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1.
JAMA ; 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34633405

RESUMO

Importance: Acutely ill inpatients with COVID-19 typically receive antithrombotic therapy, although the risks and benefits of this intervention among outpatients with COVID-19 have not been established. Objective: To assess whether anticoagulant or antiplatelet therapy can safely reduce major adverse cardiopulmonary outcomes among symptomatic but clinically stable outpatients with COVID-19. Design, Setting, and Participants: The ACTIV-4B Outpatient Thrombosis Prevention Trial was designed as a minimal-contact, adaptive, randomized, double-blind, placebo-controlled trial to compare anticoagulant and antiplatelet therapy among 7000 symptomatic but clinically stable outpatients with COVID-19. The trial was conducted at 52 US sites between September 2020 and June 2021; final follow-up was August 5, 2021. Prior to initiating treatment, participants were required to have platelet count greater than 100 000/mm3 and estimated glomerular filtration rate greater than 30 mL/min/1.73 m2. Interventions: Random allocation in a 1:1:1:1 ratio to aspirin (81 mg orally once daily; n = 164), prophylactic-dose apixaban (2.5 mg orally twice daily; n = 165), therapeutic-dose apixaban (5 mg orally twice daily; n = 164), or placebo (n = 164) for 45 days. Main Outcomes and Measures: The primary end point was a composite of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary cause. The primary analyses for efficacy and bleeding events were limited to participants who took at least 1 dose of trial medication. Results: On June 18, 2021, the trial data and safety monitoring board recommended early termination because of lower than anticipated event rates; at that time, 657 symptomatic outpatients with COVID-19 had been randomized (median age, 54 years [IQR, 46-59]; 59% women). The median times from diagnosis to randomization and from randomization to initiation of study treatment were 7 days and 3 days, respectively. Twenty-two randomized participants (3.3%) were hospitalized for COVID-19 prior to initiating treatment. Among the 558 patients who initiated treatment, the adjudicated primary composite end point occurred in 1 patient (0.7%) in the aspirin group, 1 patient (0.7%) in the 2.5-mg apixaban group, 2 patients (1.4%) in the 5-mg apixaban group, and 1 patient (0.7%) in the placebo group. The risk differences compared with placebo for the primary end point were 0.0% (95% CI not calculable) in the aspirin group, 0.7% (95% CI, -2.1% to 4.1%) in the 2.5-mg apixaban group, and 1.4% (95% CI, -1.5% to 5.0%) in the 5-mg apixaban group. Risk differences compared with placebo for bleeding events were 2.0% (95% CI, -2.7% to 6.8%), 4.5% (95% CI, -0.7% to 10.2%), and 6.9% (95% CI, 1.4% to 12.9%) among participants who initiated therapy in the aspirin, prophylactic apixaban, and therapeutic apixaban groups, respectively, although none were major. Findings inclusive of all randomized patients were similar. Conclusions and Relevance: Among symptomatic clinically stable outpatients with COVID-19, treatment with aspirin or apixaban compared with placebo did not reduce the rate of a composite clinical outcome. However, the study was terminated after enrollment of 9% of participants because of an event rate lower than anticipated. Trial Registration: ClinicalTrials.gov Identifier: NCT04498273.

2.
Neurology ; 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34635557

RESUMO

BACKGROUND AND OBJECTIVE: To evaluate phenotypic and genetic relationships between migraine and lipoprotein subfractions. METHODS: We evaluated phenotypic associations between migraine and 19 lipoprotein subfractions measures in the Women's Genome Health Study (WGHS, N=22,788). We then investigated genetic relationships between these traits using summary statistics from the International Headache Genetics Consortium (IHGC) for migraine (Ncase=54,552, Ncontrol=297,970) and combined summary data for lipoprotein subfractions (N up to 47,713). RESULTS: There 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 (TRLP) concentration but not for LDL or HDL 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 four 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. CONCLUSIONS: The current study supports the association between certain lipoprotein subfractions, especially for TRLP, and migraine in populations of European ancestry. The corresponding shared genetic components may be help identify potential targets for future migraine therapeutics. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that migraine is significantly associated with some lipoprotein subfractions.

