=1054; 45% women, median age 70, 20% non-white) and JUPITER CVD case control (N=918) (NCT01169259, NCT00239681). Linear regression revealed BALs that change consistently with n-3 treatment (n3BALs) (discovery in VITAL controls, validation in an independent VITAL CTSC substudy, cumulative FDR .05). n3BALs that are also associated with CVD in VITAL CVD were identified using adjusted conditional logistic regression (p Results: 354 BALs changed in response to randomized n-3 vs placebo. Baseline levels of 8 of these BALs were significantly associated with incident CVD (Figure, panels A, B). When combined into the multivariable BAL score, 5 were inversely and 3 positively associated with the CVD risk. The BAL score was significantly associated with CVD with fully adjusted HR/SD of 1.32, 95%CI [1.12 - 1.55] in external study, Figure panel C. N-3 therapy, statin therapy and baseline fish intake were associated with weak Y1 or -2 reduction in BAL score. Conclusions: Downstream BALs are altered in response to n-3 treatment and associate with both decreased as well as increased risk of CVD. BAL response to n-3 treatment may explain clinical heterogeneity associated with fish oil supplementation and may be utilized for selection of more specific treatment.
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- 2023
56. Abstract 40: Score Based on Immunoglobulin G N-glycans for Cardiovascular Risk Prediction: Secondary Analysis of Two Randomized Trials of Primary and Secondary Prevention
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Rosangela Hoshi, Branimir Plavša, Yanyan Liu, Irena Trbojevic-Akmacic, Robert Glynn, Paul M Ridker, Richard Cummings, Gordan Lauc, Olga Demler, and Samia Mora
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Physiology (medical) ,Cardiology and Cardiovascular Medicine - Abstract
Introduction: Immunoglobulin G (IgG) are post-translationally modified proteins with the addition of complex carbohydrate molecules (glycans). These glycans can modulate IgG inflammatory capacity and determine the transition from healthy to diseased tissue. Hypothesis: A glycan score based on certain IgG glycosylation patterns is associated with CVD risk and can improve model prediction. Methods: IgG glycosylation profiles were measured on baseline plasma samples from nested CVD case-control participants from 2 studies: JUPITER (NCT00239681; Npairs=162; discovery) and the TNT (NCT00327691; Npairs=367, validation). Lasso regression was used to select IgG glycan peaks (GPs). The linear combination of selected IgG-GPs that significantly associated with CVD in a mutually adjusted conditional regression comprised the glycan score (IgG GS ). CVD prediction using IgG GS was investigated controlling for clinical risk factors. Using a parametric approach, we calculated the area under the curve (AUC) with and without IgG GS . Results: From 24 IgG-GPs, Lasso selected 4 IgG-GPs that were also associated with incident CVD (PGS ; Fig1A), which was significantly associated with incident CVD in JUPITER after adjusting for clinical risk factors (model 2 hazard ratio [HR]: 2.1, 95% CI 1.55 - 2.84), with significant validation in TNT (HR = 1.2, 95% CI 1.03 - 1.4; Fig. 1B). The AUC was higher for the model with IgG GS (0.74, 95%CI = 0.69 - 0.81) than without (0.69, 95%CI = 0.67 - 0.71) in JUPITER; replicating in TNT: 0.72 [0.71 - 0.83] vs 0.64, [0.62 - 0.65]. The P-value for the likelihood ratio test comparing models with and without IgG GS was 5.9x10 -8 in JUPITER and .02 in TNT. Conclusions: An IgG glycan score with 4 IgG N-glycans was positively associated with incident CVD in the JUPITER primary prevention population, which replicated in TNT, a secondary prevention cohort, and improved model prediction performance.
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- 2023
57. Biological basis and proposed mechanism of action of CSL112 (apolipoprotein A-I [human]) for prevention of major adverse cardiovascular events in patients with myocardial infarction
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Serge Korjian, Syed Hassan A Kazmi, Gerald Chi, Arzu Kalayci, Jane J Lee, Usama Talib, Samuel D Wright, Danielle Duffy, Bronwyn A Kingwell, Roxana Mehran, Paul M Ridker, and C Michael Gibson
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Pharmacology (medical) ,Cardiology and Cardiovascular Medicine - Abstract
Despite current standard of care treatment, the period shortly after acute myocardial infarction (AMI) is associated with high residual cardiovascular (CV) risk, with high rates of recurrent AMI and CV death in the first 90 days following the index event. This represents an area of high unmet need that may be potentially addressed by novel therapeutic agents that optimize high-density lipoprotein cholesterol (HDL-C) function rather than increase HDL-C concentrations. Apolipoprotein A-I (apoA-I) is the major constituent of HDL and a key mediator of cholesterol efflux from macrophages within atherosclerotic plaque, a property especially relevant during the high-risk period immediately following an AMI when cholesterol efflux capacity is found to be reduced. CSL112 is a novel formulation of human plasma-derived apolipoprotein A-I (apoA-I), currently being evaluated in a Phase 3 clinical trial (AEGIS-II) for the reduction of major adverse CV events in the 90-day high-risk period post-AMI. In this review, we provide an overview of the biological properties of CSL112 that contribute to its proposed mechanism of action for potential therapeutic benefit. These properties include rapid and robust promotion of cholesterol efflux from cells abundant in atherosclerotic plaque, in addition to anti-inflammatory effects, which together, may have a stabilizing effect on atherosclerotic plaque. We provide a detailed overview of these mechanisms, in addition to information on the composition of CSL112 and how it is manufactured.
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- 2023
58. Antithrombotic prophylaxis for symptomatic outpatients with COVID-19: less is consistently more
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Jean M, Connors and Paul M, Ridker
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Fibrinolytic Agents ,Outpatients ,Anticoagulants ,COVID-19 ,Humans ,Hematology ,Heparin, Low-Molecular-Weight - Published
- 2022
59. Warfarin Dosing in Patients With CYP2C9*5 Variant Alleles
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Kathryn J. Lindley, Nita A. Limdi, Larisa H. Cavallari, Minoli A. Perera, Petra Lenzini, Julie A. Johnson, Alan H. B. Wu, Paul M Ridker, Cristi R. King, Charles S. Eby, Shitalben Patel, Shimoli V. Shah, T. Mark Beasley, Juan Li, and Brian F. Gage
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Male ,Pharmacology ,Dose-Response Relationship, Drug ,Genotype ,Anticoagulants ,Polymorphism, Single Nucleotide ,Vitamin K Epoxide Reductases ,Humans ,Female ,Pharmacology (medical) ,Aryl Hydrocarbon Hydroxylases ,Warfarin ,Alleles ,Cytochrome P-450 CYP2C9 - Abstract
Pharmacogenetic dosing improves the accuracy of warfarin dosing, but current pharmacogenetic dosing algorithms are less accurate in populations of African ancestry. The cytochrome P450 2C9*5 (CYP2C9*5) allele is found almost exclusively in populations of African ancestry, and in vitro studies suggest CYP2C9*5 is associated with reduced clearance of warfarin. The clinical relevance of this single-nucleotide variation (SNV) (formerly SNP) is uncertain. In this multicentered study of 2,298 patients (49% female, 35% Black) taking warfarin, we quantified the association between the CYP2C9*5 allele and warfarin requirements. The CYP2C9*5 SNV was present in 2.3% of Black and 0.07% of White patients. Without taking CYP2C9*5 into account, pharmacogenetic algorithms that include other SNVs overestimated the warfarin dose by 30% (95% confidence interval (19-40%), P 0.001), an average of 1.87 mg/day (SD 1.64) in heterozygotes (P 0.001). Noncarriers required a slightly (0.23 mg/day, SD 2.09) higher than predicted dose. Genotyping for CYP2C9*5 corrected the potential overdose and halved overall dosing error in heterozygotes. Patients carrying CYP2C9*5 require a clinically relevant reduction in warfarin dose. Given the potential to improve the accuracy and safety of warfarin dosing in populations of African ancestry, we have incorporated this SNV into a nonprofit website to assist warfarin initiation (www.WarfarinDosing.org).
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- 2022
60. Dissecting the IL‐6 pathway in cardiometabolic disease: A Mendelian randomization study on both IL6 and IL6R
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Arjen J, Cupido, Folkert W, Asselbergs, Pradeep, Natarajan, Paul M, Ridker, G Kees, Hovingh, A Floriaan, Schmidt, Graduate School, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, ACS - Amsterdam Cardiovascular Sciences, Cardiology, ACS - Heart failure & arrhythmias, and Experimental Vascular Medicine
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Type 2/genetics ,Coronary Artery Disease ,Polymorphism, Single Nucleotide ,Rheumatoid/drug therapy ,Arthritis, Rheumatoid ,Receptors, Interleukin-6/genetics ,Risk Factors ,Atrial Fibrillation ,Receptors ,Diabetes Mellitus ,Humans ,Pharmacology (medical) ,Polymorphism ,Interleukin-6/genetics ,Ischemic Stroke ,Pharmacology ,Interleukin-6 ,Arthritis ,Coronary Artery Disease/genetics ,Single Nucleotide ,Mendelian Randomization Analysis ,Receptors, Interleukin-6 ,Diabetes Mellitus, Type 2 ,Arthritis, Rheumatoid/drug therapy ,Diabetes Mellitus, Type 2/genetics ,Genome-Wide Association Study - Abstract
AIMS: Chronic inflammation is a risk factor for cardiovascular disease (CVD). IL-6 signalling perturbation through IL-6 or IL-6R blockade may have potential benefit on cardiovascular risk. It is unknown whether targeting either IL-6 or IL-6 receptor may result in similar effects on CVD and adverse events. We compared the anticipated effects of targeting IL-6 and IL-6 receptor on cardiometabolic risk and potential side effects. METHODS: We constructed four instruments: two main instruments with genetic variants in the IL6 and IL6R loci weighted for their association with CRP, and two after firstly filtering variants for their association with IL-6 or IL-6R expression. Analyses were performed for coronary artery disease (CAD), ischemic stroke, atrial fibrillation (AF), heart failure, type 2 diabetes (T2D), rheumatoid arthritis (RA), infection endpoints, and quantitative haematological, metabolic and anthropometric parameters. RESULTS: A 1 mg/L lower CRP by the IL6 instrument was associated with lower CAD (odds ratio [OR] 0.86, 95% confidence interval [CI] 0.77;0.96), AF and T2D risk. A 1 mg/L lower CRP by the IL6R instrument was associated with lower CAD (OR 0.90, 95% CI 0.86;0.95), any stroke and ischemic stroke, AF, RA risk and higher pneumonia risk. The eQTL-filtered results were in concordance with the main results, but with wider confidence intervals. CONCLUSIONS: IL-6 signalling perturbation by either IL6 or IL6R genetic instruments is associated with a similar risk reduction for multiple cardiometabolic diseases, suggesting that both IL-6 and IL-6R are potential therapeutic targets to lower CVD. Moreover, IL-6 rather than IL-6R inhibition might have a more favourable pneumonia risk.
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- 2022
61. Association of Interleukin 6 Inhibition With Ziltivekimab and the Neutrophil-Lymphocyte Ratio A Secondary Analysis of the RESCUE Clinical Trial
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Nicholas H, Adamstein, Jan Hein, Cornel, Michael, Davidson, Peter, Libby, Alessandra, de Remigis, Camilla, Jensen, Kathrine, Ekström, and Paul M, Ridker
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All institutes and research themes of the Radboud University Medical Center ,Vascular damage Radboud Institute for Health Sciences [Radboudumc 16] ,Cardiology and Cardiovascular Medicine - Abstract
ImportanceThe neutrophil-lymphocyte ratio (NLR) independently predicts atherosclerotic events and is a potential biomarker for residual inflammatory risk. Interleukin (IL) 1β inhibition reduces the NLR, but whether inhibition of IL-6, a cytokine downstream of IL-1, also lowers the NLR is uncertain.ObjectiveTo evaluate whether ziltivekimab, a therapeutic monoclonal antibody targeting the IL-6 ligand, associates with a lower NLR compared with placebo.Design, Setting, and ParticipantsThis was an exploratory post hoc analysis of Trial to Evaluate Reduction in Inflammation in Patients With Advanced Chronic Renal Disease Utilizing Antibody Mediated IL-6 Inhibition (RESCUE), a double-blind, randomized, placebo-controlled, phase 2 trial conducted from June 17, 2019, to January 14, 2020, with 24 weeks of follow-up. Participants were enrolled at 40 sites in the US and included adults aged 18 or older with moderate to severe chronic kidney disease and high-sensitivity C-reactive protein levels of 2 mg/L or greater. Data were analyzed from September 28, 2021, to October 2, 2022.InterventionsParticipants were randomly assigned equally to placebo or ziltivekimab, 7.5 mg, 15 mg, or 30 mg, subcutaneously every 4 weeks.Main Outcomes and MeasuresThe primary outcome was the change in the NLR at 12 weeks.ResultsA total of 264 participants (median [IQR] age, 68 [60-75] years; 135 men [51%]; 129 women [49%]) were enrolled, of which 187 (71%) had diabetes, and 126 (48%) had known atherosclerosis. The median (IQR) change in the NLR at 12 weeks was 1.56% (IQR, −15.7% to 20.0%), −13.5% (IQR, −31.6% to 3.20%), −14.3% (IQR, −26.9% to 4.62%), and −22.4% (IQR, −33.3% to −4.27%) in the placebo, 7.5-mg, 15-mg, and 30-mg groups, respectively. The estimated treatment difference compared with placebo was −14.6% (95% CI, −24.8% to −4.81%; P = .004), −15.3% (95% CI, −25.2% to −5.10%; P = .004), and −23.6% (95% CI, −33.2% to −14.2%; P Conclusions and RelevanceResults of this post hoc analysis of the RESCUE trial show that IL-6 ligand inhibition with ziltivekimab associates with a lower NLR, suggesting that it may disrupt multiple atherogenic inflammatory pathways, including those mediated by the myeloid cell compartment. The NLR may have use in monitoring ziltivekimab’s efficacy should it be introduced into clinical practice.
