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1.
Circulation ; 2021 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-33849281

RESUMO

Background: The novel ABC (Age, Biomarkers, Clinical History) scores outperform traditional risk scores for stroke, major bleeding and death in patients with atrial fibrillation (AF) receiving oral anticoagulation. To refine their utility, the ABC-AF scores needed to be validated in patients not receiving oral anticoagulation. Methods: We measured plasma levels of the ABC biomarkers (N-terminal pro-B-type natriuretic peptide, cardiac troponin-T and growth-differentiation factor-15) to apply the previously developed ABC-AF scores in patients with AF receiving aspirin (n=3,195) or aspirin and clopidogrel (n=1,110) in two large clinical trials. Calibration was assessed by comparing estimated with observed one-year risks. Cox-regression models were used for recalibration. Discrimination was evaluated separately for the aspirin only and the overall cohort (n=4,305). Results: The ABC-AF-stroke score yielded a c-index of 0.70 (95% confidence interval [CI] 0.67-0.73) in both cohorts. The ABC-AF-bleeding score had a c-index of 0.76 (95% CI 0.71-0.81) in the aspirin only cohort and 0.73 (95% CI 0.69-0.77) overall. Both scores were superior to risk scores recommended by current guidelines. The ABC-AF-death score yielded a c-index of 0.78 (95% CI 0.76-0.80) overall. Calibrated in patients receiving oral anticoagulation, the ABC-AF-stroke score underestimated, and the ABC-AF-bleeding score overestimated the risk of events in both cohorts. These scores were recalibrated for prediction of absolute event rates in the absence of oral anticoagulation. Conclusions: The biomarker-based ABC-AF scores showed better discrimination than traditional risk scores and were recalibrated for precise risk estimation in patients not receiving oral anticoagulation. They can now provide improved decision support regarding treatment of an individual patient with AF.

2.
Eur Heart J ; 2021 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-33748830

RESUMO

AIMS: Inflammation plays an important role in cardiovascular disease (CVD) development. The NOD-like receptor protein-3 (NLRP3) inflammasome contributes to the development of atherosclerosis in animal models. Components of the NLRP3 inflammasome pathway such as interleukin-1ß can therapeutically be targeted. Associations of genetically determined inflammasome-mediated systemic inflammation with CVD and mortality in humans are unknown. METHODS AND RESULTS: We explored the association of genetic NLRP3 variants with prevalent CVD and cardiovascular mortality in 538 167 subjects on the individual participant level in an explorative gene-centric approach without performing multiple testing. Functional relevance of single-nucleotide polymorphisms on NLRP3 inflammasome activation has been evaluated in monocyte-enriched peripheral blood mononuclear cells (PBMCs). Genetic analyses identified the highly prevalent (minor allele frequency 39.9%) intronic NLRP3 variant rs10754555 to affect NLRP3 gene expression. rs10754555 carriers showed significantly higher C-reactive protein and serum amyloid A plasma levels. Carriers of the G allele showed higher NLRP3 inflammasome activation in isolated human PBMCs. In carriers of the rs10754555 variant, the prevalence of coronary artery disease was significantly higher as compared to non-carriers with a significant interaction between rs10754555 and age. Importantly, rs10754555 carriers had significantly higher risk for cardiovascular mortality during follow-up. Inflammasome inducers (e.g. urate, triglycerides, apolipoprotein C3) modulated the association between rs10754555 and mortality. CONCLUSION: The NLRP3 intronic variant rs10754555 is associated with increased systemic inflammation, inflammasome activation, prevalent coronary artery disease, and mortality. This study provides evidence for a substantial role of genetically driven systemic inflammation in CVD and highlights the NLRP3 inflammasome as a therapeutic target.

3.
Open Heart ; 8(1)2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33741689

RESUMO

OBJECTIVES: Growth differentiation factor 15 (GDF-15) is a biomarker independently associated with bleeding and death in anticoagulated patients with atrial fibrillation (AF). GDF-15 is also used as one component in the more precise biomarker-based ABC (age, biomarkers, clinical history)-AF-bleeding and ABC-AF-death risk scores. Data from large trials indicate a geographic variability in regard to overall outcomes, including bleeding and mortality risk. Our aim was to assess the consistency of the association between GDF-15, ABC-AF-bleeding score and ABC-AF-death score, with major bleeding and death, across world geographic regions. METHODS: Data were available from 14 767 patients with AF from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial and 8651 patients with AF from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial in this cohort study. GDF-15 was analysed from plasma samples obtained at randomisation. The geographical consistency of the associations between outcomes and GDF-15, ABC-AF-bleeding score and ABC-AF-death scores were assessed by Cox-regression models including interactions with predefined geographical region. RESULTS: GDF-15 and the ABC-AF-bleeding score were associated with major bleeding in both trials across regions (p<0.0001). Similarly, GDF-15 and the ABC-AF-death score were associated with all-cause mortality in both trials across regions (p<0.0001). Overall, the association between GDF-15, the ABC-AF-bleeding score and ABC-AF-death risk score with major bleeding and death was consistent across regions in both ARISTOTLE and the RE-LY trial cohorts. The ABC-AF-bleeding and ABC-AF-death risk scores were consistent regarding discriminative ability when comparing geographic regions in both trial cohorts. The C-indices ranged from 0.649 to 0.760 for the ABC-AF-bleeding and from 0.677 to 0.806 for the ABC-AF-death score by different geographic regions. CONCLUSIONS: In patients with AF on anticoagulation, GDF-15 and the biomarker-based ABC-AF-bleeding and ABC-AF-death risk scores are consistently associated with respectively increased risk of major bleeding and death and have similar prognostic value across world geographic regions. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry NCT00412984 and NCT00262600.