4.
J Am Coll Cardiol ; 78(11): 1114-1123, 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34503680

RESUMO

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.

6.
Circ Genom Precis Med ; 14(4): e003288, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34270325

RESUMO

BACKGROUND: ChREBP (carbohydrate responsive element binding protein) is a transcription factor that responds to sugar consumption. Sugar-sweetened beverage (SSB) consumption and genetic variants in the CHREBP locus have separately been linked to HDL-C (high-density lipoprotein cholesterol) and triglyceride concentrations. We hypothesized that SSB consumption would modify the association between genetic variants in the CHREBP locus and dyslipidemia. METHODS: Data from 11 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (N=63 599) and the UK Biobank (N=59 220) were used to quantify associations of SSB consumption, genetic variants, and their interaction on HDL-C and triglyceride concentrations using linear regression models. A total of 1606 single nucleotide polymorphisms within or near CHREBP were considered. SSB consumption was estimated from validated questionnaires, and participants were grouped by their estimated intake. RESULTS: In a meta-analysis, rs71556729 was significantly associated with higher HDL-C concentrations only among the highest SSB consumers (ß, 2.12 [95% CI, 1.16-3.07] mg/dL per allele; P<0.0001), but not significantly among the lowest SSB consumers (P=0.81; PDiff <0.0001). Similar results were observed for 2 additional variants (rs35709627 and rs71556736). For triglyceride, rs55673514 was positively associated with triglyceride concentrations only among the highest SSB consumers (ß, 0.06 [95% CI, 0.02-0.09] ln-mg/dL per allele, P=0.001) but not the lowest SSB consumers (P=0.84; PDiff=0.0005). CONCLUSIONS: Our results identified genetic variants in the CHREBP locus that may protect against SSB-associated reductions in HDL-C and other variants that may exacerbate SSB-associated increases in triglyceride concentrations. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00005133, NCT00005121, NCT00005487, and NCT00000479.

7.
Circ Genom Precis Med ; 14(4): e003330, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34264743

RESUMO

BACKGROUND: Branched-chain amino acids (BCAAs; isoleucine, leucine, and valine) correlate with insulin resistance and poor glucose control, which may in part explain associations between type 2 diabetes and cardiovascular disease. However, the relationships of BCAAs with other cardiometabolic pathways, including inflammation and dyslipidemia, are unclear. We hypothesized that plasma BCAAs would correlate with multiple pathways of cardiometabolic dysfunction. METHODS: We conducted a cross-sectional analysis among 19 472 participants (mean age=54.9 years, SD=7.2 years) in the Women's Health Study without a history of type 2 diabetes, cardiovascular disease, or cancer. We quantified the concentrations of individual biomarkers of inflammation and lipids, across quartiles of BCAAs, adjusting for age, smoking, body mass index, physical activity, and other established cardiovascular disease risk factors at blood draw. RESULTS: Women in the highest versus lowest quartiles of plasma BCAAs had higher inflammatory markers including high-sensitivity C-reactive protein (multivariable-adjusted means: 1.96 versus 1.43 mg/L), fibrinogen (367 versus 362 mg/dL), soluble intercellular cell adhesion molecule-1 (361 versus 353 ng/mL), and glycoprotein acetylation (407 versus 371 µmol/L; P trend=0.0002 for fibrinogen; P<0.0001 for others). Similarly for lipids, women with higher BCAAs had lower HDL-C (high-density lipoprotein cholesterol; 49.0 versus 55.0 mg/dL), and higher triglycerides (143 versus 114 mg/dL), LDL-C (low-density lipoprotein cholesterol; 133 versus 124 mg/dL), and lipoprotein insulin resistance score (52.6 versus 37.3; all: P<0.0001). Similar associations with these biomarkers were observed in isoleucine, leucine, and valine, respectively. CONCLUSIONS: Higher circulating BCAA concentrations are associated with adverse profiles of biomarkers of inflammation and dyslipidemia independent of established cardiovascular disease risk factors, and thus, may reflect poorer cardiometabolic health through multiple pathways. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00000479.