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- 2022
62. Earlier treatment in adults with high lifetime risk of cardiovascular diseases: What prevention trials are feasible and could change clinical practice? Report of a National Heart, Lung, and Blood Institute (NHLBI) Workshop
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Ann Marie Navar, Lawrence J. Fine, Walter T. Ambrosius, Arleen Brown, Pamela S. Douglas, Karen Johnson, Amit V. Khera, Donald Lloyd-Jones, Erin D. Michos, Mahasin Mujahid, Daniel Muñoz, Khurram Nasir, Nicole Redmond, Paul M Ridker, Jennifer Robinson, David Schopfer, Deborah F. Tate, and Cora E. Lewis
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Comparative Effectiveness Research ,Aging ,Prevention ,Clinical Trials and Supportive Activities ,General Medicine ,Health Services ,Cardiovascular ,Atherosclerosis ,Heart Disease ,Good Health and Well Being ,Clinical Research ,Atherosclerotic cardiovascular disease ,Cardiovascular Disease ,Heart Disease - Coronary Heart Disease ,Risk assessment ,Young adults - Abstract
More than half of U.S. young adults have low ten-year but high lifetime risk of cardiovascular disease (CVD). Improving primary prevention in young adulthood may help reduce persistent CVD disparities and overall CVD morbidity and mortality. The National Heart, Lung, and Blood Institute (NHLBI) convened a workshop in 2021 to identify potential trial opportunities in CVD prevention in young adults. The workshop identified promising interventions that could be tested, including interventions that focus on a single cardiovascular risk factor (e.g., lipids or inflammation) to multiple risk factor interventions (e.g., multicomponent lifestyle interventions orfixed-low dose combination of medications). Given the sample size and duration for a trial with hard endpoints, more research is needed on the utility of intermediate endpoints identified noninvasively such as subclinical coronary atherosclerosis as a surrogate endpoint. For now, clinical outcomes trials with hard endpoints will more likely change clinical practice. Trial efficiency depends on accurate identification of high-risk young adults, which can potentially be done using traditional risk equations, coronary artery calcium screening, computerized tomography coronary angiography, and polygenic risk scores. Trials in young adults should include enhanced recruitment strategies with intense community engagement to enroll a trial population that is racially, ethnically, geographically, and socially diverse. Despite the challenges in conducting large prevention trials in young adults, recent advances including innovation in clinical trial conduct, new therapies and successful interventions in older populations, and an increasing recognition of a lifespan approach to risk assessment have made such trials more feasible than ever.DisclosuresThe views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services.
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- 2022
63. Outpatient Randomized Controlled Trials in the Covid-19 Era and Beyond
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Jean M. Connors, Maria M. Brooks, Frank C. Sciurba, Jerry A. Krishnan, Joseph R. Bledsoe, Lauren Castro, Heather Eng, Eileen Handberg, Peter C. Hou, Joshua Hulbert, Bridget-Anne Kirwan, Janet Y. Lin, Deborah Martin, Harriet Samuelson, Nancy L. Shapiro, Elaine Zaharris, Steve R. Wisniewski, and Paul M. Ridker
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- 2022
64. Triglyceride Lowering with Pemafibrate to Reduce Cardiovascular Risk
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Aruna, Das Pradhan, Robert J, Glynn, Jean-Charles, Fruchart, Jean G, MacFadyen, Elaine S, Zaharris, Brendan M, Everett, Stuart E, Campbell, Ryu, Oshima, Pierre, Amarenco, Dirk J, Blom, Eliot A, Brinton, Robert H, Eckel, Marshall B, Elam, João S, Felicio, Henry N, Ginsberg, Assen, Goudev, Shun, Ishibashi, Jacob, Joseph, Tatsuhiko, Kodama, Wolfgang, Koenig, Lawrence A, Leiter, Alberto J, Lorenzatti, Boris, Mankovsky, Nikolaus, Marx, Børge G, Nordestgaard, Dénes, Páll, Kausik K, Ray, Raul D, Santos, Handrean, Soran, Andrey, Susekov, Michal, Tendera, Koutaro, Yokote, Nina P, Paynter, Julie E, Buring, Peter, Libby, Paul M, Ridker, and Maureen, McClelland
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Hypertriglyceridemia ,Apolipoprotein C-III ,Cholesterol, HDL ,Hyperlipidemias ,General Medicine ,Cholesterol, LDL ,Cholesterol ,Diabetes Mellitus, Type 2 ,Double-Blind Method ,Cardiovascular Diseases ,Heart Disease Risk Factors ,Risk Factors ,PROMINENT Investigators ,General & Internal Medicine ,Humans ,PPAR alpha ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,11 Medical and Health Sciences ,Triglycerides ,Hypolipidemic Agents - Abstract
Background High triglyceride levels are associated with increased cardiovascular risk, but whether reductions in these levels would lower the incidence of cardiovascular events is uncertain. Pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, reduces triglyceride levels and improves other lipid levels. Methods In a multinational, double-blind, randomized, controlled trial, we assigned patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia (triglyceride level, 200 to 499 mg per deciliter), and high-density lipoprotein (HDL) cholesterol levels of 40 mg per deciliter or lower to receive pemafibrate (0.2-mg tablets twice daily) or matching placebo. Eligible patients were receiving guideline-directed lipid-lowering therapy or could not receive statin therapy without adverse effects and had low-density lipoprotein (LDL) cholesterol levels of 100 mg per deciliter or lower. The primary efficacy end point was a composite of nonfatal myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes. Results Among 10,497 patients (66.9% with previous cardiovascular disease), the median baseline fasting triglyceride level was 271 mg per deciliter, HDL cholesterol level 33 mg per deciliter, and LDL cholesterol level 78 mg per deciliter. The median follow-up was 3.4 years. As compared with placebo, the effects of pemafibrate on lipid levels at 4 months were -26.2% for triglycerides, -25.8% for very-low-density lipoprotein (VLDL) cholesterol, -25.6% for remnant cholesterol (cholesterol transported in triglyceride-rich lipoproteins after lipolysis and lipoprotein remodeling), -27.6% for apolipoprotein C-III, and 4.8% for apolipoprotein B. A primary end-point event occurred in 572 patients in the pemafibrate group and in 560 of those in the placebo group (hazard ratio, 1.03; 95% confidence interval, 0.91 to 1.15), with no apparent effect modification in any prespecified subgroup. The overall incidence of serious adverse events did not differ significantly between the groups, but pemafibrate was associated with a higher incidence of adverse renal events and venous thromboembolism and a lower incidence of nonalcoholic fatty liver disease. Conclusions Among patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia, and low HDL and LDL cholesterol levels, the incidence of cardiovascular events was not lower among those who received pemafibrate than among those who received placebo, although pemafibrate lowered triglyceride, VLDL cholesterol, remnant cholesterol, and apolipoprotein C-III levels. (Funded by the Kowa Research Institute; PROMINENT ClinicalTrials.gov number, NCT03071692.)
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- 2022
65. Technology-Assisted Self-Selection of Candidates for Nonprescription Statin Therapy
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Steven E. Nissen, Kathy Wolski, Melanie Morris, Paul M. Ridker, Sara Travis, Christie M. Ballantyne, Jennifer Hynson, Tracy Y. Wang, William W. Miller, and Hutchinson Howard Gerard
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medicine.medical_specialty ,Statin ,medicine.drug_class ,business.industry ,Public health ,Concordance ,nutritional and metabolic diseases ,Confidence interval ,Emergency medicine ,Clinical endpoint ,medicine ,Rosuvastatin ,Statin therapy ,Cardiology and Cardiovascular Medicine ,business ,Selection (genetic algorithm) ,medicine.drug - Abstract
Background Although statins reduce cardiovascular morbidity and mortality, only about one-half of eligible patients receive treatment. Safe and appropriate consumer access to statins could have a significant positive public health impact. Objectives This study compares the concordance between a participant and clinician assessment of eligibility for statin therapy using a technology-assisted approach. Methods A total of 500 participants, 83 with limited literacy, completed an at-home Web-based application to assess appropriateness for treatment with rosuvastatin 5 mg. The Web application is designed to assess eligibility for a moderate-intensity statin based on current guidelines and deny access to individuals with contraindications to rosuvastatin. Subsequently, participants visited a research site where clinicians, blinded to the information the participant entered, performed an independent Web application assessment. The Web application is programmed for 1 of 3 rosuvastatin treatment outcomes: “OK to use,” “not right for you,” or “ask a doctor.” The primary endpoint was the percent of participants whose self-selected eligibility for nonprescription rosuvastatin was concordant with clinician assessment. Results For the primary endpoint, participant selection for statin therapy was concordant with clinician selection in 481 (96.2%) of 500 participants (95% confidence interval: 94.1%-97.7%), of whom 23 (4.6%) were deemed appropriate and 458 (91.6%) were deemed inappropriate for treatment. Discordance was due to incorrect self-selection (“OK to use”) in 3 cases, incorrect rejection (“not right for you”) in 14 cases and an incorrect “ask a doctor” outcome in 2 cases. Conclusions The use of a technology-assisted approach to consumer self-selection for statin therapy resulted in participant self-selection that showed substantial agreement with clinician selection.
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- 2021
66. Association of neutrophil-to-lymphocyte ratio with non-calcified coronary artery burden in psoriasis: Findings from an observational cohort study
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Joel M. Gelfand, Amit K. Dey, Heather L. Teague, Paul M. Ridker, Justin A. Rodante, Martin P. Playford, David A. Bluemke, Marcus Y. Chen, Nehal N. Mehta, and Nicholas H Adamstein
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medicine.medical_specialty ,Neutrophils ,Inflammation ,Coronary Artery Disease ,030204 cardiovascular system & hematology ,030218 nuclear medicine & medical imaging ,Cohort Studies ,Coronary artery disease ,03 medical and health sciences ,0302 clinical medicine ,Predictive Value of Tests ,Psoriasis ,Internal medicine ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Lymphocytes ,Prospective Studies ,Neutrophil to lymphocyte ratio ,business.industry ,fungi ,medicine.disease ,Coronary arteries ,C-Reactive Protein ,medicine.anatomical_structure ,Cardiology ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Body mass index ,Biomarkers ,Cohort study ,Artery - Abstract
Inflammation in the form of elevated high-sensitivity c-reactive protein (hs-CRP) has been shown to be critical in the development of atherothrombosis. Psoriasis, a chronic inflammatory skin disease, is associated with high systemic-inflammation, elevated neutrophil-to-lymphocyte ratio (NLR) and accelerated non-calcified coronary artery burden (NCB) by coronary computed tomography angiography (CCTA). We hypothesized that NLR would associate with early, rupture-prone atherosclerosis assessed as NCB independent of hs-CRP.316 consecutive psoriasis participants were recruited with 233 having one-year follow-up as part of a prospective, observational cohort study design. CCTA scans were performed to assess NCB in all three major epicardial coronary arteries.Patients with above average NLR (mean: 2.29 ± 1.21) were older (mean ± SD; 52.0 ± 12.8 vs. 47.9 ± 12.6, p = 0.002), had higher hs-CRP (med. IQR: 2.3 (0.9-7.3) vs. 1.4 (0.7-3.2), p = 0.001) and had higher NCB (mean ± SD; 1.21 ± 0.58 vs. 1.13 ± 0.49, p = 0.018) when compared to patients with below average NLR. NLR associated with psoriasis area severity index score (β = 0.14, p = 0.017), hs-CRP (β = 0.16, p = 0.005), as well as NCB independent of traditional risk factors, body mass index, statin use and hs-CRP (β = 0.08, p = 0.009). One year of biologic therapy for psoriasis was associated with a reduction in NLR (-14.5%, p 0.001), and this change in NLR associated with change in NCB in fully adjusted models and beyond hs-CRP (β = 0.17, p = 0.002).NLR associated with psoriasis severity, hs-CRP and NCB at baseline. Biologic therapy reduced NLR over time and this change in NLR associated with the change in NCB at one-year. Taken together, these findings suggest that NLR may capture psoriasis patients at higher risk of NCB due to residual inflammation not fully captured by hs-CRP.