4.
Am J Cardiol ; 2021 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-33757788

RESUMO

Prevalence of atrial fibrillation (AF) increases with age, along with comorbidities and, thus, polypharmacy. Non-adherence is associated with polypharmacy. This study aimed to identify patients at risk for cardiovascular events according to their pharmacological treatment intensity and adherence. Patients (n=18,113) with a mean age of 71.5±8.7 years, at high cardiovascular risk were followed between December 2005 until December 2007 for a median time of 2 years. The association between polypharmacy and adherence and their impact on cardiovascular and bleeding events were explored. Adherence was defined as a study drug intake of ≥80%. Patients with more co-medications had a higher body mass index, higher prevalence of hypertension, coronary heart disease, heart failure, and diabetes mellitus (all p<0.0001) compared to ≤4 or 5-8 co-medications, but no differences in history of stroke (p=0.68) or transient ischemic attack (p=0.065). Across all treatments, the adjusted hazard ratios (HRs) increased in patients with more co-medications (>=9 vs <=4) for all-cause death (HR 1.30; 1.06-1.59), major bleeding (HR 1.65; 1.33-2.05), and all bleeding events (HR 1.44; 1.31-1.59). Yearly event rates were higher in non-adherent than adherent patients for stroke and systemic embolism (SSE) (3.14 vs 1.00), all-cause death (7.76 vs. 2.66), major bleeding (6.21 vs. 2.65), and all bleeding (28.71 vs. 19.05; all p<0.0001). After an event the patients were more likely to become non-adherent (adherence after SSE 30.3%, after major bleeding 33.4%, after all bleeding 66.7%; all p<0.0001). The treatment effects were consistent to the overall group in the different polypharmacy groups. In conclusion, polypharmacy and non-adherence are risk indicators for increased adverse cardiovascular and bleeding events. Dabigatran is safe to use across the full spectrum of AF patients, independent of the number of co-medications and adherence. Patients with co-medications and comorbidities require special attention and encouragement to adhere to oral anticoagulation.

6.
Cardiovasc Res ; 2021 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-33386845

RESUMO

AIMS: Patients with atrial fibrillation (AF) and rheumatic heart disease (RHD), especially mitral stenosis, are assumed to be at high risk of stroke, irrespective of other factors. We aimed to re-evaluate stroke risk factors in a contemporary cohort of AF patients. METHODS AND RESULTS: We analyzed data of 15,400 AF patients presenting to an emergency department and who were enrolled in the global RE-LY AF registry, representing 47 countries from all inhabited continents. Follow-up occurred at 1 year after enrollment. A total of 1,788 (11.6%) patients had RHD. These patients were younger (51.4 ± 15.7 vs. 67.8 ± 13.6 years), more likely to be female (66.2% vs. 44.7%) and had a lower mean CHA2DS2-VASc score (2.1 ± 1.7 vs. 3.7 ± 2.2) as compared to patients without RHD (all p < 0.001). Significant mitral stenosis (average mean transmitral gradient 11.5 ± 6.5 mmHg) was the predominant valve lesion in those with RHD (59.6%). Patients with RHD had a higher baseline rate of anticoagulation use (60.4% vs. 45.2%, p < 0.001). Unadjusted stroke rates at 1 year were 2.8% and 4.1% for patients with and without RHD, respectively. The performance of the CHA2DS2-VASc score was modest in both groups (stroke at 1 year, c-statistics 0.69, 95% confidence interval [CI] 0.60-0.78 and 0.63, 95% CI 0.61-0.66, respectively). In the overall cohort, advanced age, female sex, prior stroke, tobacco use and non-use of anticoagulation were predictors for stroke (all p < 0.05). Mitral stenosis was not associated with stroke risk (adjusted odds ratio 1.07, 95% CI 0.67-1.72, p = 0.764). CONCLUSIONS: The performance of the CHA2DS2-VASc score was modest in AF patients both with and without RHD. In this cohort, moderate-to-severe mitral stenosis was not an independent risk factor for stroke. TRANSLATIONAL PERSPECTIVE: Based on studies conducted several decades ago, the presence of moderate-to-severe mitral stenosis has been associated with a very high risk of stroke in patients with AF. Our results, based on a large, global sample of contemporary patients with AF that contained a significant proportion of individuals with RHD, challenge the assumption that mitral stenosis is a major, independent risk factor for stroke. The performance of the widely used CHA2DS2-VASc score was modest in both patients with and without RHD. At least one ongoing randomized trial is evaluating the optimal antithrombotic strategy in patients with AF and RHD.