8.
Rheumatology (Oxford) ; 60(6): 2963-2968, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34144603

RESUMO

OBJECTIVES: Methotrexate is widely used at low dosages (LD-MTX) for non-oncologic indications and is associated with a variety of adverse effects (AEs). We sought to determine whether concentrations of the active metabolite, MTX polyglutamates (MTX-PGs) 1-5, correlate with AEs. METHOD: We examined data from the LD-MTX arm of the randomized double-blind Cardiovascular Inflammation Reduction Trial (CIRT). All AEs were blindly adjudicated and monitoring laboratories were tested centrally. The MTX-PGs 1-5 were assessed in one reference laboratory using liquid chromatography-tandem mass spectrometry. Based on prior literature, MTX-PGs 3-5 were chosen as the exposure of interest and quartiles of MTX-PGs 3-5 were assessed for their relationship with all AEs and each pre-specified category of AE using adjusted Cox proportional hazards regression. RESULTS: Of the 2391 subjects randomized to LD-MTX, MTX-PG levels were available for 1319 subjects (median dosage 16.1 mg/week) from the 8 month visit. We followed these subjects for a median of 2.2 years [interquartile range (IQR) 1.5-2.9]. Higher MTX-PG3-5 levels were related to an increased risk of anaemia [compared with quartile 1 (Q1); hazard ratio (HR) for Q4 1.27 (95% CI 0.98, 1.65), P for trend = 0.05] and a decreased risk of thrombocytopenia [HR for Q4 0.52 (95% CI 0.32, 0.84), P for trend = 0.05]. MTX-PG3-5 levels >134 nmol/l were associated with an increased risk of liver abnormalities [HR 1.36 (95% CI 1.08, 1.72)]. CONCLUSIONS: Higher MTX- PG3-5 levels were modestly associated with LD-MTX AEs, including anaemia and liver function abnormalities, but a reduced risk of thrombocytopenia and haemorrhage. CLINICAL TRIAL REGISTRATION: NCT01594333.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Metotrexato/análogos & derivados , Ácido Poliglutâmico/análogos & derivados , Idoso , Antirreumáticos/efeitos adversos , Doenças Cardiovasculares/prevenção & controle , Método Duplo-Cego , Feminino , Humanos , Masculino , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Ácido Poliglutâmico/efeitos adversos
10.
ACR Open Rheumatol ; 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33932148

RESUMO

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.

11.
JAMA Cardiol ; 2021 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-33993205

RESUMO

Importance: In patients treated with ω-3 fatty acids, it remains uncertain whether achieved levels of eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) are associated with cardiovascular outcomes. Objective: To determine the association between plasma levels of EPA and DHA and cardiovascular outcomes in a trial of ω-3 fatty acids compared with corn oil placebo. Design, Setting, and Participants: A double-blind, multicenter trial enrolled patients at high cardiovascular risk with elevated triglyceride levels and low levels of high-density lipoprotein cholesterol at 675 centers (enrollment from October 30, 2014, to June 14, 2017; study termination January 8, 2020; last visit May 14, 2020). Interventions: Participants were randomized to receive 4 g daily of ω-3 carboxylic acid (CA) or an inert comparator, corn oil. Main Outcomes and Measures: The primary prespecified end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization. The primary outcome measure was the hazard ratio, adjusted for baseline characteristics, for patients treated with the ω-3 CA compared with corn oil for the top tertile of achieved EPA and DHA plasma levels 12 months after randomization. Results: Of the 13 078 total participants, 6539 (50%) were randomized to receive ω-3 CA and 6539 (50%) randomized to corn oil. ω-3 Fatty acid levels were available at both baseline and 12 months after randomization in 10 382 participants (5175 ω-3 CA patients [49.8%] and 5207 corn oil-treated patients [50.2%]; mean [SD] age, 62.5 [8.9] years, 3588 [34.6%] were women, 9025 [86.9%] were White, and 7285 [70.2%] had type 2 diabetes). The median plasma levels at 12 months in ω-3 CA patients were 89 µg/mL (interquartile range [IQR], 46-131 µg/mL) for EPA and 91 µg/mL (IQR, 71-114 µg/mL) for DHA with top tertile levels of 151 µg/mL (IQR, 132-181 µg/mL) and 118 µg/mL (IQR, 102-143 µg/mL), respectively. Compared with corn oil, the adjusted hazard ratios for the highest tertile of achieved plasma levels were 0.98 (95% CI, 0.83-1.16; P = .81) for EPA, and 1.02 (95% CI, 0.86-1.20; P = .85 for DHA. Sensitivity analyses based on changes in plasma and red blood cell levels of EPA and DHA and primary and secondary prevention subgroups showed similar results. Conclusions and Relevance: Among patients treated with ω-3 CA, the highest achieved tertiles of EPA and DHA were associated with neither benefit nor harm in patients at high cardiovascular risk. Trial Registration: ClinicalTrials.gov Identifier: NCT02104817.