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- 2021
67. Effect of statin therapy on muscle symptoms: an individual participant data meta-analysis of large-scale, randomised, double-blind trials
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Christina Reith, Colin Baigent, Lisa Blackwell, Jonathan Emberson, Enti Spata, Kelly Davies, Heather Halls, Lisa Holland, Kate Wilson, Jane Armitage, Charlie Harper, David Preiss, Alistair Roddick, Anthony Keech, John Simes, Rory Collins, Elizabeth Barnes, Jordan Fulcher, William G Herrington, Adrienne Kirby, Borislava Mihaylova, Rachel O'Connell, Pierre Amarenco, Philip Barter, D John Betteridge (deceased), Michael Blazing, Jackie Bosch, Louise Bowman, Eugene Braunwald, Christopher P Cannon, Michael Clearfield, Stuart Cobbe, Helen M Colhoun, Björn Dahlöf, Barry Davis, James de Lemos, John R Downs, Paul N Durrington, Bengt Fellström, Ian Ford, Maria Grazia Franzosi, John Fuller (deceased), Curt Furberg, Robert Glynn, David Gordon, Antonio Gotto Jr, Richard Grimm, Ajay Gupta, C Morton Hawkins, Graham A Hitman, Hallvard Holdaas (deceased), Alan Jardine, J Wouter Jukema, John JP Kastelein, Sharon Kean, John Kjekshus, Genell Knatterud (deceased), Robert H Knopp (deceased), Wolfgang Koenig, Michael Koren, Vera Krane, Martin Landray, John LaRosa, Roberto Latini, Eva Lonn, Donata Lucci, Jean MacFadyen, Peter Macfarlane, Stephen MacMahon, Aldo Maggioni, Roberto Marchioli, Ian Marschner, Lemuel Moyé, Sabina Murphy, Andrew Neil, Enrico B Nicolis, Chris Packard, Sarah Parish, Terje R Pedersen, Richard Peto, Marc Pfeffer, Neil Poulter, Sara Pressel, Jeffrey Probstfield, Mahboob Rahman, Paul M Ridker, Michele Robertson, Frank Sacks, Naveed Sattar, Roland Schmieder, Patrick W Serruys, Peter Sever, John Shaw (deceased), James Shepherd (deceased), Lara Simpson, Peter Sleight (deceased), Luigi Tavazzi, Gianni Tognoni, Andrew Tonkin, Stella Trompet, Christoph Wanner, Hans Wedel, Stephen Weis, K Michael Welch, Harvey White, John Wikstrand, Lars Wilhelmsen, Stephen Wiviott, Robin Young, Salim Yusuf, Faiez Zannad, Hiroyuki Arashi, Robert Byington, Robert Clarke, Marcus Flather, Uri Goldbourt, Shinya Goto, Jemma Hopewell, Kees Hovingh, Patricia Kearney, George Kitas, Connie Newman, Marc S Sabatine, Greg Schwartz, Liam Smeeth, Jonathan Tobert, John Varigos, Junichi Yamaguchi, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, ACS - Pulmonary hypertension & thrombosis, Experimental Vascular Medicine, ACS - Amsterdam Cardiovascular Sciences, and Collaboration, Cholesterol Treatment Trialists'
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Male ,Muscles ,Australia ,Humans ,Female ,General Medicine ,Myalgia ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,Middle Aged ,Atherosclerosis ,Randomized Controlled Trials as Topic - Abstract
Background: Statin therapy is effective for the prevention of atherosclerotic cardiovascular disease and is widely prescribed, but there are persisting concerns that statin therapy might frequently cause muscle pain or weakness. We aimed to address these through an individual participant data meta-analysis of all recorded adverse muscle events in large, long-term, randomised, double-blind trials of statin therapy. Methods: Randomised trials of statin therapy were eligible if they aimed to recruit at least 1000 participants with a scheduled treatment duration of at least 2 years, and involved a double-blind comparison of statin versus placebo or of a more intensive versus a less intensive statin regimen. We analysed individual participant data from 19 double-blind trials of statin versus placebo (n=123 940) and four double-blind trials of a more intensive versus a less intensive statin regimen (n=30 724). Standard inverse-variance-weighted meta-analyses of the effects on muscle outcomes were conducted according to a prespecified protocol. Findings: Among 19 placebo-controlled trials (mean age 63 years [SD 8], with 34 533 [27·9%] women, 59 610 [48·1%] participants with previous vascular disease, and 22 925 [18·5%] participants with diabetes), during a weighted average median follow-up of 4·3 years, 16 835 (27·1%) allocated statin versus 16 446 (26·6%) allocated placebo reported muscle pain or weakness (rate ratio [RR] 1·03; 95% CI 1·01–1·06). During year 1, statin therapy produced a 7% relative increase in muscle pain or weakness (1·07; 1·04–1·10), corresponding to an absolute excess rate of 11 (6–16) events per 1000 person-years, which indicates that only one in 15 ([1·07–1·00]/1·07) of these muscle-related reports by participants allocated to statin therapy were actually due to the statin. After year 1, there was no significant excess in first reports of muscle pain or weakness (0·99; 0·96–1·02). For all years combined, more intensive statin regimens (ie, 40–80 mg atorvastatin or 20–40 mg rosuvastatin once per day) yielded a higher RR than less intensive or moderate-intensity regimens (1·08 [1·04–1·13] vs 1·03 [1·00–1·05]) compared with placebo, and a small excess was present (1·05 [0·99–1·12]) for more intensive regimens after year 1. There was no clear evidence that the RR differed for different statins, or in different clinical circumstances. Statin therapy yielded a small, clinically insignificant increase in median creatine kinase values of approximately 0·02 times the upper limit of normal. Interpretation: Statin therapy caused a small excess of mostly mild muscle pain. Most (>90%) of all reports of muscle symptoms by participants allocated statin therapy were not due to the statin. The small risks of muscle symptoms are much lower than the known cardiovascular benefits. There is a need to review the clinical management of muscle symptoms in patients taking a statin. Funding: British Heart Foundation, Medical Research Council, Australian National Health and Medical Research Council.
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- 2022
68. Reducing cardiovascular risk with immunomodulators: a randomised active comparator trial among patients with rheumatoid arthritis
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Daniel H, Solomon, Jon T, Giles, Katherine P, Liao, Paul M, Ridker, Pamela M, Rist, Robert J, Glynn, Rachel, Broderick, Fengxin, Lu, Meredith T, Murray, Kathleen, Vanni, Leah M, Santacroce, Shady, Abohashem, Philip M, Robson, Zahi, Fayad, Venkatesh, Mani, Ahmed, Tawakol, Joan, Bathon, and Guillermo, Valenzuela
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Rheumatology ,Immunology ,Immunology and Allergy ,General Biochemistry, Genetics and Molecular Biology - Abstract
ObjectiveRecent large-scale randomised trials demonstrate that immunomodulators reduce cardiovascular (CV) events among the general population. However, it is uncertain whether these effects apply to rheumatoid arthritis (RA) and if certain treatment strategies in RA reduce CV risk to a greater extent.MethodsPatients with active RA despite use of methotrexate were randomly assigned to addition of a tumour necrosis factor (TNF) inhibitor (TNFi) or addition of sulfasalazine and hydroxychloroquine (triple therapy) for 24 weeks. Baseline and follow-up18F-fluorodeoxyglucose-positron emission tomography/CT scans were assessed for change in arterial inflammation, an index of CV risk, measured as an arterial target-to-background ratio (TBR) in the carotid arteries and aorta.Results115 patients completed the protocol. The two treatment groups were well balanced with a median age of 58 years, 71% women, 57% seropositive and a baseline disease activity score in 28 joints of 4.8 (IQR 4.0, 5.6). Baseline TBR was similar across the two groups. Significant TBR reductions were observed in both groups—ΔTNFi: −0.24 (SD=0.51), Δtriple therapy: −0.19 (SD=0.51)—without difference between groups (difference in Δs: −0.02, 95% CI −0.19 to 0.15, p=0.79). While disease activity was significantly reduced across both treatment groups, there was no association with change in TBR (β=0.04, 95% CI −0.03 to 0.10).ConclusionWe found that addition of either a TNFi or triple therapy resulted in clinically important improvements in vascular inflammation. However, the addition of a TNFi did not reduce arterial inflammation more than triple therapy.Trial registration numberNCT02374021.
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- 2022
69. Genome-wide meta-analyses reveal novel loci for verbal short-term memory and learning
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Jari Lahti, Samuli Tuominen, Qiong Yang, Giulio Pergola, Shahzad Ahmad, Najaf Amin, Nicola J. Armstrong, Alexa Beiser, Katharina Bey, Joshua C. Bis, Eric Boerwinkle, Jan Bressler, Archie Campbell, Harry Campbell, Qiang Chen, Janie Corley, Simon R. Cox, Gail Davies, Philip L. De Jager, Eske M. Derks, Jessica D. Faul, Annette L. Fitzpatrick, Alison E. Fohner, Ian Ford, Myriam Fornage, Zachary Gerring, Hans J. Grabe, Francine Grodstein, Vilmundur Gudnason, Eleanor Simonsick, Elizabeth G. Holliday, Peter K. Joshi, Eero Kajantie, Jaakko Kaprio, Pauliina Karell, Luca Kleineidam, Maria J. Knol, Nicole A. Kochan, John B. Kwok, Markus Leber, Max Lam, Teresa Lee, Shuo Li, Anu Loukola, Tobias Luck, Riccardo E. Marioni, Karen A. Mather, Sarah Medland, Saira S. Mirza, Mike A. Nalls, Kwangsik Nho, Adrienne O’Donnell, Christopher Oldmeadow, Jodie Painter, Alison Pattie, Simone Reppermund, Shannon L. Risacher, Richard J. Rose, Vijay Sadashivaiah, Markus Scholz, Claudia L. Satizabal, Peter W. Schofield, Katharina E. Schraut, Rodney J. Scott, Jeannette Simino, Albert V. Smith, Jennifer A. Smith, David J. Stott, Ida Surakka, Alexander Teumer, Anbupalam Thalamuthu, Stella Trompet, Stephen T. Turner, Sven J. van der Lee, Arno Villringer, Uwe Völker, Robert S. Wilson, Katharina Wittfeld, Eero Vuoksimaa, Rui Xia, Kristine Yaffe, Lei Yu, Habil Zare, Wei Zhao, David Ames, John Attia, David A. Bennett, Henry Brodaty, Daniel I. Chasman, Aaron L. Goldman, Caroline Hayward, M. Arfan Ikram, J. Wouter Jukema, Sharon L. R. Kardia, Todd Lencz, Markus Loeffler, Venkata S. Mattay, Aarno Palotie, Bruce M. Psaty, Alfredo Ramirez, Paul M. Ridker, Steffi G. Riedel-Heller, Perminder S. Sachdev, Andrew J. Saykin, Martin Scherer, Peter R. Schofield, Stephen Sidney, John M. Starr, Julian Trollor, William Ulrich, Michael Wagner, David R. Weir, James F. Wilson, Margaret J. Wright, Daniel R. Weinberger, Stephanie Debette, Johan G. Eriksson, Thomas H. Mosley, Lenore J. Launer, Cornelia M. van Duijn, Ian J. Deary, Sudha Seshadri, Katri Räikkönen, Epidemiology, Radiology & Nuclear Medicine, VU University medical center, Department of Psychology and Logopedics, University of Helsinki, HUS Children and Adolescents, Lastentautien yksikkö, Children's Hospital, Clinicum, Helsinki University Hospital Area, Institute for Molecular Medicine Finland, Department of Public Health, HUSLAB, HUS Helsinki and Uusimaa Hospital District, Cognitive and Brain Aging, Faculty Common Matters (Faculty of Medicine), Centre of Excellence in Complex Disease Genetics, Research Programs Unit, Aarno Palotie / Principal Investigator, Genomics of Neurological and Neuropsychiatric Disorders, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, and Medicum
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EXPRESSION ,Multifactorial Inheritance ,DATABASE ,Memory, Short-Term/physiology ,3112 Neurosciences ,CADHERIN ,Brain ,EPISODIC MEMORY ,ASSOCIATION ,Verbal Learning ,3124 Neurology and psychiatry ,NETWORKS ,Cellular and Molecular Neuroscience ,Psychiatry and Mental health ,WORKING-MEMORY ,QUALITY-CONTROL ,SDG 3 - Good Health and Well-being ,physiology [Memory, Short-Term] ,SCHIZOPHRENIA ,1182 Biochemistry, cell and molecular biology ,Learning ,COGNITIVE FUNCTIONS ,3111 Biomedicine ,ddc:610 ,Molecular Biology - Abstract
Abstract Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.
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- 2022
70. Association of Physical Activity With Bioactive Lipids and Cardiovascular Events
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Rosangela A. Hoshi, Yanyan Liu, Heike Luttmann-Gibson, Saumya Tiwari, Franco Giulianini, Allen M. Andres, Jeramie D. Watrous, Nancy R. Cook, Karen H. Costenbader, Olivia I. Okereke, Paul M Ridker, JoAnn E. Manson, I-Min Lee, Manickavasagar Vinayagamoorthy, Susan Cheng, Trisha Copeland, Mohit Jain, Daniel I. Chasman, Olga V. Demler, and Samia Mora
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Cardiovascular Diseases ,Risk Factors ,Physiology ,Humans ,Cholesterol, LDL ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,Rosuvastatin Calcium ,Cardiology and Cardiovascular Medicine ,Exercise - Abstract
Background: To clarify the mechanisms underlying physical activity (PA)-related cardioprotection, we examined the association of PA with plasma bioactive lipids (BALs) and cardiovascular disease (CVD) events. We additionally performed genome-wide associations. Methods: PA-bioactive lipid associations were examined in VITAL (VITamin D and OmegA-3 TriaL)-clinical translational science center (REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01169259; N=1032) and validated in JUPITER (Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin)-NC (REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00239681; N=589), using linear models adjusted for age, sex, race, low-density lipoprotein-cholesterol, total-C, and smoking. Significant BALs were carried over to examine associations with incident CVD in 2 nested CVD case-control studies: VITAL-CVD (741 case-control pairs) and JUPITER-CVD (415 case-control pairs; validation). Results: We detected 145 PA-bioactive lipid validated associations (false discovery rate Conclusions: We identified a PA-related bioactive lipidome profile out of which 12 BALs also had opposite associations with incident CVD events.
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- 2022
71. Targeting innate immunity-driven inflammation in CKD and cardiovascular disease
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Thimoteus Speer, Stefanie Dimmeler, Stefan J. Schunk, Danilo Fliser, and Paul M Ridker
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Inflammation ,Nephrology ,Cardiovascular Diseases ,Humans ,Renal Insufficiency, Chronic ,Atherosclerosis ,Immunity, Innate - Abstract
Mortality among patients with chronic kidney disease (CKD) is largely a consequence of cardiovascular disease (CVD) and is a particular concern given the increasing prevalence of CKD. Sterile inflammation triggered by activation of the innate immune system is an important driver of both CKD and associated CVD. Several endogenous mediators, including lipoproteins, crystals such as silica, urate and cholesterol crystals, or compounds released from dying cells interact with pattern recognition receptors expressed on a variety of different cell types, leading to the release of pro-inflammatory cytokines. Disturbed regulation of the haematopoietic system by damage-associated molecular patterns, or as a consequence of clonal haematopoiesis or trained innate immunity, also contributes to the development of inflammation. In observational and genetic association studies, inflammation is linked to the progression of CKD and cardiovascular events. In 2017, the CANTOS trial of canakinumab provided evidence that inhibiting inflammation driven by NLRP3-IL-1-IL-6-mediated signalling significantly reduced cardiovascular event rates in individuals with and without CKD. Other approaches to target innate immune pathways are now under investigation for their ability to reduce cardiovascular events and slow disease progression among patients with atherosclerosis and stage 3 and 4 CKD. This Review summarizes current understanding of the role of inflammation in the pathogenesis of CKD and its associated CVD, and how this knowledge may translate into novel therapeutics.