7.
Am Heart J ; 233: 92-101, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33400910

RESUMO

BACKGROUND: In patients with coronary heart disease (CHD), atrial fibrillation (AF) is associated with increased morbidity and mortality. We investigated the associations between clinical risk factors and biomarkers with incident AF in patients with CHD. METHODS AND RESULTS: Around 13,153 patients with optimally treated CHD included in the STabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY (STABILITY) trial with plasma samples obtained at randomization. Mean follow-up time was 3.5 years. The association between clinical risk factors and biomarkers with incident AF was estimated with Cox-regression models. Validation was performed in 1,894 patients with non-ST-elevation acute coronary syndrome included in the FRISC-II trial. The median (min-max) age was 64 years (range 26-92) and 2,514 (19.1%) were women. A total of 541 patients, annual incidence rate of 1.2%, developed AF during follow-up. In multivariable models, older age, higher levels of NT-proBNP, higher body mass index (BMI), male sex, geographic regions, low physical activity, and heart failure were independently associated with increased risk of incident AF with hazard ratios ranging from 1.04 to 1.79 (P ≤ .05). NT-proBNP improved the C-index from 0.70 to 0.71. In the validation cohort, age, BMI, and NT-proBNP were associated with increased risk of incident AF with similar hazard ratios. CONCLUSIONS: In patients with optimally treated CHD, the incidence of new AF was 1.2% per year. Age, NT-proBNP as a marker of impaired cardiac function, and BMI were the strongest factors, independently and consistently associated with incident AF. Male sex and low physical activity may also contribute to the risk of AF in patients with CHD.


Assuntos
Fibrilação Atrial/sangue , Doença das Coronárias/sangue , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Índice de Massa Corporal , Doença das Coronárias/tratamento farmacológico , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Comportamento Sedentário , Fatores Sexuais
8.
PLoS Med ; 18(1): e1003513, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33439866

RESUMO

BACKGROUND: Circulating biomarkers are associated with the development of coronary heart disease (CHD) and its complications by reflecting pathophysiological pathways and/or organ dysfunction. We explored the associations between 157 cardiovascular (CV) and inflammatory biomarkers and CV death using proximity extension assays (PEA) in patients with chronic CHD. METHODS AND FINDINGS: The derivation cohort consisted of 605 cases with CV death and 2,788 randomly selected non-cases during 3-5 years follow-up included in the STabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY (STABILITY) trial between 2008 and 2010. The replication cohort consisted of 245 cases and 1,042 non-cases during 12 years follow-up included in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study between 1997 and 2000. Biomarker levels were measured with conventional immunoassays and/or with the OLINK PEA panels CVD I and Inflammation. Associations with CV death were evaluated by Random Survival Forest (RF) and Cox regression analyses. Both cohorts had the same median age (65 years) and 20% smokers, while there were slight differences in male sex (82% and 76%), hypertension (70% and 78%), and diabetes (39% and 30%) in the respective STABILITY and LURIC cohorts. The analyses identified 18 biomarkers with confirmed independent association with CV death by Boruta analyses and statistical significance (all p < 0.0001) by Cox regression when adjusted for clinical characteristics in both cohorts. Most prognostic information was carried by N-terminal prohormone of brain natriuretic peptide (NTproBNP), hazard ratio (HR for 1 standard deviation [SD] increase of the log scale of the distribution of the biomarker in the replication cohort) 2.079 (95% confidence interval [CI] 1.799-2.402), and high-sensitivity troponin T (cTnT-hs) HR 1.715 (95% CI 1.491-1.973). The other proteins with independent associations were growth differentiation factor 15 (GDF-15) HR 1.728 (95% CI 1.527-1.955), transmembrane immunoglobulin and mucin domain protein (TIM-1) HR 1.555 (95% CI 1.362-1.775), renin HR 1.501 (95% CI 1.305-1.727), osteoprotegerin (OPG) HR 1.488 (95% CI 1.297-1.708), soluble suppression of tumorigenesis 2 protein (sST2) HR 1.478 (95% CI 1.307-1.672), cystatin-C (Cys-C) HR 1.370 (95% CI 1.243-1.510), tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) HR 1.205 (95% CI 1.131-1.285), carbohydrate antigen 125 (CA-125) HR 1.347 (95% CI 1.226-1.479), brain natriuretic peptide (BNP) HR 1.399 (95% CI 1.255-1.561), interleukin 6 (IL-6) HR 1.478 (95% CI 1.316-1.659), hepatocyte growth factor (HGF) HR 1.259 (95% CI 1.134-1.396), spondin-1 HR 1.295 (95% CI 1.156-1.450), fibroblast growth factor 23 (FGF-23) HR 1.349 (95% CI 1.237-1.472), chitinase-3 like protein 1 (CHI3L1) HR 1.284 (95% CI 1.129-1.461), tumor necrosis factor receptor 1 (TNF-R1) HR 1.486 (95% CI 1.307-1.689), and adrenomedullin (AM) HR 1.750 (95% CI 1.490-2.056). The study is limited by the differences in design, size, and length of follow-up of the 2 studies and the lack of results from coronary angiograms and follow-up of nonfatal events. CONCLUSIONS: Profiles of levels of multiple plasma proteins might be useful for the identification of different pathophysiological pathways associated with an increased risk of CV death in patients with chronic CHD. TRIAL REGISTRATION: ClinicalTrials.gov NCT00799903.