12.
Circ Res ; 128(11): 1728-1746, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-33998272

RESUMO

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.

13.
Lancet ; 397(10289): 2060-2069, 2021 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-34015342

RESUMO

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<0·0001). Effects were stable over the 24-week treatment period. Dose-dependent reductions were also observed for fibrinogen, serum amyloid A, haptoglobin, secretory phospholipase A2, and lipoprotein(a). Ziltivekimab was well tolerated, did not affect the total cholesterol to HDL cholesterol ratio, and there were no serious injection-site reactions, sustained grade 3 or 4 neutropenia or thrombocytopenia. INTERPRETATION: Ziltivekimab markedly reduced biomarkers of inflammation and thrombosis relevant to atherosclerosis. On the basis of these data, a large-scale cardiovascular outcomes trial will investigate the effect of ziltivekimab in patients with chronic kidney disease, increased high-sensitivity CRP, and established cardiovascular disease. FUNDING: Novo Nordisk.

15.
Neurology ; 96(20): e2481-e2487, 2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-33795393

RESUMO

OBJECTIVE: To assess support for a causal relationship between hemostatic measures and migraine susceptibility using genetic instrumental analysis. METHODS: Two-sample Mendelian randomization instrumental analyses leveraging available genome-wide association study (GWAS) summary statistics were applied to hemostatic measures as potentially causal for migraine and its subtypes, migraine with aura (MA) and migraine without aura (MO). Twelve blood-based measures of hemostasis were examined, including plasma level or activity of 8 hemostatic factors and 2 fibrinopeptides together with 2 hemostasis clinical tests. RESULTS: There were significant instrumental effects between increased coagulation factor VIII activity (FVIII; odds ratio [95% confidence interval] 1.05 [1.03, 1.08]/SD, p = 6.08 × 10-05), von Willebrand factor level (vWF; 1.05 [1.03, 1.08]/SD, p = 2.25 × 10-06), and phosphorylated fibrinopeptide A level (1.13 [1.07, 1.19]/SD, p = 5.44 × 10-06) with migraine susceptibility. When extended to migraine subtypes, FVIII, vWF, and phosphorylated fibrinopeptide A showed slightly stronger effects with MA than overall migraine. Fibrinogen level was inversely linked with MA (0.76 [0.64, 0.91]/SD, p = 2.32 × 10-03) but not overall migraine. None of the hemostatic factors was linked with MO. In sensitivity analysis, effects for fibrinogen and phosphorylated fibrinopeptide A were robust, whereas independent effects of FVIII and vWF could not be distinguished, and FVIII associations were potentially affected by pleiotropy at the ABO locus. Causal effects from migraine to the hemostatic measures were not supported in reverse Mendelian randomization. However, MA was not included due to lack of instruments. CONCLUSIONS: The findings support potential causality of increased FVIII, vWF, and phosphorylated fibrinopeptide A and decreased fibrinogen in migraine susceptibility, especially for MA, potentially revealing etiologic relationships between hemostasis and migraine.