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- 2022
72. Autoimmune diseases and atherothrombotic risk
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Paul M Ridker
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Risk Factors ,Humans ,General Medicine ,Atherosclerosis ,Autoimmune Diseases - Published
- 2022
73. Testing the Effects of Disease‐Modifying Antirheumatic Drugs on Vascular Inflammation in Rheumatoid Arthritis: Rationale and Design of the TARGET Trial
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Katherine P. Liao, Venkatesh Mani, Pamela M. Rist, Paul M. Ridker, Zahi A. Fayad, Fengxin Lu, Joan M. Bathon, Rachel Broderick, Robert J. Glynn, Nina P. Paynter, Ahmed Tawakol, Jon T. Giles, Kathleen M M Vanni, Meredith Murray, and Daniel H. Solomon
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Aorta ,medicine.medical_specialty ,education.field_of_study ,business.industry ,Population ,Hydroxychloroquine ,Review Article ,Diseases of the musculoskeletal system ,medicine.disease ,Gastroenterology ,Etanercept ,Rheumatology ,RC925-935 ,Sulfasalazine ,medicine.artery ,Internal medicine ,Rheumatoid arthritis ,medicine ,Adalimumab ,Methotrexate ,education ,business ,medicine.drug - Abstract
Individuals with rheumatoid arthritis (RA) are at increased risk for atherosclerotic cardiovascular disease (ASCVD) events relative to the general population, potentially mediated by atherosclerotic plaques that are more inflamed and rupture prone. We sought to address whether RA immunomodulators reduce vascular inflammation, thereby reducing ASCVD risk, and whether such reduction depends on the type of immunomodulator. The TARGET (Treatments Against RA and Effect on 18-Fluorodeoxyglucose [18 F-FDG] Positron Emission Tomography [PET]/Computed Tomography [CT]) trial (NCT02374021) will enroll 150 patients with RA with active disease and an inadequate response to methotrexate. Participants will be randomized to add either a tumor necrosis factor (TNF) inhibitor (etanercept or adalimumab) or sulfasalazine and hydroxychloroquine to their background methotrexate. Participants will undergo full-body 18 F-FDG-labelled PET scanning at baseline and after 6 months. Efficacy and safety evaluations will occur every 6 weeks, with therapy modified in a treat-to-target approach. The primary outcome is the comparison of change in arterial inflammation in the wall of the aorta and carotid arteries between the randomized treatment groups, specifically, the change in the mean of the maximum target-to-background ratio of arterial 18 F-FDG uptake in the most diseased segment of either the aorta and carotid arteries. A secondary analysis will compare the effects of achieving low disease activity or remission with those of moderate to high disease activity on vascular inflammation. The TARGET trial will test, for the first time, whether RA treatments reduce arterial inflammation and whether such reduction differs according to treatment strategy with either TNF inhibitors or a combination of nonbiologic disease-modifying antirheumatic drugs.
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- 2021
74. Interleukin-6 Signaling and Anti-Interleukin-6 Therapeutics in Cardiovascular Disease
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Paul M. Ridker and Manas Rane
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Inflammasomes ,Physiology ,medicine.medical_treatment ,Interleukin-1beta ,Myocardial Ischemia ,Inflammation ,Disease ,030204 cardiovascular system & hematology ,Antibodies, Monoclonal, Humanized ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Renal Dialysis ,NLR Family, Pyrin Domain-Containing 3 Protein ,medicine ,Animals ,Humans ,030212 general & internal medicine ,Renal Insufficiency, Chronic ,Interleukin 6 ,Cell Proliferation ,Immunity, Cellular ,Innate immune system ,biology ,Interleukin-6 ,business.industry ,Cell regulation ,Interleukin ,Cell Differentiation ,Thrombosis ,Atherosclerosis ,Aneurysm ,Receptors, Interleukin-6 ,Immunity, Innate ,Disease Models, Animal ,C-Reactive Protein ,Cytokine ,Cardiovascular Diseases ,Immunology ,biology.protein ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business - Abstract
IL (interleukin)-6 is a pivotal cytokine of innate immunity, which enacts a broad set of physiological functions traditionally associated with host defense, immune cell regulation, proliferation, and differentiation. Following recognition of innate immune pathways leading from the NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasome to IL-1 to IL-6 and on to the hepatically derived clinical biomarker CRP (C-reactive protein), an expanding literature has led to understanding of the proatherogenic role for IL-6 in cardiovascular disease and thus the potential for IL-6 inhibition as a novel method for vascular protection. In this review, we provide an overview of the mechanisms by which IL-6 signaling occurs and how that impacts upon pharmacological inhibition; describe murine models of IL-6 and atherogenesis; summarize human epidemiological data outlining the utility of IL-6 as a biomarker of vascular risk; outline genetic data suggesting a causal role for IL-6 in systemic atherothrombosis and aneurysm formation; and then detail the potential role of IL-6 inhibition in stable coronary disease, acute coronary syndromes, heart failure, and the atherothrombotic complications associated with chronic kidney disease and end-stage renal failure. Finally, we review anti-inflammatory and antithrombotic findings for ziltivekimab, a novel IL-6 ligand inhibitor being developed specifically for use in atherosclerotic disease and poised to be tested formally in a large-scale cardiovascular outcomes trial focused on individuals with chronic kidney disease and elevated levels of CRP, a population at high residual atherothrombotic risk, high residual inflammatory risk, and considerable unmet clinical need.
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- 2021
75. IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial
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G. Kees Hovingh, Larry Lo, Mads D M Engelmann, Paul M. Ridker, Pablo Pergola, Florian M.M. Baeres, Peter Libby, Rescue Investigators, Milana Ivkovic, Michael H. Davidson, Matt Devalaraja, Dominic S. Raj, Douglas Kling, Experimental Vascular Medicine, Vascular Medicine, and ACS - Atherosclerosis & ischemic syndromes
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Male ,medicine.medical_specialty ,Injections, Subcutaneous ,Population ,Inflammation ,Disease ,030204 cardiovascular system & hematology ,Antibodies, Monoclonal, Humanized ,Placebo ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Internal medicine ,medicine ,Humans ,030212 general & internal medicine ,Renal Insufficiency, Chronic ,education ,Interleukin 6 ,Aged ,education.field_of_study ,biology ,Interleukin-6 ,business.industry ,Thrombosis ,General Medicine ,Middle Aged ,Atherosclerosis ,medicine.disease ,C-Reactive Protein ,Treatment Outcome ,biology.protein ,Biomarker (medicine) ,Female ,medicine.symptom ,business ,Biomarkers ,Kidney disease - Abstract
Background: IL-6 has emerged as a pivotal factor in atherothrombosis. Yet, the safety and efficacy of IL-6 inhibition among individuals at high atherosclerotic risk but without a systemic inflammatory disorder is unknown. We therefore addressed whether ziltivekimab, a fully human monoclonal antibody directed against the IL-6 ligand, safely and effectively reduces biomarkers of inflammation and thrombosis among patients with high cardiovascular risk. We focused on individuals with elevated high-sensitivity CRP and chronic kidney disease, a group with substantial unmet clinical need in whom previous studies in inflammation inhibition have shown efficacy for cardiovascular event reduction. Methods: RESCUE is a randomised, double-blind, phase 2 trial done at 40 clinical sites in the USA. Inclusion criteria were age 18 years or older, moderate to severe chronic kidney disease, and high-sensitivity CRP of at least 2 mg/L. Participants were randomly allocated (1:1:1:1) to subcutaneous administration of placebo or ziltivekimab 7·5 mg, 15 mg, or 30 mg every 4 weeks up to 24 weeks. The primary outcome was percentage change from baseline in high-sensitivity CRP after 12 weeks of treatment with ziltivekimab compared with placebo, with additional biomarker and safety data collected over 24 weeks of treatment. Primary analyses were done in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of assigned treatment. The trial is registered with ClinicalTrials.gov, NCT03926117. Findings: Between June 17, 2019, and Jan 14, 2020, 264 participants were enrolled into the trial, of whom 66 were randomly assigned to each of the four treatment groups. At 12 weeks after randomisation, median high-sensitivity CRP levels were reduced by 77% for the 7·5 mg group, 88% for the 15 mg group, and 92% for the 30 mg group compared with 4% for the placebo group. As such, the median pairwise differences in percentage change in high-sensitivity CRP between the ziltivekimab and placebo groups, after aligning for strata, were –66·2% for the 7·5 mg group, –77·7% for the 15 mg group, and –87·8% for the 30 mg group (all p
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- 2021
76. Canakinumab Effects on Erythropoiesis, Cardiovascular Risk, and Clonal Hematopoiesis: Proteogenomic Analysis of the Cantos Randomized Clinical Trial
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Janghee Woo, Darlene Lu, Andrew Lewandowski, Paul M. Ridker, Benjamin L. Ebert, and David Steensma
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
77. Multi-phenotype analyses of hemostatic traits with cardiovascular events reveal novel genetic associations
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Gerard Temprano‐Sagrera, Colleen M. Sitlani, William P. Bone, Miguel Martin‐Bornez, Benjamin F. Voight, Alanna C. Morrison, Scott M. Damrauer, Paul S. de Vries, Nicholas L. Smith, Maria Sabater‐Lleal, Abbas Dehghan, Adam S Heath, Alanna C Morrison, Alex P Reiner, Andrew Johnson, Anne Richmond, Annette Peters, Astrid van Hylckama Vlieg, Barbara McKnight, Bruce M Psaty, Caroline Hayward, Cavin Ward‐Caviness, Christopher O’Donnell, Daniel Chasman, David P Strachan, David A Tregouet, Dennis Mook‐Kanamori, Dipender Gill, Florian Thibord, Folkert W Asselbergs, Frank W.G. Leebeek, Frits R Rosendaal, Gail Davies, Georg Homuth, Gerard Temprano, Harry Campbell, Herman A Taylor, Jan Bressler, Jennifer E Huffman, Jerome I Rotter, Jie Yao, James F Wilson, Joshua C Bis, Julie M Hahn, Karl C Desch, Kerri L Wiggins, Laura M Raffield, Lawrence F Bielak, Lisa R Yanek, Marcus E Kleber, Martina Mueller, Maryam Kavousi, Massimo Mangino, Melissa Liu, Michael R Brown, Matthew P Conomos, Min‐A Jhun, Ming‐Huei Chen, Moniek P.M. de Maat, Nathan Pankratz, Nicholas L Smith, Patricia A Peyser, Paul Elliot, Paul S de Vries, Peng Wei, Philipp S Wild, Pierre E Morange, Pim van der Harst, Qiong Yang, Ngoc‐Quynh Le, Riccardo Marioni, Ruifang Li, Scott M Damrauer, Simon R Cox, Stella Trompet, Stephan B Felix, Uwe Völker, Weihong Tang, Wolfgang Koenig, J. Wouter Jukema, Xiuqing Guo, Sara Lindstrom, Lu Wang, Erin N Smith, William Gordon, Mariza de Andrade, Jennifer A Brody, Jack W Pattee, Jeffrey Haessler, Ben M Brumpton, Daniel I Chasman, Pierre Suchon, Constance Turman, Marine Germain, James MacDonald, Sigrid K Braekkan, Sebastian M Armasu, Rabecca D Jackson, Jonas B Nielsen, Franco Giulianini, Marja K Puurunen, Manal Ibrahim, Susan R Heckbert, Theo K Bammler, Kelly A Frazer, Bryan M McCauley, Kent Taylor, James S Pankow, Alexander P Reiner, Maiken E Gabrielsen, Jean‐François Deleuze, Chris J O’Donnell, Jihye Kim, Peter Kraft, John‐Bjarne Hansen, John A Heit, Charles Kooperberg, Kristian Hveem, Paul M Ridker, Pierre‐Emmanuel Morange, Andrew D Johnson, Christopher Kabrhel, David‐Alexandre Trégouët, Rainer Malik, Ganesh Chauhan, Matthew Traylor, Muralidharan Sargurupremraj, Yukinori Okada, Aniket Mishra, Loes Rutten‐Jacobs, Anne‐Katrin Giese, Sander W van der Laan, Solveig Gretarsdottir, Christopher D Anderson, Michael Chong, Hieab HH Adams, Tetsuro Ago, Peter Almgren, Philippe Amouyel, Hakan Ay, Traci M Bartz, Oscar R Benavente, Steve Bevan, Giorgio B Boncoraglio, Robert D Brown, Adam S Butterworth, Caty Carrera, Cara L Carty, Wei‐Min Chen, John W Cole, Adolfo Correa, Ioana Cotlarciuc, Carlos Cruchaga, John Danesh, Paul IW de Bakker, Anita L DeStefano, Marcel den Hoed, Qing Duan, Stefan T Engelter, Guido J Falcone, Rebecca F Gottesman, Raji P Grewal, Vilmundur Gudnason, Stefan Gustafsson, Tamara B Harris, Ahamad Hassan, Aki S Havulinna, Elizabeth G Holliday, George Howard, Fang‐Chi Hsu, Hyacinth I Hyacinth, M Arfan Ikram, Erik Ingelsson, Marguerite R Irvin, Xueqiu Jian, Jordi Jiménez‐Conde, Julie A Johnson, J Wouter Jukema, Masahiro Kanai, Keith L Keene, Brett M Kissela, Dawn O Kleindorfer, Michiaki Kubo, Leslie A Lange, Carl D Langefeld, Claudia Langenberg, Lenore J Launer, Jin‐Moo Lee, Robin Lemmens, Didier Leys, Cathryn M Lewis, Wei‐Yu Lin, Arne G Lindgren, Erik Lorentzen, Patrik K Magnusson, Jane Maguire, Ani Manichaikul, Patrick F McArdle, James F Meschia, Braxton D Mitchell, Thomas H Mosley, Michael A Nalls, Toshiharu Ninomiya, Martin J O’Donnell, Sara L Pulit, Kristiina Rannikmäe, Kathryn M Rexrode, Kenneth Rice, Stephen S Rich, Natalia S Rost, Peter M Rothwell, Tatjana Rundek, Ralph L Sacco, Saori Sakaue, Michele M Sale, Veikko Salomaa, Bishwa R Sapkota, Reinhold Schmidt, Carsten O Schmidt, Ulf Schminke, Pankaj