9.
Am Heart J ; 2020 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-33296688

RESUMO

BACKGROUND: Non-vitamin K antagonist oral anticoagulants (NOACs) are the preferred class of medications for prevention of stroke and systemic embolism in patients with atrial fibrillation unless contraindications exist. Five large, international, randomized, controlled trials of NOACs versus either warfarin or aspirin have been completed to date. DESIGN: COMBINE AF incorporates de-identified individual patient data from 77,282 patients with atrial fibrillation at risk for stroke randomized to NOAC, warfarin, or aspirin from 5 pivotal randomized controlled trials. All patients randomized in the constituent trials are included. Variables common to ≥3 of the constituent trials are included in the master database. Individual trial data sets from the 4 coordinating centers were combined at the Duke Clinical Research Institute. The final database will be securely shared with the 4 academic coordinating centers. The combined master database will be used to perform statistical analyses aimed at better understanding underlying risk factors and outcomes in patients with atrial fibrillation treated with oral anticoagulants, with a special focus on patient subgroups and uncommon outcomes. The initial analysis from COMBINE AF will be a network meta-analysis investigating the relative efficacy and safety of pooled higher-dose NOACs versus pooled lower-dose NOACs versus warfarin with respect to multiple time-to-event efficacy and safety outcomes. COMBINE AF is registered with PROSPERO (CRD42020178771). CONCLUSIONS: In conclusion, COMBINE AF provides a rich and robust database consisting of individual patient data and will offer opportunities to investigate oral anticoagulants across many patient subgroups. Data sharing and collaboration across academic institutions and investigators will serve as overarching themes.

10.
J Am Heart Assoc ; : e018984, 2020 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-33292046

RESUMO

Background To explore the pathophysiological features of ischemic stroke in patients with atrial fibrillation (AF), we evaluated the association between 268 plasma proteins and subsequent ischemic stroke in 2 large AF cohorts receiving oral anticoagulation. Methods and Results A case-cohort sample of patients with AF from the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, including 282 cases with ischemic stroke or systemic embolism and a random sample of 4124 without these events, during 1.9 years of follow-up was used for identification. Validation was provided by a similar case-cohort sample of patients with AF from the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial, including 149 cases with ischemic stroke/systemic embolism and a random sample of 1062 without these events. In plasma obtained before randomization, 268 unique biomarkers were measured with OLINK proximity extension assay panels (CVD II, CVD III, and Inflammation) and conventional immunoassays. The association between biomarkers and outcomes was evaluated by random survival forest and adjusted Cox regression. According to random survival forest or Cox regression analyses, the biomarkers most strongly and consistently associated with ischemic stroke/systemic embolism were matrix metalloproteinase-9, NT-proBNP (N-terminal pro-B-type natriuretic peptide), osteopontin, sortilin, soluble suppression of tumorigenesis 2, and trefoil factor-3. The corresponding hazard ratios (95% CIs) for an interquartile difference were as follows: 1.18 (1.00-1.38), 1.55 (1.28-1.88), 1.28 (1.07-1.53), 1.19 (1.02-1.39), 1.23 (1.05-1.45), and 1.19 (0.97-1.45), respectively. Conclusions In patients with AF, of 268 unique biomarkers, the 6 biomarkers most strongly associated with subsequent ischemic stroke/systemic embolism represent fibrosis/remodeling (matrix metalloproteinase-9 and soluble suppression of tumorigenesis 2), cardiac dysfunction (NT-proBNP), vascular calcification (osteopontin), metabolism (sortilin), and mucosal integrity/ischemia (trefoil factor-3). Registration URL: https://www.clinicaltrials.gov. Unique Identifiers: NCT00412984 and NCT00262600.