Assuntos
Hemostasia/genética , Enxaqueca com Aura/genética , Enxaqueca sem Aura/genética , Estudos de Casos e Controles , Fator VII/metabolismo , Fator VIII/metabolismo , Fator XI/metabolismo , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Fibrinogênio/metabolismo , Fibrinopeptídeo A/metabolismo , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Coeficiente Internacional Normatizado , Análise da Randomização Mendeliana , Transtornos de Enxaqueca/sangue , Transtornos de Enxaqueca/epidemiologia , Transtornos de Enxaqueca/genética , Enxaqueca com Aura/sangue , Enxaqueca com Aura/epidemiologia , Enxaqueca sem Aura/sangue , Enxaqueca sem Aura/epidemiologia , Tempo de Tromboplastina Parcial , Inibidor 1 de Ativador de Plasminogênio/sangue , Tempo de Protrombina , Ativador de Plasminogênio Tecidual/sangue , Fator de von Willebrand/metabolismo
17.
Eur Heart J ; 42(22): 2170-2185, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-33393990

RESUMO

Chronic kidney disease (CKD) is associated with high cardiovascular risk. CKD patients exhibit a specific lipoprotein pattern termed 'uraemic dyslipidaemia', which is characterized by rather normal low-density lipoprotein cholesterol, low high-density lipoprotein cholesterol, and high triglyceride plasma levels. All three lipoprotein classes are involved in the pathogenesis of CKD-associated cardiovascular diseases (CVDs). Uraemia leads to several modifications of the structure of lipoproteins such as changes of the proteome and the lipidome, post-translational protein modifications (e.g. carbamylation) and accumulation of small-molecular substances within the lipoprotein moieties, which affect their functionality. Lipoproteins from CKD patients interfere with lipid transport and promote inflammation, oxidative stress, endothelial dysfunction as well as other features of atherogenesis, thus contributing to the development of CKD-associated CVD. While, lipid-modifying therapies play an important role in the management of CKD patients, their efficacy is modulated by kidney function. Novel therapeutic agents to prevent the adverse remodelling of lipoproteins in CKD and to improve their functional properties are highly desirable and partially under development.


Assuntos
Doenças Cardiovasculares , Dislipidemias , Insuficiência Renal Crônica , Doenças Cardiovasculares/etiologia , Humanos , Lipoproteínas , Triglicerídeos
18.
J Cardiovasc Comput Tomogr ; 15(4): 372-379, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33390348

RESUMO

BACKGROUND: 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. METHODS: 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. RESULTS: Patients with above average NLR (>mean: 2.29 â€‹± â€‹1.21) were older (mean â€‹± â€‹SD; 52.0 â€‹± â€‹12.8 vs. 47.9 â€‹± â€‹12.6, p â€‹= â€‹0.002), had higher hs-CRP (med. IQR: 2.3 (0.9-7.3) vs. 1.4 (0.7-3.2), p â€‹= â€‹0.001) and had higher NCB (mean â€‹± â€‹SD; 1.21 â€‹± â€‹0.58 vs. 1.13 â€‹± â€‹0.49, p â€‹= â€‹0.018) when compared to patients with below average NLR. NLR associated with psoriasis area severity index score (ߠ​= â€‹0.14, p â€‹= â€‹0.017), hs-CRP (ߠ​= â€‹0.16, p â€‹= â€‹0.005), as well as NCB independent of traditional risk factors, body mass index, statin use and hs-CRP (ߠ​= â€‹0.08, p â€‹= â€‹0.009). One year of biologic therapy for psoriasis was associated with a reduction in NLR (-14.5%, p â€‹< â€‹0.001), and this change in NLR associated with change in NCB in fully adjusted models and beyond hs-CRP (ߠ​= â€‹0.17, p â€‹= â€‹0.002). CONCLUSION: 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.

