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1.
J Neurol ; 2020 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-32410017

RESUMO

BACKGROUND: Silent brain infarcts (SBI), a finding on neuroimaging, are associated with higher risk of future stroke. Atrial Fibrillation (AF) has been previously identified as a cause of SBI. OBJECTIVES: The aim of this study is to determine the prevalence of and risk factors for SBI in patients with AF and low-to-moderate embolic risk according to CHADS2 and CHA2DS2VASc score. METHODS: Patients with a history of AF based on medical records who scored 0-1 in the CHADS2 score were selected from the Seville urban area using the Andalusian electronic healthcare database (DIRAYA). Demographic and clinical data were collected and a 3T brain MRI was performed on patients older than 50 years and with absence of neurological symptoms. RESULTS: 66 of the initial 443 patients (14.9%) and 41 of the 349 patients with low risk according to CHA2DS2VASc score (11.7%) presented at least 1 SBI. After adjusted multivariable analysis, an older age (OR 3.84, 95% CI 1.07-13.76) and left atrial (LA) enlargement (OR 3.13, 95% CI 1.15-8.55) were associated with SBI in the whole cohort, while only LA enlargement was associated with SBI in the low-risk cohort (OR 3.19, 95% CI 1.33-7.63). CONCLUSIONS: LA enlargement on echocardiogram was associated with SBI in patients with AF and low or moderate embolic risk according to CHADS2 and in the low-risk population according to CHA2DS2VASc. Although further studies are needed, a neuroimaging screening might be justified in these patients to guide medical therapies to improve stroke prevention.

2.
Nat Rev Neurol ; 16(5): 247-264, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32322099

RESUMO

Despite many years of research, no biomarkers for stroke are available to use in clinical practice. Progress in high-throughput technologies has provided new opportunities to understand the pathophysiology of this complex disease, and these studies have generated large amounts of data and information at different molecular levels. The integration of these multi-omics data means that thousands of proteins (proteomics), genes (genomics), RNAs (transcriptomics) and metabolites (metabolomics) can be studied simultaneously, revealing interaction networks between the molecular levels. Integrated analysis of multi-omics data will provide useful insight into stroke pathogenesis, identification of therapeutic targets and biomarker discovery. In this Review, we detail current knowledge on the pathology of stroke and the current status of biomarker research in stroke. We summarize how proteomics, metabolomics, transcriptomics and genomics are all contributing to the identification of new candidate biomarkers that could be developed and used in clinical stroke management.

3.
Eur J Neurol ; 2020 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-32347993

RESUMO

BACKGROUND: Cover paroxysmal atrial fibrillation (pAF) is the most frequent cause of cardiac embolism. Our goal was to discover parameters associated with early pAF detection with intensive cardiac monitoring. METHODS: Crypto-AF was a multicenter prospective study (four Comprehensive Stroke Centers) to detect pAF in non-lacunar cryptogenic stroke continuously monitored within the first 28 days. We assessed: stroke severity, infarct pattern, large vessel occlusion at baseline (LVO), EKG analysis, supraventricular extrasystolia in Holter, left atria volume index (LAVI) and BNP level. The percentage of pAF detection and pAF episodes lasting more than 5 hours were registered. RESULTS: Out of 296 patients included 264 patients completed the monitoring period with 23.1% (61/264) of pAF detection. Patients with pAF were older OR 1.04 (95% CI 1.01-1.08); they had more hemorrhagic infarction OR 4.03 (95% CI 1.44-11.22), they were more likely to have LVO OR 4.29 (95% CI 2.31-7.97) (p < 0.0001), they had larger LAVI OR 1.03 (95% CI 1.01-1.1) (p = 0.0002) and higher level of BNP OR 1.01 (95% CI 1.0-1.1). The age and LVO were independently associated with pAF detection, OR 1.06 (1.00; 1.16) and OR 4.58 (2.27; 21.38) respectively. Patients with LVO had higher cumulative incidence of pAF (log rank p <0.001) and more percentage of PAF>5 hours 29.6% (21/71) Vs. 8.3% (12/144) OR 4.62 (95% CI 2.11-10.08), (p<0.001). In mean follow up of 26.82 months (SD 10.15) the stroke recurrence rate was 4.6% (12/260). CONCLUSIONS: LVO in cryptogenic stroke emerged as an independent marker of pAF.