11.
Artigo em Inglês | MEDLINE | ID: mdl-33367487

RESUMO

AIMS: Whether diabetes without insulin therapy is an independent cardiovascular (CV) risk factor in atrial fibrillation (AF) has recently been questioned. We investigated the prognostic relevance of diabetes with or without insulin treatment in patients in the ARISTOTLE trial. METHODS AND RESULTS: Patients with AF and increased stroke risk randomized to apixaban vs. warfarin were classified according to diabetes status: no diabetes; diabetes on no diabetes medications; diabetes on non-insulin antidiabetic drugs only; or insulin-treated. The associations between such patient subgroups and stroke/systemic embolism (SE), myocardial infarction (MI), and CV death were examined by Cox proportional hazard regression, both unadjusted and adjusted for other prognostic variables. Patients with diabetes were younger and had a higher body mass index. Median CHA2DS2VASc score was 4.0 in patients with diabetes and 3.0 in patients without diabetes. We found no significant difference in stroke/SE incidence across patient subgroups. Compared with no diabetes, only insulin-treated diabetes was significantly associated with higher risk. When adjusted for clinical variables, compared with no diabetes, the hazard ratios (HRs) for MI (95% confidence intervals) were for diabetes on no medication: 1.15 (0.62-2.14); for diabetes on non-insulin antidiabetic drugs: 1.32 (0.90-1.94); for insulin-treated diabetes: 2.34 (1.43-3.82); interaction P = 0.008. HRs for CV death were for diabetes on no medication: 1.19 (0.86-166); for diabetes on non-insulin antidiabetic drugs: 1.12 (0.88-1.42); for insulin-treated diabetes 1.85 (1.36-2.53), interaction P = 0.001. CONCLUSION: In anticoagulated patients with AF, a higher risk of MI and CV death is largely confined to diabetes treated with insulin.

12.
Heart ; 2020 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-32938772

RESUMO

AIMS: The ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial randomised patients with atrial fibrillation at risk of stroke to apixaban or warfarin. We sought to describe patients from ARISTOTLE who prematurely permanently discontinued study drug. METHODS/RESULTS: We performed a posthoc analysis of patients from ARISTOTLE who prematurely permanently discontinued study drug during the study or follow-up period. Discontinuation rates and reasons for discontinuation were described. Death, thromboembolism (stroke, transient ischaemic attack, systemic embolism), myocardial infarction and major bleeding rates were stratified by ≤30 days or >30 days after discontinuation. A total of 4063/18 140 (22.4%) patients discontinued study drug at a median of 7.3 (2.2, 15.2) months after randomisation. Patients with discontinuation were more likely to be female and had a higher prevalence of cardiovascular disease, diabetes, renal impairment and anaemia. Premature permanent discontinuation was more common in those randomised to warfarin than apixaban (23.4% vs 21.4%; p=0.002). The most common reasons for discontinuation were patient request (46.1%) and adverse event (34.9%), with no significant difference between treatment groups. The cumulative incidence of clinical events ≤30 days after premature permanent discontinuation for all-cause death, thromboembolism, myocardial infarction, and major bleeding was 5.8%, 2.6%, 0.9%, and 3.0%, respectively. No significant difference was seen between treatment groups with respect to clinical outcomes after discontinuation. CONCLUSION: Premature permanent discontinuation of study drug in ARISTOTLE was common, less frequent in patients receiving apixaban than warfarin and was followed by high 30-day rates of death, thromboembolism and major bleeding. Initiatives are needed to reduce discontinuation of oral anticoagulation.

13.
Eur Heart J ; 41(41): 4037-4046, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32984892

RESUMO

AIMS: The global COVID-19 pandemic is caused by the SARS-CoV-2 virus entering human cells using angiotensin-converting enzyme 2 (ACE2) as a cell surface receptor. ACE2 is shed to the circulation, and a higher plasma level of soluble ACE2 (sACE2) might reflect a higher cellular expression of ACE2. The present study explored the associations between sACE2 and clinical factors, cardiovascular biomarkers, and genetic variability. METHODS AND RESULTS: Plasma and DNA samples were obtained from two international cohorts of elderly patients with atrial fibrillation (n = 3999 and n = 1088). The sACE2 protein level was measured by the Olink Proteomics® Multiplex CVD II96 × 96 panel. Levels of the biomarkers high-sensitive cardiac troponin T (hs-cTnT), N-terminal probrain natriuretic peptide (NT-proBNP), growth differentiation factor 15 (GDF-15), C-reactive protein, interleukin-6, D-dimer, and cystatin-C were determined by immunoassays. Genome-wide association studies were performed by Illumina chips. Higher levels of sACE2 were statistically significantly associated with male sex, cardiovascular disease, diabetes, and older age. The sACE2 level was most strongly associated with the levels of GDF-15, NT-proBNP, and hs-cTnT. When adjusting for these biomarkers, only male sex remained associated with sACE2. We found no statistically significant genetic regulation of the sACE2 level. CONCLUSIONS: Male sex and clinical or biomarker indicators of biological ageing, cardiovascular disease, and diabetes are associated with higher sACE2 levels. The levels of GDF-15 and NT-proBNP, which are associated both with the sACE2 level and a higher risk for mortality and cardiovascular disease, might contribute to better identification of risk for severe COVID-19 infection.