Sharma, Agnieszka Slowik, Cathie LM Sudlow, Christian Tanislav, Turgut Tatlisumak, Kent D Taylor, Vincent NS Thijs, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Steffen Tiedt, Christophe Tzourio, Cornelia M van Duijn, Matthew Walters, Nicholas J Wareham, Sylvia Wassertheil‐Smoller, James G Wilson, Salim Yusuf, Najaf Amin, Hugo S Aparicio, Donna K Arnett, John Attia, Alexa S Beiser, Claudine Berr, Julie E Buring, Mariana Bustamante, Valeria Caso, Yu‐Ching Cheng, Seung Hoan Choi, Ayesha Chowhan, Natalia Cullell, Jean‐François Dartigues, Hossein Delavaran, Pilar Delgado, Marcus Dörr, Gunnar Engström, Ian Ford, Wander S Gurpreet, Anders Hamsten, Laura Heitsch, Atsushi Hozawa, Laura Ibanez, Andreea Ilinca, Martin Ingelsson, Motoki Iwasaki, Rebecca D Jackson, Katarina Jood, Pekka Jousilahti, Sara Kaffashian, Lalit Kalra, Masahiro Kamouchi, Takanari Kitazono, Olafur Kjartansson, Manja Kloss, Peter J Koudstaal, Jerzy Krupinski, Daniel L Labovitz, Cathy C Laurie, Christopher R Levi, Linxin Li, Lars Lind, Cecilia M Lindgren, Vasileios Lioutas, Yong Mei Liu, Oscar L Lopez, Hirata Makoto, Nicolas Martinez‐Majander, Koichi Matsuda, Naoko Minegishi, Joan Montaner, Andrew P Morris, Elena Muiño, Martina Müller‐Nurasyid, Bo Norrving, Soichi Ogishima, Eugenio A Parati, Leema Reddy Peddareddygari, Nancy L Pedersen, Joanna Pera, Markus Perola, Alessandro Pezzini, Silvana Pileggi, Raquel Rabionet, Iolanda Riba‐Llena, Marta Ribasés, Jose R Romero, Jaume Roquer, Anthony G Rudd, Antti‐Pekka Sarin, Ralhan Sarju, Chloe Sarnowski, Makoto Sasaki, Claudia L Satizabal, Mamoru Satoh, Naveed Sattar, Norie Sawada, Gerli Sibolt, Ásgeir Sigurdsson, Albert Smith, Kenji Sobue, Carolina Soriano‐Tárraga, Tara Stanne, O Colin Stine, David J Stott, Konstantin Strauch, Takako Takai, Hideo Tanaka, Kozo Tanno, Alexander Teumer, Liisa Tomppo, Nuria P Torres‐Aguila, Emmanuel Touze, Shoichiro Tsugane, Andre G Uitterlinden, Einar M Valdimarsson, Sven J van der Lee, Henry Völzke, Kenji Wakai, David Weir, Stephen R Williams, Charles DA Wolfe, Quenna Wong, Huichun Xu, Taiki Yamaji, Dharambir K Sanghera, Olle Melander, Christina Jern, Daniel Strbian, Israel Fernandez‐Cadenas, W T Longstreth, Arndt Rolfs, Jun Hata, Daniel Woo, Jonathan Rosand, Guillaume Pare, Jemma C Hopewell, Danish Saleheen, Kari Stefansson, Bradford B Worrall, Steven J Kittner, Sudha Seshadri, Myriam Fornage, Hugh S Markus, Joanna MM Howson, Yoichiro Kamatani, Stephanie Debette, Martin Dichgans, and VU University medical center
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Hemostasis ,genome-wide association study ,genetic pleiotropy ,Hematology ,Polymorphism, Single Nucleotide ,Hemostatics ,blood coagulation ,cardiovascular diseases ,Phenotype ,Cardiovascular Diseases ,Tissue Plasminogen Activator ,hemostasis ,Humans ,Genetic Predisposition to Disease ,Factor XI ,Genome-Wide Association Study - Abstract
Background: Multi-phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. This is the first study to date to comprehensively analyze the shared genetic effects within different hemostatic traits, and between these and their associated disease outcomes. Objectives: To discover novel genetic associations by combining summary data of correlated hemostatic traits and disease events. Methods: Summary statistics from genome wide-association studies (GWAS) from seven hemostatic traits (factor VII [FVII], factor VIII [FVIII], von Willebrand factor [VWF] factor XI [FXI], fibrinogen, tissue plasminogen activator [tPA], plasminogen activator inhibitor 1 [PAI-1]) and three major cardiovascular (CV) events (venous thromboembolism [VTE], coronary artery disease [CAD], ischemic stroke [IS]), were combined in 27 multi-trait combinations using metaUSAT. Genetic correlations between phenotypes were calculated using Linkage Disequilibrium Score Regression (LDSC). Newly associated loci were investigated for colocalization. We considered a significance threshold of 1.85 × 10−9 obtained after applying Bonferroni correction for the number of multi-trait combinations performed (n = 27). Results: Across the 27 multi-trait analyses, we found 4 novel pleiotropic loci (XXYLT1, KNG1, SUGP1/MAU2, TBL2/MLXIPL) that were not significant in the original individual datasets, were not described in previous GWAS for the individual traits, and that presented a common associated variant between the studied phenotypes. Conclusions: The discovery of four novel loci contributes to the understanding of the relationship between hemostasis and CV events and elucidate common genetic factors between these traits.
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- 2022
78. Abstract 140: Plasma Interleukin-6 Levels And Cardiovascular Events In The Cirt Trial: Consistent Associations For Incident Coronary, Cerebrovascular, And Peripheral Artery Disease
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Lucas Marinho, Aaron W Aday, Nancy R Cook, Alan R Morrison, Navneet Narula, Jagat Narula, Francesca Bartoli-Leonard, Elena Aikawa, Jocelyn M Beach, Paul M Ridker, and Aruna D Pradhan
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Cardiology and Cardiovascular Medicine - Abstract
Introduction: Inflammation is causally related to atherothrombosis. Interleukin-1β (IL-1β) and interleukin-18 (IL-18) require NLRP3 inflammasome for activation and have downstream effects on interleukin-6 (IL-6), a marker previously associated with high risk of coronary artery and cerebrovascular disease (CCVD). However, data pertaining to peripheral artery disease (PAD) are sparse and could offer druggable targets in this disease. Methods: We conducted a prospective cohort study of 4248 patients with type 2 diabetes or metabolic syndrome and prior coronary artery disease who participated in the NIH-funded Cardiovascular Inflammation Reduction Trial (CIRT). Participants were followed for up to 5 years for incident CCVD and symptomatic PAD events. Randomized treatment with low-dose methotrexate (vs. placebo) had no effect on event rates or plasma levels of inflammatory biomarkers. Baseline levels of IL-1β, IL-18, and IL-6 were tested for association with incident vascular events. Kaplan-Meier curves and Cox proportional hazards models (adjusted for traditional risk factors) were estimated. Results: In multivariable adjusted analyses, hazard ratios for the lowest (referent) to highest baseline quartiles of IL-6 were 1.0, 1.5, 1.8, and 2.0 (p-trend Conclusion: In this contemporary cohort of secondary prevention patients, elevated IL-6 was associated with both incident CCVD and PAD. These data support exploration of direct IL-6 inhibition for PAD prevention, a strategy currently being pursued to reduce risk of coronary artery and cerebrovascular disease.
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- 2022
79. TET2-Driven Clonal Hematopoiesis and Response to Canakinumab: An Exploratory Analysis of the CANTOS Randomized Clinical Trial
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Eric C. Svensson, Aviv Madar, Catarina D. Campbell, Yunsheng He, Marc Sultan, Margaret L. Healey, Huilei Xu, Katie D’Aco, Anita Fernandez, Clarisse Wache-Mainier, Peter Libby, Paul M. Ridker, Michael T. Beste, and Craig T. Basson
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DNA-Binding Proteins ,C-Reactive Protein ,Humans ,Clonal Hematopoiesis ,Cardiology and Cardiovascular Medicine ,Antibodies, Monoclonal, Humanized ,Atherosclerosis ,Original Investigation ,Dioxygenases - Abstract
IMPORTANCE: Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of atherosclerotic cardiovascular disease, and mouse experiments suggest that CHIP related to Tet2 loss of function in myeloid cells accelerates atherosclerosis via augmented interleukin (IL) 1β signaling. OBJECTIVE: To assess whether individuals with CHIP have greater cardiovascular event reduction in response to IL-1β neutralization in the Canankinumab Anti-inflammatory Thrombosis Outcomes Trial (CANTOS). DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial took place from April 2011 to June 2017 at more than 1000 clinical sites in 39 countries. Targeted deep sequencing of genes previously associated with CHIP in a subset of trial participants using genomic DNA prepared from baseline peripheral blood samples were analyzed. All participants had prior myocardial infarction and elevated high-sensitivity C-reactive protein level above 0.20 mg/dL. Analysis took place between June 2017 and December 2021. INTERVENTIONS: Canakinumab, an anti–IL-1β antibody, given at doses of 50, 150, and 300 mg once every 3 months. MAIN OUTCOMES AND MEASURES: Major adverse cardiovascular events (MACE). RESULTS: A total of 338 patients (8.6%) were identified in this subset with evidence for clonal hematopoiesis. As expected, the incidence of CHIP increased with age; the mean (SD) age of patients with CHIP was 66.3 (9.2) years and 61.5 (9.6) years in patients without CHIP. Unlike other populations that were not preselected for elevated C-reactive protein, in the CANTOS population variants in TET2 were more common than DNMT3A (119 variants in 103 patients vs 86 variants in 85 patients). Placebo-treated patients with CHIP showed a nonsignificant increase in the rate of MACE compared with patients without CHIP using a Cox proportional hazard model (hazard ratio, 1.32 [95% CI, 0.86-2.04]; P = .21). Exploratory analyses of placebo-treated patients with a somatic variant in either TET2 or DNMT3A (n = 58) showed an equivocal risk for MACE (hazard ratio, 1.65 [95% CI, 0.97-2.80]; P = .06). Patients with CHIP due to somatic variants in TET2 also had reduced risk for MACE while taking canakinumab (hazard ratio, 0.38 [95% CI, 0.15-0.96]) with equivocal difference compared with others (P for interaction = .14). CONCLUSIONS AND RELEVANCE: These results are consistent with observations of increased risk for cardiovascular events in patients with CHIP and raise the possibility that those with TET2 variants may respond better to canakinumab than those without CHIP. Future studies are required to further substantiate this hypothesis. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01327846
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- 2022
80. Effect Measure Modification by Covariates in Mediation: Extending Regression-Based Causal Mediation Analysis
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Yi Li, Maya B Mathur, Daniel Solomon, Paul M. Ridker, Robert J. Glynn, and Kazuki Yoshida
- Abstract
In this paper, we generalize the closed-form regression-based mediation analysis approach proposed by Valeri and VanderWeele (2013, 2015) to accommodate effect measure modification by the covariates. We show that covariate levels can affect the presence and magnitude of EMM of the conditional NDE and NIE, and that the dependence of the NDE and NIE depend on covariates is affected by the link functions of mediator and outcome models as well as the strength of EMM and of exposure-mediator interaction. Our proposed approach is implemented in R package regmedint (version 1.0.0), available at https://cran.r-project.org/web/packages/regmedint/index.html.
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- 2022
81. The neutrophil–lymphocyte ratio and incident atherosclerotic events: analyses from five contemporary randomized trials
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Jean G. MacFadyen, Ira Tabas, Paul M. Ridker, Nehal N. Mehta, Robert J. Glynn, Nicholas H Adamstein, Amit K. Dey, Peter Libby, and Lynda M. Rose
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medicine.medical_specialty ,Neutrophils ,030204 cardiovascular system & hematology ,Placebo ,Gastroenterology ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,law ,Internal medicine ,medicine ,Humans ,Rosuvastatin ,Lymphocytes ,030212 general & internal medicine ,Randomized Controlled Trials as Topic ,Proportional hazards model ,business.industry ,fungi ,Hazard ratio ,Clnical Research ,Antibodies, Monoclonal ,Atherosclerosis ,Confidence interval ,Race Factors ,Canakinumab ,Cardiology and Cardiovascular Medicine ,business ,Mace ,medicine.drug - Abstract
Aims The neutrophil–lymphocyte ratio (NLR) is a readily available inflammatory biomarker that may associate with atherosclerosis and predict cardiovascular (CV) events. The aims of this study are to determine whether the NLR predicts incident major adverse cardiovascular events (MACE) and is modified by anti-inflammatory therapy. Methods and results Baseline and on-treatment NLRs were calculated from complete blood counts among 60 087 participants randomized in the CANTOS, JUPITER, SPIRE-1, SPIRE-2, and CIRT trials to receive placebo or canakinumab, rosuvastatin, bococizumab, or methotrexate, respectively, and followed up for MACE. All analyses were performed first in CANTOS, and then externally validated in the other four trials. For the five trials, hazard ratios for major CV events and mortality comparing NLR quartiles were computed using Cox proportional hazards models, and the effect of each randomized intervention on the NLR was evaluated in comparison to placebo. The NLR modestly correlated with interleukin-6, C-reactive protein, and fibrinogen levels but minimally with lipids. In all five randomized trials, baseline NLR predicted incident CV events and death; the per-quartile increase in risk of MACE was 20% in CANTOS [95% confidence interval (CI) 14–25%, P Conclusion The NLR, an easily obtained inflammatory biomarker, independently predicts CV risk and all-cause mortality, and is reduced by interleukin-1β blockade with canakinumab.