6.
Antioxidants (Basel) ; 9(4)2020 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-32244303

RESUMO

Nitrones have a well-recognized capacity as spin-traps and are considered powerful free radical scavengers, which are two important issues in hypoxia-induced oxidative stress and cell death in brain ischemia. Consequently, nitrones have been proposed as therapeutic agents in acute ischemic stroke (AIS). In this paper, we update the biological and pharmacological characterization of ISQ-201, a previously identified cholesteronitrone hybrid with antioxidant and neuroprotective activity. This study characterizes ISQ-201 as a neuroprotective agent against the hypoxia-induced ischemic injury. Transitory four-vessel occlusion and middle cerebral artery occlusion (tMCAO) were used to induce cerebral ischemia. Functional outcomes were determined using neurofunctional tests. Infarct area, neuronal death, and apoptosis induction were evaluated. In addition, ISQ-201 reactivity towards free radicals was studied in a theoretical model. ISQ-201 significantly decreased the ischemia-induced neuronal death and apoptosis, in a dose-dependent manner, showing its therapeutic effect when administered up until 6 h after post-ischemic reperfusion onset, effects that remained after 3 months from the ischemic episode. Furthermore, ISQ-201 significantly reduced infarct volume, leading to recovery of the motor function in the tMCAO model. Finally, the theoretical study confirmed the reactivity of ISQ-201 towards hydroxyl radicals. The results reported here prompted us to suggest ISQ-201 as a promising candidate for the treatment of AIS.

7.
Epigenetics ; : 1-10, 2020 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-32202197

RESUMO

DNA methylation is dynamic, varies throughout the life course, and its levels are influenced by lifestyle and environmental factors, as well as by genetic variation. The leading genetic variants at stroke risk loci identified to date explain roughly 1-2% of stroke heritability. Most of these single nucleotide polymorphisms are situated within a regulatory sequence marked by DNase I hypersensitivity sites, which would indicate involvement of an epigenetic mechanism. To detect epigenetic variants associated with stroke occurrence and stroke subtypes.A two-stage case-control epigenome-wide association study was designed. The discovery sample with 401 samples included 218 ischaemic stroke (IS) patients, assessed at Hospital del Mar (Barcelona, Spain) and 183 controls from the REGICOR cohort. In two independent samples (N = 226 and N = 166), we replicated 22 CpG sites differentially methylated in IS in 21 loci, including 2 CpGs in locus ZFHX3, which includes known genetic variants associated with stroke. The pathways associated with these loci are inflammation and angiogenesis. The meta-analysis identified 384 differentially methylated CpGs, including loci of known stroke and vascular risk genetic variants, enriched by loci involved in lipid metabolism, adipogenesis, circadian clock, and glycolysis pathways.We identified a set of 22 CpGs in 21 loci associated with IS. Our analysis suggests that DNA methylation changes may contribute to orchestrating gene expression that contributes to IS.

8.
Artigo em Inglês | MEDLINE | ID: mdl-32098866

RESUMO

OBJECTIVE: Prognosis of stroke is negatively affected by complications, in particular stroke-associated pneumonia (SAP). We hypothesized that inflammatory and stress biomarkers predict SAP during hospitalization and outcome 3 months after stroke. METHODS: We pooled the clinical data of 2 acute stroke studies with identical assessment: the STRoke Adverse outcome is associated WIth NoSoKomial Infections (STRAWINSKI) and PREDICT studies. Measurement of biomarkers (ultrasensitive procalcitonin [PCTus]; midregional pro-adrenomedullin; midregional pro-atrial natriuretic peptide [MRproANP]; ultrasensitive copeptin [CPus]; C-terminal pro-endothelin) was performed from serum samples drawn on the first 4 days of hospital admission. RESULTS: The combined cohort consists of 573 cases with available backup samples to perform the analysis. SAP was associated with increased admission and maximum levels of all biomarkers. Furthermore, all biomarkers were associated with death and correlated with functional outcome 3 months after stroke. The multivariate logistic regression model retained ultrasensitive CPus and PCTus beyond clinical risk factors for predicting SAP, improving the receiver operating characteristic area under the curve (AUC) from 0.837 to 0.876. In contrast, the biomarkers did not improve the prediction of death and functional outcome in the multivariate model. Cardioembolic strokes were significantly associated with higher values of all biomarkers, whereas discrimination was best for MRproANP (AUC = 0.811 for maximum value). CONCLUSIONS: The tested biomarkers are associated with SAP and poor functional outcome. However, these biomarkers only slightly improve prediction of SAP and do not improve long-term outcome prediction over clinical parameters. MRproANP showed the best discrimination for identifying cardioembolic stroke, warranting further studies to confirm our finding. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov NCT01264549 and NCT01079728.