Assuntos
Fibrilação Atrial/sangue , Betacoronavirus , Infecções por Coronavirus/sangue , Peptidil Dipeptidase A/sangue , Pneumonia Viral/sangue , Idoso , Antitrombinas/uso terapêutico , Fibrilação Atrial/complicações , Fibrilação Atrial/tratamento farmacológico , Biomarcadores/sangue , Estudos de Coortes , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/epidemiologia , Dabigatrana/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/epidemiologia , Pirazóis/uso terapêutico , Piridonas/uso terapêutico , Fatores de Risco , Acidente Vascular Cerebral/prevenção & controle , Varfarina/uso terapêutico
14.
JAMA Netw Open ; 3(9): e2015943, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32936298

RESUMO

Importance: Most patients with atrial fibrillation (AF) and coronary artery disease have indications for preventing stroke with oral anticoagulation therapy and preventing myocardial infarction and stent thrombosis with platelet inhibition. Objective: To evaluate whether the recently developed ABC (age, biomarkers, and clinical history)-bleeding risk score might be useful to identify patients with AF with different risks of bleeding during concomitant aspirin and anticoagulation therapy. Design, Setting, and Participants: The biomarkers in the ABC-bleeding risk score (growth differentiation factor 15, hemoglobin, and troponin) were measured in blood samples collected at randomization between 2006 and 2010 in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial and between 2005 and 2009 in the RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) trial, both of which were multinational randomized clinical trials. The trials were reported 2011 and 2009, respectively. A total of 24 349 patients with AF (14 980 patients from the ARISTOTLE trial and 9369 patients from the RE-LY trial) were analyzed in the present cohort study. The median (interquartile range) length of follow-up was 1.8 (1.3-2.3) years in the ARISTOTLE cohort and 2.0 (1.6-2.3) years in the RE-LY cohort. Data analysis was performed from February 2018 to June 2019. Exposures: Concomitant aspirin treatment during study follow-up. Main Outcomes and Measures: Time to first occurrence of a major bleeding was determined according to International Society on Thrombosis and Hemostasis definition. Hazard ratios were estimated with Cox models adjusted for ABC-bleeding risk score and randomized treatment. Results: The median (interquartile range) age was 70 (63-76) years in the ARISTOTLE cohort and 72 (67-77) years in the RE-LY cohort (5238 patients [35.6%] in the ARISTOTLE cohort and 3086 patients [36.4%] in the RE-LY cohort were women). The total number of patients with a first major bleeding event was 651 (207 with aspirin and 444 without) in ARISTOTLE and 463 (238 with aspirin and 225 without) in RE-LY. For both cohorts, in those with a low ABC-bleeding risk score, the absolute bleeding rate was low even with concomitant aspirin treatment, whereas in those with a higher ABC-bleeding risk score, the rate of bleeding was higher with concomitant aspirin compared with oral anticoagulation alone (ARISTOTLE, hazard ratio, 1.65; 95% CI, 1.40-1.95; P < .001; RE-LY, hazard ratio, 1.70; 95% CI, 1.42-2.04; P < .001). Thus, a low annual ABC-bleeding risk (eg, 0.5% without aspirin use) would with concomitant aspirin result in an annual rate of 0.8%, and a high estimated ABC-bleeding risk (eg, 3.0%) would result in a substantially higher rate of 5.0%. Conclusions and Relevance: These findings suggest that the ABC-bleeding risk score identifies patients with different risks of bleeding when combining aspirin and oral anticoagulation. The ABC-bleeding risk score may, therefore, be a useful tool for decision support concerning intensity and duration of combination antithrombotic treatment in patients with AF and coronary artery disease.