- Published
- 2021
82. ASSOCIATION OF BASELINE MODEST ALCOHOL CONSUMPTION AND CORONARY MICROVASCULAR DYSFUNCTION IN THE CARDIOVASCULAR INFLAMMATION REDUCTION TRIAL (CIRT-CFR)
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Ana Carolina Do Amaral Henrique De Souza, Filipe Moura, Jon Mark Hainer, Hicham Skali, Ron Blankstein, Sharmila Dorbala, Fadi G. Hage, Rob S.B. Beanlands, Paul M. Ridker, Marcelo F. Di Carli, and Viviany R. Taqueti
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Cardiology and Cardiovascular Medicine - Published
- 2023
83. From RESCUE to ZEUS: will interleukin-6 inhibition with ziltivekimab prove effective for cardiovascular event reduction?
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Paul M. Ridker
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Cardiovascular event ,medicine.medical_specialty ,Physiology ,Anti-Inflammatory Agents ,Inflammation ,Cardiovascular Research Onlife ,Antibodies, Monoclonal, Humanized ,Risk Assessment ,Zeus (malware) ,Coronary artery disease ,Physiology (medical) ,Internal medicine ,medicine ,Humans ,Interleukin 6 ,Randomized Controlled Trials as Topic ,biology ,Interleukin-6 ,business.industry ,C-reactive protein ,Atherosclerosis ,medicine.disease ,Treatment Outcome ,Cardiovascular Diseases ,Heart Disease Risk Factors ,biology.protein ,Cardiology ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Signal Transduction - Published
- 2021
84. Inhibition of IL1β by Canakinumab May Be Effective against Diverse Molecular Subtypes of Lung Cancer: An Exploratory Analysis of the CANTOS Trial
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Eric C. Svensson, Paul M. Ridker, Jason Baum, Bharani Bharani-Dharan, Ying A Wang, Siyan Xu, Xiaoshan Wang, Anne-Marie Martin, Margaret F. Prescott, Margaret Dugan, Michael T. Beste, Angela Silvestro, Wong Connie C, and Lynne Krajkovich
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Male ,0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,Interleukin-1beta ,Anti-Inflammatory Agents ,Inflammation ,Antibodies, Monoclonal, Humanized ,Circulating Tumor DNA ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Biomarkers, Tumor ,Humans ,Medicine ,Longitudinal Studies ,Lung cancer ,Dose-Response Relationship, Drug ,Adiponectin ,business.industry ,Incidence ,Cancer ,Thrombosis ,medicine.disease ,Canakinumab ,C-Reactive Protein ,Treatment Outcome ,030104 developmental biology ,030220 oncology & carcinogenesis ,Mutation ,Monoclonal ,Female ,Tumor necrosis factor alpha ,Interleukin 18 ,Immunotherapy ,medicine.symptom ,business ,medicine.drug - Abstract
In the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), inhibition of the IL1β inflammatory pathway by canakinumab has been shown to significantly reduce lung cancer incidence and mortality. Here we performed molecular characterization of CANTOS patients who developed lung cancer during the study, including circulating tumor DNA (ctDNA) and soluble inflammatory biomarker analysis. Catalogue of Somatic Mutations in Cancer (COSMIC) database ctDNA mutations were detected in 65% (46/71) of the CANTOS patients with lung cancer, with 51% (36/71) having detectable ctDNA at the time point closest to lung cancer diagnosis and 43% (29/67) having detectable ctDNA at trial randomization. Mutations commonly found in lung cancer were observed with no evidence of enrichment in any mutation following canakinumab treatment. Median time to lung cancer diagnosis in patients with (n = 29) versus without (n = 38) detectable COSMIC ctDNA mutations at baseline was 407 days versus 837 days (P = 0.011). For serum inflammatory biomarker analysis, circulating levels of C-reactive protein (CRP), IL6, IL18, IL1 receptor antagonist, TNFα, leptin, adiponectin, fibrinogen, and plasminogen activator inhibitor-1 were determined. Patients with the highest level of baseline CRP or IL6, both downstream of IL1β signaling, trended toward a shorter time to lung cancer diagnosis. Other inflammation markers outside of the IL1β pathway at baseline did not trend with time to lung cancer diagnosis. These results provide further evidence for the importance of IL1β-mediated protumor inflammation in lung cancer and suggest canakinumab's effect may be mediated in part by delaying disease progression of diverse molecular subtypes of lung cancer. Significance: These findings suggest that targeting the IL1β inflammatory pathway might be critical in reducing tumor-promoting inflammation and lung cancer incidence.
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- 2020
85. Pulmonary Adverse Events in Patients Receiving Low‐Dose Methotrexate in the Randomized, Double‐Blind, Placebo‐Controlled Cardiovascular Inflammation Reduction Trial
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Daniel H. Solomon, Robert J. Glynn, Paul F. Dellaripa, Paul M. Ridker, Nina P. Paynter, Jeffrey A. Sparks, and Chang Xu
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Adult ,Male ,medicine.medical_specialty ,Immunology ,Placebo ,law.invention ,03 medical and health sciences ,Sex Factors ,0302 clinical medicine ,Double-Blind Method ,Rheumatology ,Randomized controlled trial ,Risk Factors ,law ,Internal medicine ,medicine ,Humans ,Immunology and Allergy ,030212 general & internal medicine ,Risk factor ,Adverse effect ,Pneumonitis ,Inflammation ,030203 arthritis & rheumatology ,business.industry ,Hazard ratio ,Age Factors ,Pneumonia ,Middle Aged ,medicine.disease ,Methotrexate ,Cardiovascular Diseases ,Female ,Metabolic syndrome ,business ,Immunosuppressive Agents ,medicine.drug - Abstract
OBJECTIVE We previously reported that low-dose methotrexate (MTX) was associated with an increased risk of pulmonary adverse events (AEs) in a large randomized, placebo-controlled trial. Herein, we report details on the predictors and severity of pulmonary AEs. METHODS We conducted a prespecified analysis of pulmonary AEs in the Cardiovascular Inflammation Reduction Trial. Adults with known cardiovascular disease and diabetes/metabolic syndrome were randomly allocated to receive low-dose MTX (target dose 15-20 mg/week) or placebo after a 6-8-week open-label run-in phase in which all patients received low-dose MTX. Individuals with systemic inflammatory diseases were excluded. Pulmonary AEs were adjudicated in a blinded manner. We described severe pulmonary AEs and examined associations of baseline characteristics with pulmonary AEs in patients receiving low-dose MTX. RESULTS A total of 2,391 subjects were randomized to receive low-dose MTX and 2,395 to receive placebo. There were 13 severe pulmonary AEs (0.5%) and 7 cases of possible pneumonitis (0.3%) in the low-dose MTX group, compared to 8 (0.3%) and 1 (
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- 2020
86. Effects of Interleukin-1β Inhibition on Incident Hip and Knee Replacement
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Paul M. Ridker, Ronenn Roubenoff, Jens Praestgaard, Daniel H. Solomon, Linda Mindeholm, Herman Gram, Philip G. Conaghan, C. Scotti, Tom Thuren, and Matthias Schieker
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Male ,medicine.medical_specialty ,Arthroplasty, Replacement, Hip ,medicine.medical_treatment ,Placebo-controlled study ,Knee replacement ,Osteoarthritis ,Antibodies, Monoclonal, Humanized ,Placebo ,01 natural sciences ,Osteoarthritis, Hip ,Article ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Randomized controlled trial ,law ,Internal medicine ,Internal Medicine ,medicine ,Humans ,030212 general & internal medicine ,0101 mathematics ,Arthroplasty, Replacement, Knee ,Adverse effect ,business.industry ,Incidence ,010102 general mathematics ,Hazard ratio ,Interleukin-18 ,General Medicine ,Middle Aged ,Osteoarthritis, Knee ,medicine.disease ,Canakinumab ,Female ,business ,medicine.drug - Abstract
Background: Osteoarthritis is a common inflammatory disorder with no disease-modifying therapies. Whether inhibition of interleukin-1β (IL-1β) can reduce the consequences of large joint osteoarthritis is unclear. Objective: To determine whether IL-1β inhibition with canakinumab reduces incident total hip or knee replacement (THR/TKR). Design: Exploratory analysis of a randomized trial. (ClinicalTrials.gov: NCT01327846) Setting: 1091 clinical sites in 39 countries. Participants: 10 061 CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) participants. Intervention: Random allocation to placebo or canakinumab (50, 150, or 300 mg) subcutaneously once every 3 months. Measurements: The primary and secondary outcomes were time to first incident THR/TKR and time to first occurrence of an osteoarthritis-related adverse event (AE). Data were obtained through blinded ascertainment of trial clinical and safety databases. Results: Median follow-up was 3.7 years. For the individual canakinumab dose groups, compared with placebo, hazard ratios (HRs) for incident THR/TKR during follow-up were 0.60 (95% CI, 0.38 to 0.95) for the 50-mg group, 0.53 (CI, 0.33 to 0.84) for the 150-mg group, and 0.60 (CI, 0.38 to 0.93) for the 300-mg group. Thus, in the pooled canakinumab groups, compared with the placebo group, incidence rates for THR/TKR were 0.31 and 0.54 events per 100 person-years (HR, 0.58 [CI, 0.42 to 0.80]; P = 0.001), respectively. The HR for the secondary end point of osteoarthritis-related AEs was 0.73 (CI, 0.61 to 0.87). Similar findings were observed in analyses restricted to participants with a history of osteoarthritis. Limitation: Because the parent trial was not designed to examine the efficacy of IL-1β inhibitors in osteoarthritis, information on structural joint outcomes was not collected. Conclusion: Findings from this exploratory analysis of a randomized controlled trial support further investigation of IL-1β inhibition for treatment of large joint osteoarthritis. Primary Funding Source: Novartis Pharmaceuticals.
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- 2020
87. ApoA-I Infusion Therapies Following Acute Coronary Syndrome: Past, Present, and Future
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Arzu Kalayci, C. Michael Gibson, Paul M. Ridker, Samuel D. Wright, Bronwyn A. Kingwell, Serge Korjian, Gerald Chi, Jane J. Lee, Pierluigi Tricoci, S. Hassan Kazmi, Clara Fitzgerald, Alka Shaunik, Gail Berman, Danielle Duffy, and Peter Libby
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Cholesterol ,Apolipoprotein A-I ,Cholesterol, HDL ,Humans ,Acute Coronary Syndrome ,Cardiology and Cardiovascular Medicine ,Atherosclerosis - Abstract
Purpose of Review The elevated adverse cardiovascular event rate among patients with low high-density lipoprotein cholesterol (HDL-C) formed the basis for the hypothesis that elevating HDL-C would reduce those events. Attempts to raise endogenous HDL-C levels, however, have consistently failed to show improvements in cardiovascular outcomes. However, steady-state HDL-C concentration does not reflect the function of this complex family of particles. Indeed, HDL functions correlate only weakly with serum HDL-C concentration. Thus, the field has pivoted from simply raising the quantity of HDL-C to a focus on improving the putative anti-atherosclerotic functions of HDL particles. Such functions include the ability of HDL to promote the efflux of cholesterol from cholesterol-laden macrophages. Apolipoprotein A-I (apoA-I), the signature apoprotein of HDL, may facilitate the removal of cholesterol from atherosclerotic plaque, reduce the lesional lipid content and might thus stabilize vulnerable plaques, thereby reducing the risk of cardiac events. Infusion of preparations of apoA-I may improve cholesterol efflux capacity (CEC). This review summarizes the development of apoA-I therapies, compares their structural and functional properties and discusses the findings of previous studies including their limitations, and how CSL112, currently being tested in a phase III trial, may overcome these challenges. Recent Findings Three major ApoA-I-based approaches (MDCO-216, CER-001, and CSL111/CSL112) have aimed to enhance reverse cholesterol transport. These three therapies differ considerably in both lipid and protein composition. MDCO-216 contains recombinant ApoA-I Milano, CER-001 contains recombinant wild-type human ApoA-I, and CSL111/CSL112 contains native ApoA-I isolated from human plasma. Two of the three agents studied to date (apoA-1 Milano and CER-001) have undergone evaluation by intravascular ultrasound imaging, a technique that gauges lesion volume well but does not assess other important variables that may relate to clinical outcomes. ApoA-1 Milano and CER-001 reduce lecithin-cholesterol acyltransferase (LCAT) activity, potentially impairing the function of HDL in reverse cholesterol transport. Furthermore, apoA-I Milano can compete with and alter the function of the recipient’s endogenous apoA-I. In contrast to these agents, CSL112, a particle formulated using human plasma apoA-I and phosphatidylcholine, increases LCAT activity and does not lead to the malfunction of endogenous apoA-I. CSL112 robustly increases cholesterol efflux, promotes reverse cholesterol transport, and now is being tested in a phase III clinical trial. Summary Phase II-b studies of MDCO-216 and CER-001 failed to produce a significant reduction in coronary plaque volume as assessed by IVUS. However, the investigation to determine whether the direct infusion of a reconstituted apoA-I reduces post-myocardial infarction coronary events is being tested using CSL112, which is dosed at a higher level than MDCO-216 and CER-001 and has more favorable pharmacodynamics.