19.
Eur Heart J ; 42(9): 896-903, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33417682

RESUMO

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 < 0.0001], 31% in SPIRE-1 (95% CI 14-49%, P = 0.00007), 27% in SPIRE-2 (95% CI 12-43%, P = 0.0002), 9% in CIRT (95% CI 0.2-20%, P = 0.045), and 11% in JUPITER (95% CI 1-22%, P = 0.03). While lipid-lowering agents had no significant impact on the NLR, anti-inflammatory therapy with canakinumab lowered the NLR (P < 0.0001). CONCLUSION: The NLR, an easily obtained inflammatory biomarker, independently predicts CV risk and all-cause mortality, and is reduced by interleukin-1ß blockade with canakinumab.


Assuntos
Aterosclerose , Neutrófilos , Anticorpos Monoclonais , Aterosclerose/tratamento farmacológico , Humanos , Linfócitos , Ensaios Clínicos Controlados Aleatórios como Assunto
20.
JAMA Cardiol ; 6(4): 437-447, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33471027

RESUMO

Importance: Risk profiles for premature coronary heart disease (CHD) are unclear. Objective: To examine baseline risk profiles for incident CHD in women by age at onset. Design, Setting, and Participants: A prospective cohort of US female health professionals participating in the Women's Health Study was conducted; median follow-up was 21.4 years. Participants included 28 024 women aged 45 years or older without known cardiovascular disease. Baseline profiles were obtained from April 30, 1993, to January 24, 1996, and analyses were conducted from October 1, 2017, to October 1, 2020. Exposures: More than 50 clinical, lipid, inflammatory, and metabolic risk factors and biomarkers. Main Outcomes and Measures: Four age groups were examined (<55, 55 to <65, 65 to <75, and ≥75 years) for CHD onset, and adjusted hazard ratios (aHRs) were calculated using stratified Cox proportional hazard regression models with age as the time scale and adjusting for clinical factors. Women contributed to different age groups over time. Results: Of the clinical factors in the women, diabetes had the highest aHR for CHD onset at any age, ranging from 10.71 (95% CI, 5.57-20.60) at CHD onset in those younger than 55 years to 3.47 (95% CI, 2.47-4.87) at CHD onset in those 75 years or older. Risks that were also noted for CHD onset in participants younger than 55 years included metabolic syndrome (aHR, 6.09; 95% CI, 3.60-10.29), hypertension (aHR, 4.58; 95% CI, 2.76-7.60), obesity (aHR, 4.33; 95% CI, 2.31-8.11), and smoking (aHR, 3.92; 95% CI, 2.32-6.63). Myocardial infarction in a parent before age 60 years was associated with 1.5- to 2-fold risk of CHD in participants up to age 75 years. From approximately 50 biomarkers, lipoprotein insulin resistance had the highest standardized aHR: 6.40 (95% CI, 3.14-13.06) for CHD onset in women younger than 55 years, attenuating with age. In comparison, weaker but significant associations with CHD in women younger than 55 years were noted (per SD increment) for low-density lipoprotein cholesterol (aHR, 1.38; 95% CI, 1.10-1.74), non-high-density lipoprotein cholesterol (aHR, 1.67; 95% CI, 1.36-2.04), apolipoprotein B (aHR, 1.89; 95% CI, 1.52-2.35), triglycerides (aHR, 2.14; 95% CI, 1.72-2.67), and inflammatory biomarkers (1.2- to 1.8-fold)-all attenuating with age. Some biomarkers had similar CHD age associations (eg, physical inactivity, lipoprotein[a], total high-density lipoprotein particles), while a few had no association with CHD onset at any age. Most risk factors and biomarkers had associations that attenuated with increasing age at onset. Conclusions and Relevance: In this cohort study, diabetes and insulin resistance, in addition to hypertension, obesity, and smoking, appeared to be the strongest risk factors for premature onset of CHD. Most risk factors had attenuated relative rates at older ages.

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