15.
J Am Heart Assoc ; 9(18): e017155, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32865097

RESUMO

Background We compared different methods of estimated glomerular filtration rate (eGFR) and their association with cardiovascular death and major bleeding in 14 980 patients with atrial fibrillation in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial. Methods and Results eGFR was calculated using equations based on creatinine (Cockcroft-Gault, Modification of Diet in Renal Disease, and Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) and/or cystatin C (CKD-EPICysC and CKD-EPICysC+Creatinine). These 5 eGFR equations, as well as the individual variables that are used in these equations, were assessed for correlation and discriminatory ability for cardiovascular death and major bleeding. The median age was 70.0 years, and 35.6% were women. The median eGFR was highest with Cockcroft-Gault (74.1 mL/min) and CKD-EPICysC (74.2 mL/min), and lowest with Modification of Diet in Renal Disease (66.5 mL/min). Correlation between methods ranged from 0.49 (Cockroft-Gault and CKD-EPICysC) to 0.99 (Modification of Diet in Renal Disease and CKD-EPI). Among the eGFR equations, those based on cystatin C yielded the highest C indices for cardiovascular death and major bleeding: 0.628 (CKD-EPICysC) and 0.612 (CKD-EPICysC+Creatinine), respectively. A model based on the variables within the different eGFR equations (age, sex, weight, creatinine, and cystatin C) yielded the highest discriminatory value for both outcomes, with a C index of 0.673 and 0.656, respectively. Conclusions In patients with atrial fibrillation on anticoagulation, correlation between eGFR calculated using different methods varied substantially. Cystatin C-based eGFRs seem to provide the most robust information for predicting death and bleeding. A model based on the individual variables within the eGFR equations, however, provided the highest discriminatory value. Our findings may help refine risk stratification in patients with atrial fibrillation and define how renal function should be determined in future atrial fibrillation studies. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT00412984.

16.
J Am Heart Assoc ; 9(17): e016360, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32809893

RESUMO

Background The cysteine protease legumain is increased in patients with atherosclerosis, but its causal role in atherogenesis and cardiovascular disease is still unclear. The aim of the study was to investigate the association of legumain with clinical outcome in a large cohort of patients with acute coronary syndrome. Methods and Results Serum levels of legumain were analyzed in 4883 patients with acute coronary syndrome from a substudy of the PLATO (Platelet Inhibition and Patient Outcomes) trial. Levels were analyzed at admission and after 1 month follow-up. Associations between legumain and a composite of cardiovascular death, spontaneous myocardial infarction or stroke, and its individual components were assessed by multivariable Cox regression analyses. At baseline, a 50% increase in legumain level was associated with a hazard ratio (HR) of 1.13 (95% CI, 1.04-1.21), P=0.0018, for the primary composite end point, adjusted for randomized treatment. The association remained significant after adjustment for important clinical and demographic variables (HR, 1.10; 95% CI, 1.02-1.19; P=0.013) but not in the fully adjusted model. Legumain levels at 1 month were not associated with the composite end point but were negatively associated with stroke (HR, 0.62; 95% CI, 0.44-0.88; P=0.0069), including in the fully adjusted model (HR, 0.57; 95% CI, 0.37-0.88; P=0.0114). Conclusions Baseline legumain was associated with the primary outcome in patients with acute coronary syndrome, but not in the fully adjusted model. The association between high levels of legumain at 1 month and decreased occurrence of stroke could be of interest from a mechanistic point of view, illustrating the potential dual role of legumain during atherogenesis and acute coronary syndrome. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT00391872.

17.
Artigo em Inglês | MEDLINE | ID: mdl-32845314

RESUMO

AIMS: It is increasingly recognised that tools are required for assessing and benchmarking quality of care in order to improve it. The European Society of Cardiology (ESC) is developing a suite of quality indicators (QIs) to evaluate cardiovascular care and support the delivery of evidence-based care. This paper describes the methodology used for their development. METHODS AND RESULTS: We propose a four-step process for the development of the ESC QIs. For a specific clinical area with a gap in care delivery, the QI development process includes: 1) the identification of key domains of care by constructing a conceptual framework of care; 2) the construction of candidate QIs by conducting a systematic review of the literature; 3) the selection of a final set of QIs by obtaining expert opinions using the modified Delphi method; and 4) the undertaking of a feasibility assessment by evaluating different ways of defining the QI specifications for the proposed data collection source. For each of the four steps, key methodological areas need to be addressed to inform the implementation process and avoid misinterpretation of the measurement results. CONCLUSION: Detailing the methodology for the ESC QIs construction enables healthcare providers to develop valid and feasible metrics to measure and improve the quality of cardiovascular care. As such, high-quality evidence may be translated into clinical practice and the 'evidence-practice' gap closed.