- Published
- 2022
88. Clinical predictors of COVID-19 severity and bleeding in the ACTIV-4B COVID-19 outpatient thrombosis prevention trial
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Jean M. Connors, Maria M. Brooks, Frank C. Sciurba, Zhuxuan Fu, and Paul M. Ridker
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Clinical Trials as Topic ,Outpatients ,Anticoagulants ,COVID-19 ,Humans ,Hemorrhage ,Thrombosis ,Hematology - Published
- 2022
89. Genome-wide pharmacogenetics of anti-drug antibody response to bococizumab highlights key residues in HLA DRB1 and DQB1
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Daniel I, Chasman, Craig L, Hyde, Franco, Giulianini, Rebecca D, Danning, Ellen Q, Wang, Timothy, Hickling, Paul M, Ridker, and A Katrina, Loomis
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Multidisciplinary ,Gene Frequency ,Haplotypes ,Pharmacogenetics ,Antibody Formation ,Antibodies, Monoclonal ,Humans ,Genetic Predisposition to Disease ,Proprotein Convertase 9 ,Antibodies, Monoclonal, Humanized ,Alleles ,Genome-Wide Association Study ,HLA-DRB1 Chains - Abstract
In this largest to-date genetic analysis of anti-drug antibody (ADA) response to a therapeutic monoclonal antibody (MAb), genome-wide association was performed for five measures of ADA status among 8844 individuals randomized to bococizumab, which targets PCSK9 for LDL-C lowering and cardiovascular protection. Index associations prioritized specific amino acid substitutions at theDRB1andDQB1MHC class II genes rather than canonical haplotypes. Two clusters of missense variants atDRB1were associated with general ADA measures (residues 9, 11, 13; and 96, 112, 120, 180) and a third cluster of missense variants inDQB1was associated with ADA measures including neutralizing antibody (NAb) titers (residues 66, 67, 71, 74, 75). The structural disposition of the missense substitutions implicates peptide antigen binding and CD4 effector function, mechanisms that are potentially generalizable to other therapeutic mAbs.Clinicaltrials.gov: NCT01968954, NCT01968967, NCT01968980, NCT01975376, NCT01975389, NCT02100514.
- Published
- 2022
90. Genetics are not likely to offer clinically useful predictions for elevated liver enzyme levels in patients using low dose methotrexate
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Jing Cui, Daniel I. Chasman, Soumya Raychaudhuri, Chang Xu, Paul M. Ridker, Daniel H. Solomon, and Elizabeth W. Karlson
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Anesthesiology and Pain Medicine ,Methotrexate ,Rheumatology ,Risk Factors ,Humans ,Chemical and Drug Induced Liver Injury ,Genome-Wide Association Study - Abstract
To examine genetic influence on the risk of elevations in liver function tests (AST and ALT) among patients using low-dose methotrexate (LD-MTX).We examined data from the LD-MTX arm of a randomized double-blind placebo-controlled trial conducted among subjects without rheumatic disease. Genome wide association studies (GWAS) were performed in subjects of European ancestry to test the association between single nucleotide polymorphisms (SNPs) and the log transformed maximum values of AST, ALT, and dichotomized outcome with AST or ALT2 times upper limit of normal (ULN). The association between variants in MTX metabolism candidate genes and the outcomes was also tested. Furthermore, associations between a drug induced liver injury (DILI) weighted genetic risk score (wGRS) and the outcomes were tested, combining 10 SNPs and 11 classical HLA alleles associated with DILI.In genome-wide genetic analyses among 1,429 subjects of European ancestry who were randomized to receive LD-MTX, two SNPs reached genome wide significance for association with log transformed maximum ALT. We observed associations between established candidate genes in MTX pharmacogenetics and log transformed maximum AST and ALT, as well as in dichotomized outcome with AST or ALT2 x ULN. There was no association between DILI wGRS or candidate variants and AST, ALT, or DILI response.Modest evidence was observed that common variants affected AST and ALT levels in subjects of European ancestry on LD-MTX, but this genetic effect is not useful as a clinical predictor of MTX toxicity.
- Published
- 2022
91. Coronary Flow Reserve, Inflammation and Myocardial Strain in the Cardiovascular Inflammation Reduction Trial (CIRT-CFR)
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Viviany R. Taqueti, Amil Shah, Brendan M. Everett, Aruna Pradhan, Gregory Piazza, Courtney Bibbo, Jon Hainer, Victoria Morgan, Ana Carolina do A.H. de Souza, Hicham Skali, Ron Blankstein, Sharmila Dorbala, Samuel Z. Goldhaber, Michel R. Le May, Benjamin Chow, Robert A. deKemp, Fadi Hage, Rob SB Beanlands, Peter Libby, Robert Glynn, Scott D. Solomon, Paul M. Ridker, and Marcelo Di Carli
- Published
- 2022
92. Inhibiting Interleukin-6 to Reduce Cardiovascular Event Rates
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Paul M. Ridker
- Subjects
Cardiovascular event ,medicine.medical_specialty ,biology ,business.industry ,Inflammation ,medicine.disease ,Infarct size ,law.invention ,Randomized controlled trial ,law ,Internal medicine ,medicine ,Cardiology ,biology.protein ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Interleukin 6 ,Reperfusion injury - Published
- 2021
93. Triglyceride-Rich Lipoprotein Cholesterol, Small Dense LDL Cholesterol, and Incident Cardiovascular Disease
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Aruna D. Pradhan, Edward K. Duran, Julie E. Buring, Nancy R. Cook, Aaron W. Aday, and Paul M. Ridker
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Male ,medicine.medical_specialty ,Lipoproteins ,030204 cardiovascular system & hematology ,Article ,Cohort Studies ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Epidemiology ,medicine ,Humans ,Prospective Studies ,030212 general & internal medicine ,Myocardial infarction ,Triglycerides ,Dyslipidemias ,Cholesterol ,business.industry ,Vascular disease ,Incidence ,Hazard ratio ,Cholesterol, LDL ,Middle Aged ,medicine.disease ,Confidence interval ,chemistry ,Cardiovascular Diseases ,Cardiology ,Female ,Cardiology and Cardiovascular Medicine ,business ,Dyslipidemia ,Follow-Up Studies ,Lipoprotein - Abstract
BACKGROUND: Elevated triglyceride-rich lipoprotein (TRL) and small-dense low-density lipoprotein (sdLDL) particles are hallmarks of atherogenic dyslipidemia, and their cholesterol content is hypothesized to drive atherosclerotic risk. Prospective epidemiological data pertaining to cholesterol content of TRLs and sdLDL in primary prevention populations are mostly limited to coronary heart disease. OBJECTIVES: The purpose of this study was to prospectively evaluate whether triglyceride-rich lipoprotein cholesterol (TRL-C) and small-dense low-density lipoprotein cholesterol (sdLDL-C) concentrations associate with composite and individual incident cardiovascular disease (CVD) outcomes including myocardial infarction (MI), ischemic stroke (IS), and peripheral artery disease (PAD). METHODS: In a prospective case-cohort study within the Women’s Health Study, TRL-C and sdLDL-C (mg/dl) were directly measured in baseline blood specimens of case subjects (n = 480) and the reference subcohort (n = 496). Risk associations were evaluated for total CVD (MI, IS, PAD, and CVD death), coronary and cerebrovascular disease (MI, IS, CVD death), and individual outcomes (MI, IS, and PAD). Models were adjusted for traditional risk factors, low-density lipoprotein cholesterol, and high-sensitivity C-reactive protein. RESULTS: The risk of both composite outcomes significantly increased across quartiles of TRL-C and sdLDL-C. TRL-C was significantly associated with MI and PAD (MI hazard ratio [HR](Q4): 3.05 [95% confidence interval (CI): 1.46 to 6.39]; ptrend = 0.002; PAD HR(Q4): 2.58 [95% CI: 1.18 to 5.63]; p(trend) = 0.019), whereas sdLDL-C was significantly associated with MI alone (HR(Q4): 3.71 [95% CI: 1.59 to 8.63]; p(trend) < 0.001). Both markers weakly associated with IS. Association patterns were similar for continuous exposures and, for TRL-C, among subjects with low atherogenic particle concentrations (apolipoprotein B
- Published
- 2020
94. Targeting cardiovascular inflammation: next steps in clinical translation
- Author
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Paul M. Ridker, Thomas F. Lüscher, Lucas C. Godoy, Patrick R. Lawler, Subodh Verma, Deepak L. Bhatt, Robert O. Bonow, University of Zurich, and Lawler, Patrick R
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Acute coronary syndrome ,medicine.medical_specialty ,Myocardial Infarction ,610 Medicine & health ,Inflammation ,Disease ,030204 cardiovascular system & hematology ,2705 Cardiology and Cardiovascular Medicine ,11459 Center for Molecular Cardiology ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,030212 general & internal medicine ,Myocardial infarction ,Acute Coronary Syndrome ,Intensive care medicine ,biology ,business.industry ,C-reactive protein ,Atherosclerosis ,medicine.disease ,3. Good health ,Clinical trial ,C-Reactive Protein ,Atheroma ,Cardiovascular Diseases ,biology.protein ,570 Life sciences ,Observational study ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Biomarkers - Abstract
Systemic vascular inflammation plays multiple maladaptive roles which contribute to the progression and destabilization of atherosclerotic cardiovascular disease (ASCVD). These roles include: (i) driving atheroprogression in the clinically stable phase of disease; (ii) inciting atheroma destabilization and precipitating acute coronary syndromes (ACS); and (iii) responding to cardiomyocyte necrosis in myocardial infarction (MI). Despite an evolving understanding of these biologic processes, successful clinical translation into effective therapies has proven challenging. Realizing the promise of targeting inflammation in the prevention and treatment of ASCVD will likely require more individualized approaches, as the degree of inflammation differs among cardiovascular patients. A large body of evidence has accumulated supporting the use of high-sensitivity C-reactive protein (hsCRP) as a clinical measure of inflammation. Appreciating the mechanistic diversity of ACS triggers and the kinetics of hsCRP in MI may resolve purported inconsistencies from prior observational studies. Future clinical trial designs incorporating hsCRP may hold promise to enable individualized approaches. The aim of this Clinical Review is to summarize the current understanding of how inflammation contributes to ASCVD progression, destabilization, and adverse clinical outcomes. We offer forward-looking perspective on what next steps may enable successful clinical translation into effective therapeutic approaches—enabling targeting the right patients with the right therapy at the right time—on the road to more individualized ASCVD care.
- Published
- 2020
95. Hypothyroidism and Kidney Function: A Mendelian Randomization Study
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Samia Mora, Paul M. Ridker, Christina Ellervik, and Daniel I. Chasman
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Thyroid Hormones ,Endocrinology, Diabetes and Metabolism ,Thyroid Gland ,Renal function ,030209 endocrinology & metabolism ,Thyroid Function Tests ,Kidney ,Kidney Function Tests ,Bioinformatics ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,Hypothyroidism ,Mendelian randomization ,Humans ,Medicine ,Aged ,Aged, 80 and over ,Creatinine ,biology ,Mechanism (biology) ,business.industry ,Mendelian Randomization Analysis ,Middle Aged ,Cystatin C ,chemistry ,030220 oncology & carcinogenesis ,biology.protein ,Female ,Kidney Diseases ,Observational study ,Thyroid function ,business ,Genome-Wide Association Study ,Glomerular Filtration Rate ,Thyroid Dysfunction: Hypothyroidism, Thyrotoxicosis, and Thyroid Function Tests - Abstract
Background: Uncertainty in the mechanism and directionality of observational associations between thyroid function and kidney function may be addressed by genetic analysis with an instrumental variable method termed bidirectional Mendelian randomization (MR). Methods: In the Women's Genome Health Study (WGHS), observational associations between thyroid measures and kidney function were evaluated. Genetic instruments for MR were from recent genome-wide association studies (GWAS) of hypothyroidism, thyrotropin (TSH), and free thyroxine (fT4) concentrations within the reference range, thyroid peroxidase antibodies (TPOAb), estimated glomerular filtration rate from creatinine (eGFR(crea)), eGFR from cystatin C (eGFR(cys)), and chronic kidney disease (CKD). In WGHS individual-level data, these instruments were used for bidirectional MR between thyroid (N = 3336) and kidney (N = 23,186) functions. To increase power, MR was also performed using GWAS summary statistics from the Chronic Kidney Disease Genetics Consortium (CKDGen) for eGFR(crea) (N = 567,460), eGFR(cys) (N = 24,063), CKD [N(total) = 480,698, N(cases) = 41,395], and urinary albumin/creatinine ratio (UACR/N = 54,450). Results: In the WGHS, hypothyroidism was observationally associated with decreased eGFR(crea) [beta (standard error, SE): −0.024 (0.009) ln(mL/min/1.73 m(2)), p = 0.01]. By MR, hypothyroidism was associated with decreased eGFR(crea) in the WGHS [beta (SE): −0.007 (0.002) per doubled odds hypothyroidism, p = 1.7 × 10(−3)] and in CKDGen [beta (SE): −0.004 (0.0005), p = 2.0 × 10(−22)], and robust to sensitivity analysis. Hypothyroidism was also associated by MR with increased CKD in CKDGen (odds ratio, OR [confidence interval, CI]: 1.05 [1.03–1.08], p = 3.3 × 10(−5)), but not in the WGHS (OR [CI]: 1.02 [0.95–1.10], p = 0.57). Increased TSH within the reference range had an MR association with increased eGFR(crea) in the WGHS [beta (SE): −0.018 (0.007) ln(mL/min/1.73 m(2))/standard deviation, SD, p = 6.5 × 10(−3)] and CKDGen [beta (SE): −0.008 (0.001) ln(mL/min/1.73 m(2))/SD, p = 6.8 × 10(−17)], and with CKD in CKDGen (OR [CI]: 1.10 [1.04–1.15], p = 3.1 × 10(−4)). There were no MR associations of hypothyroidism or TSH with eGFR(cys) or UACR, and MR associations of fT4 in the reference range with kidney function were inconsistent in both the WGHS and CKDGen. However, by MR in CKDGen, TPOAb were robustly associated with decreased eGFR(crea) [beta (SE): −0.041 (0.009), p = 6.2 × 10(−6)] and decreased eGFR(cys) [beta (SE): −0.294 (0.065), p = 6.2 × 10(−6)]. TPOAb were less robustly associated with CKD but not associated with UACR. In reverse MR in the WGHS, kidney function was not consistently associated with thyroid function. Conclusions: Bidirectional MR supports a directional association from hypothyroidism, increased TSH, and TPOAb, but not fT4, to decreased eGFR(crea) and increased CKD.
- Published
- 2020
96. Exercise reduces inflammatory cell production and cardiovascular inflammation via instruction of hematopoietic progenitor cells
- Author
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Kamila Naxerova, Hajera Amatullah, Vanessa Frodermann, Gerard Pasterkamp, I-Hsiu Lee, Fanny Herisson, Nicolas Severe, David Rohde, Gregory R. Wojtkiewicz, Paul M. Ridker, Jana Grune, Friedrich Felix Hoyer, Matthias Nahrendorf, Saskia C. A. de Jager, Yoshiko Iwamoto, Karin Gustafsson, Peter Libby, Lisa Honold, Sebastian Cremer, Gustavo Santos Masson, Ruslan I. Sadreyev, Shuang Zhang, Kate L. Jeffrey, Filip K. Swirski, Gabriel Courties, Fei Ji, Cameron S. McAlpine, Stephen P. Schmidt, Maximilian J. Schloss, Jean G. MacFadyen, Ian D. van Koeverden, and David T. Scadden
- Subjects
0301 basic medicine ,Stromal cell ,Leukocytosis ,Adipose tissue ,Inflammation ,Biochemistry ,General Biochemistry, Genetics and Molecular Biology ,Epigenome ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Physical Conditioning, Animal ,Leukocytes ,Animals ,Humans ,Medicine ,Progenitor cell ,Exercise ,Homeodomain Proteins ,Leptin receptor ,Biochemistry, Genetics and Molecular Biology(all) ,business.industry ,Leptin ,General Medicine ,Atherosclerosis ,Hematopoietic Stem Cells ,Hematopoiesis ,030104 developmental biology ,medicine.anatomical_structure ,Adipose Tissue ,Cardiovascular Diseases ,030220 oncology & carcinogenesis ,Immunology ,Receptors, Leptin ,Bone marrow ,Sedentary Behavior ,medicine.symptom ,Transcriptome ,business ,Genetics and Molecular Biology(all) - Abstract
A sedentary lifestyle, chronic inflammation and leukocytosis increase atherosclerosis; however, it remains unclear whether regular physical activity influences leukocyte production. Here we show that voluntary running decreases hematopoietic activity in mice. Exercise protects mice and humans with atherosclerosis from chronic leukocytosis but does not compromise emergency hematopoiesis in mice. Mechanistically, exercise diminishes leptin production in adipose tissue, augmenting quiescence-promoting hematopoietic niche factors in leptin-receptor-positive stromal bone marrow cells. Induced deletion of the leptin receptor in Prrx1-creERT2; Leprfl/fl mice reveals that leptin’s effect on bone marrow niche cells regulates hematopoietic stem and progenitor cell (HSPC) proliferation and leukocyte production, as well as cardiovascular inflammation and outcomes. Whereas running wheel withdrawal quickly reverses leptin levels, the impact of exercise on leukocyte production and on the HSPC epigenome and transcriptome persists for several weeks. Together, these data show that physical activity alters HSPCs via modulation of their niche, reducing hematopoietic output of inflammatory leukocytes. The beneficial effects of exercise on cardiovascular disease are linked to decreased inflammation through crosstalk between adipose tissue and hematopoietic progenitor cells in the bone marrow.
- Published
- 2019
97. Coronary Artery Disease Polygenic Risk Score Identifies Patients at Higher Risk for Recurrent Cardiovascular Events in the CANTOS Trial
- Author
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Claudia Hon, Ma’en Obeidat, Jason M. Laramie, Philippe Marc, Pablo Serrano-Fernandez, Paul M. Ridker, Margaret L Healey, Michael T. Beste, Arkady I Gusev, Aviv Madar, Huilei Xu, Nicole Hartmann, Denise Yates, Scott Kennedy, Sergio Kaiser, and Eric C. Svensson
- Subjects
Clinical Trials as Topic ,Treatment response ,medicine.medical_specialty ,business.industry ,Coronary Artery Disease ,General Medicine ,Antibodies, Monoclonal, Humanized ,Atherosclerosis ,medicine.disease ,Coronary artery disease ,Canakinumab ,Disease severity ,Risk Factors ,Internal medicine ,medicine ,Humans ,Polygenic risk score ,Myocardial infarction ,business ,Disease burden ,Mace ,medicine.drug - Abstract
No formal abstract in format we plan to submit to journal (a short report). Informally, the work presented here adds to a body of evidence that shows how polygenic risk scores (PRS) for coronary artery disease (CAD) can be used to inform on patient's disease severity, disease progression, and potential for treatment response stratification. Key results include, patients in highest tertile PRS have a higher CAD disease burden at baseline (measured by number of myocardial infractions at trail start), progress faster in CAD (measured by time to first major adverse cardiovascular event, MACE), and may respond better to Canakinumab therapy at the highest dose of 300mg.
- Published
- 2021
98. Phenotypic and Genotypic Associations Between Migraine and Lipoprotein Subfractions
- Author
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Iyas Daghlas, Tobias Kurth, Franco Giulianini, Yanjun Guo, Paul M. Ridker, Pamela M. Rist, Samia Mora, Padhraig Gormley, and Daniel I. Chasman
- Subjects
Genetics ,Genotype ,Lipoproteins ,Migraine Disorders ,Odds ratio ,Biology ,medicine.disease ,Phenotype ,Genetic correlation ,Migraine ,Pleiotropy ,Mendelian randomization ,medicine ,Humans ,Female ,Neurology (clinical) ,Lipoprotein ,Research Article ,Genome-Wide Association Study - Abstract
Background and ObjectiveTo evaluate phenotypic and genetic relationships between migraine and lipoprotein subfractions.MethodsWe evaluated phenotypic associations between migraine and 19 lipoprotein subfraction measures in the Women's Genome Health Study (n = 22,788). We then investigated genetic relationships between these traits using summary statistics from the International Headache Genetics Consortium for migraine (ncase = 54,552, ncontrol = 297,970) and combined summary data for lipoprotein subfractions (n up to 47,713).ResultsThere was a significant phenotypic association (odds ratio 1.27 [95% confidence interval 1.12–1.44]) and a significant genetic correlation at 0.18 (p = 0.001) between migraine and triglyceride-rich lipoproteins (TRLPs) concentration but not for low-density lipoprotein or high-density lipoprotein subfractions. Mendelian randomization (MR) estimates were largely null, implying that pleiotropy rather than causality underlies the genetic correlation between migraine and lipoprotein subfractions. Pleiotropy was further supported in cross-trait meta-analysis, revealing significant shared signals at 4 loci (chr2p21 harboring THADA, chr5q13.3 harboring HMGCR, chr6q22.31 harboring HEY2, and chr7q11.23 harboring MLXIPL) between migraine and lipoprotein subfractions. Three of these loci were replicated for migraine (p < 0.05) in a smaller sample from the UK Biobank. The shared signal at chr5q13.3 colocalized with expression of HMGCR, ANKDD1B, and COL4A3BP in multiple tissues.ConclusionsThe study supports the association between certain lipoprotein subfractions, especially for TRLP, and migraine in populations of European ancestry. The corresponding shared genetic components may help identify potential targets for future migraine therapeutics.Classification of EvidenceThis study provides Class I evidence that migraine is significantly associated with some lipoprotein subfractions.
- Published
- 2021
99. Obesity Partially Mediates the Diabetogenic Effect of Lowering LDL Cholesterol
- Author
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Peitao Wu, Giulianini Franco, Daniel I. Chasman, Jerome I. Rotter, Georgy Hindy, Tom G. Richardson, M. Arfan Ikram, Ping An, Rafael R C Cuadrat, Jørgen K. Kanters, Sridharan Raghavan, Paul M. Ridker, Rita R. Kalyani, Jonas L. Isaksen, Morten S. Olesen, Xiuqing Guo, André G. Uitterlinden, Marju Orho-Melander, Lluís Masana, Lisa R. Yanek, Iyas Daghlas, Mohsen Ghanbari, Mary F. Feitosa, Jennifer A. Brody, Jose C Florez, Ulrika Ericson, James S. Floyd, Bianca Porneala, Jianwen Cai, Dhananjay Vaidya, Jee-Young Moon, James B. Meigs, George Davey Smith, Ching-Ti Liu, Susanne Jäger, Maryam Kavousi, Josée Dupuis, Christina Ellervik, Qibin Qi, Fariba Ahmadizar, Matthias B. Schulze, Mark O. Goodarzi, Dipender Gill, Josep M Mercader, Bruce M. Psaty, Laura M. Raffield, Leslie A. Lange, Colleen M. Sitlani, Robert C. Kaplan, Jie Yao, Jordi Merino, Michael A. Province, Epidemiology, and Internal Medicine
- Subjects
Research design ,medicine.medical_specialty ,Cardiovascular and Metabolic Risk ,Diabetes risk ,Endocrinology, Diabetes and Metabolism ,Adipose tissue ,Type 2 diabetes ,SDG 3 - Good Health and Well-being ,Risk Factors ,Diabetes mellitus ,Internal medicine ,Mendelian randomization ,Internal Medicine ,medicine ,Humans ,Obesity ,Advanced and Specialized Nursing ,business.industry ,Odds ratio ,Cholesterol, LDL ,Mendelian Randomization Analysis ,medicine.disease ,Endocrinology ,Diabetes Mellitus, Type 2 ,business ,Genome-Wide Association Study - Abstract
OBJECTIVE LDL cholesterol (LDLc)-lowering drugs modestly increase body weight and type 2 diabetes risk, but the extent to which the diabetogenic effect of lowering LDLc is mediated through increased BMI is unknown. RESEARCH DESIGN AND METHODS We conducted summary-level univariable and multivariable Mendelian randomization (MR) analyses in 921,908 participants to investigate the effect of lowering LDLc on type 2 diabetes risk and the proportion of this effect mediated through BMI. We used data from 92,532 participants from 14 observational studies to replicate findings in individual-level MR analyses. RESULTS A 1-SD decrease in genetically predicted LDLc was associated with increased type 2 diabetes odds (odds ratio [OR] 1.12 [95% CI 1.01, 1.24]) and BMI (β = 0.07 SD units [95% CI 0.02, 0.12]) in univariable MR analyses. The multivariable MR analysis showed evidence of an indirect effect of lowering LDLc on type 2 diabetes through BMI (OR 1.04 [95% CI 1.01, 1.08]) with a proportion mediated of 38% of the total effect (P = 0.03). Total and indirect effect estimates were similar across a number of sensitivity analyses. Individual-level MR analyses confirmed the indirect effect of lowering LDLc on type 2 diabetes through BMI with an estimated proportion mediated of 8% (P = 0.04). CONCLUSIONS These findings suggest that the diabetogenic effect attributed to lowering LDLc is partially mediated through increased BMI. Our results could help advance understanding of adipose tissue and lipids in type 2 diabetes pathophysiology and inform strategies to reduce diabetes risk among individuals taking LDLc-lowering medications.
- Published
- 2021
100. Abstract 9784: Association of Physical Activity with Bioactive Lipids, BMI, and Risk of Future Cardiovascular Events - Mediation Analysis from the Vitamin D and Omega-3 Trial (Vital) and Jupiter Studies
- Author
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Rosangela Hoshi, Yanyan Liu, Yanjun Guo, Saumya Tiwari, Heike Gibson, Allen M Andres, Jeramie Watrous, Nancy R Cook, Trisha Copeland, Karen Costenbader, Olivia Okereke, Paul M Ridker, Joann Manson, I-min M Lee, Susan Cheng, Mohit Jain, Olga Demler, and Samia Mora
- Subjects
Physiology (medical) ,Cardiology and Cardiovascular Medicine - Abstract
Introduction: To better understand the cardioprotective mechanisms of regular physical activity (PA), we examined its association with plasma bioactive lipids (BAL) and prospective cardiovascular disease (CVD) events and evaluated the extent to which BMI might mediate this association. Hypothesis: 1) Higher PA associates with a bioactive lipid profile related to lower CVD risk; 2) BMI mediates the PA-BAL and BAL-CVD associations. Methods: Using linear models (adjusted for age, sex, race, smoking, LDL, and total cholesterol), self-reported PA was examined with BAL assayed by an untargeted metabolomics platform in VITAL (N=1032) with validation in JUPITER (N=589). After performing mediation analysis through BMI (same adjustments), we evaluated both BMI-mediated and non-mediated PA-BAL associations with incident CVD using similarly adjusted conditional logistic regression in two nested CVD case-control studies: VITAL-CVD (770 pairs, followed by mediation analysis) and JUPITER-CVD (415 case-control pairs - validation) Results: We detected 237 significant PA-BAL associations in VITAL with replication in JUPITER (FDRvice-versa . Conclusion: We identified a signature of 22 PA-related BAL, which were also associated with incident CVD in two independent case-control studies. Although BMI-mediated associations were predominant, non-mediated effects were also detected, implying that more than one pathway may play a role in the PA-CVD relationship.
- Published
- 2021
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