18.
Artigo em Inglês | MEDLINE | ID: mdl-32623598

RESUMO

PURPOSE: Describe CYP2C19 sequencing results in the largest series of clopidogrel-treated cases with stent thrombosis (ST), the closest clinical phenotype to clopidogrel resistance. Evaluate the impact of CYP2C19 genetic variation detected by next-generation sequencing (NGS) with comprehensive annotation and functional studies. METHODS: Seventy ST cases on clopidogrel identified from the PLATO trial (n = 58) and Mayo Clinic biorepository (n = 12) were matched 1:1 with controls for age, race, sex, diabetes mellitus, presentation, and stent type. NGS was performed to cover the entire CYP2C19 gene. Assessment of exonic variants involved measuring in vitro protein expression levels. Intronic variants were evaluated for potential splicing motif variations. RESULTS: Poor metabolizers (n = 4) and rare CYP2C19*8, CYP2C19*15, and CYP2C19*11 alleles were identified only in ST cases. CYP2C19*17 heterozygote carriers were observed more frequently in cases (n = 29) than controls (n = 18). Functional studies of CYP2C19 exonic variants (n = 11) revealed 3 cases and only 1 control carrying a deleterious variant as determined by in vitro protein expression studies. Greater intronic variation unique to ST cases (n = 169) compared with controls (n = 84) was observed with predictions revealing 13 allele candidates that may lead to a potential disruption of splicing and a loss-of-function effect of CYP2C19 in ST cases. CONCLUSION: NGS detected CYP2C19 poor metabolizers and paradoxically greater number of so-called rapid metabolizers in ST cases. Rare deleterious exonic variation occurs in 4%, and potentially disruptive intronic alleles occur in 16% of ST cases. Additional studies are required to evaluate the role of these variants in platelet aggregation and clopidogrel metabolism.

19.
Thromb Res ; 193: 180-189, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32717643

RESUMO

BACKGROUND: Atrial fibrillation (AF) is associated with a 5-fold increased risk of thromboembolic stroke. Extracellular vesicles (EVs) convey pathophysiological information and are possible biomarkers for risk of stroke. METHODS: EVs were measured in 836 patients with AF (of which 280 were stroke cases) selected from the ARISTOTLE trial and in a cohort of unselected 70 year old individuals (n = 1007, reference material). EVs from platelets, leukocytes, erythrocytes and inflammatory endothelial cells were measured using flow cytometry and a solid-phase proximity ligation assay. RESULTS: Concentrations of EVs were higher in the ARISTOTLE patients than in the PIVUS cohort for all the EV groups except EVs from endothelial cells (p < 0.0001). The distributions of the concentrations of the EVs were similar among the control group and the stroke cases for all of the sources of EVs in the ARISTOTLE study. EVs were modestly correlated with the levels of NT-ProBNP, Cystatin C, GDF-15 and D-dimer. Stronger correlations were found for platelet EVs as well as phosphatidyl serine positive EVs that were correlated with CD40 ligand in the ARISTOTLE study. Leukocyte EVs were correlated with IL-6 in both the ARISTOTLE and the PIVUS study, implicating them in different physiological processes. CONCLUSIONS: Higher levels of EVs were found in anticoagulated patients with AF and a higher risk of stroke than in a general population of similar age, possibly due to the high disease burden in AF patients. Our data with EVs representing a broad repertoire of activated blood cells in AF patients suggest that EVs are likely not a key mediator of occurrence of stroke in this population.

20.
J Am Coll Cardiol ; 76(2): 162-171, 2020 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-32646565

RESUMO

BACKGROUND: The long-term prognostic impact of post-discharge bleeding in the unique population of patients with acute coronary syndrome (ACS) treated without percutaneous coronary intervention (PCI) remains unexplored. OBJECTIVES: The aim of this study was to assess the association between post-discharge bleeding and subsequent mortality after ACS according to index strategy (PCI or no PCI) and to contrast with the association between post-discharge myocardial infarction (MI) and subsequent mortality. METHODS: In a harmonized dataset of 4 multicenter randomized trials (APPRAISE-2 [Apixaban for Prevention of Acute Ischemic Events-2], PLATO [Study of Platelet Inhibition and Patient Outcomes], TRACER [Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome], and TRILOGY ACS [Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes]), the association between post-discharge noncoronary artery bypass graft-related GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) moderate, severe, or life-threatening bleeding (landmark 7 days post-ACS) and subsequent all-cause mortality was evaluated in a time-updated Cox proportional hazards analysis. Interaction with index treatment strategy was assessed. Results were contrasted with risk for mortality following post-discharge MI. RESULTS: Among 45,011 participants, 1,133 experienced post-discharge bleeding events (2.6 per 100 patient-years), and 2,149 died during follow-up. The risk for mortality was significantly higher <30 days (adjusted hazard ratio: 15.7; 95% confidence interval: 12.3 to 20.0) and 30 days to 12 months (adjusted hazard ratio: 2.7; 95% confidence interval: 2.1 to 3.4) after bleeding, and this association was consistent in participants treated with or without PCI for their index ACS (p for interaction = 0.240). The time-related association between post-discharge bleeding and mortality was similar to the association between MI and subsequent mortality in participants treated with and without PCI (p for interaction = 0.696). CONCLUSIONS: Post-discharge bleeding after ACS is associated with a similar increase in subsequent all-cause mortality in participants treated with or without PCI and has an equivalent prognostic impact as post-discharge MI.

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