9.
Sci Rep ; 10(1): 2806, 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32071341

RESUMO

Acenocoumarol is an oral anticoagulant with significant interindividual dose variations. Variants in CYP2C9 and VKORC1 have been associated with acenocoumarol maintenance dose. We analysed whether any of the 49 polymorphisms in CYP2C9 and VKORC1 previously associated with acenocoumarol maintenance dose in a Genome-Wide Association study (GWAs) in Dutch population are associated with stroke recurrence, intracranial haemorrhage (ICH) and acenocoumarol maintenance dose in a Spanish population. We performed a GWAs using Human Core Exome-chip (Illumina) in 78 patients stroke patients treated with acenocoumarol for secondary prevention enrolled as part of the prospective investigator-initiated study (IIS) SEDMAN Study. Patients were followed-up a median of 12.8 months. Three and eight patients had recurrent stroke and ICH events, respectively. We found 14 of the 49 published variants associated with acenocoumarol maintenance dose (p < 0.05). Six polymorphisms were associated with stroke recurrence and four variants with ICH (p < 0.05). In conclusion, variants in VKORC1 and CYP2C9 are associated with acenocoumarol maintenance dose, stroke recurrence and ICH in a Spanish cohort. These results highlight the relevance of studying pharmacogenetics associated with efficacy and safety of anticoagulant drugs and justify studies with larger sample size and different ethnic populations.

10.
J Clin Sleep Med ; 16(2): 243-250, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31992414

RESUMO

STUDY OBJECTIVES: The objective of this study was to determine which respiratory and architectural sleep parameters are related to cognitive function and cognitive status (mild cognitive impairment [MCI] versus normal cognitive aging [NCA]) in community-dwelling individuals with hypertension. Additionally, it aimed to determine whether the results changed in the presence or absence of vascular brain lesions (silent brain infarcts and extensive white matter hyperintensities [WMHs]). METHODS: In a cohort of individuals with hypertension and without previous stroke or dementia, we conducted in-hospital polysomnography including electroencephalography, electro-oculography, electromyography, and magnetic resonance imaging to assess silent brain infarcts and WMHs. Cognitive testing was carried out with a screening test (Dementia Rating Scale version 2 [DRS-2]) and a complete cognitive visit. RESULTS: This study included 158 participants with a median age of 65.0 years; 32.3% were females, and the median apnea-hypopnea index was 22.3 events/h. MCI was diagnosed in 24 study participants, and the rest had NCA. Regarding respiratory parameters, total DRS-2 scores (ß; 95% CI) 0.121; 0.026, 0.215 were positively associated with mean O2 saturation, whereas total (-0.022; -0.036, -0.009), executive function (-0.016; -0.026, -0.006) and memory (-0.017; -0.029, -0.004) DRS-2 scores were all negatively associated with the percent of time with oxygen saturation < 90% after correcting for education, vascular risk factors, and magnetic resonance imaging lesions. Regarding sleep architecture, Attention DRS-2 scores (0.0153; 0.001, 0.306) were independently associated with total sleep time. Similar results were obtained in the absence of silent brain infarcts or WMHs in the stratified analysis. None of the sleep parameters were associated with cognitive status. CONCLUSIONS: Low oxygen saturation contributes to cognitive performance, and this effect appears even in the absence of vascular brain lesions in individuals with hypertension.

11.
J Alzheimers Dis ; 73(4): 1585-1595, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31958084

RESUMO

CCL23 is a chemokine implicated in inflammation and host defense responses. It has been recently associated with acquired brain damage and stroke outcomes. In this study, we reported the role of CCL23 in Alzheimer's disease (AD). We evaluated the levels of CCL23 in 659 individuals: cognitively normal, mild cognitive impaired (MCI), and AD patients. Two cross-sectional (study 1, n = 53; study 2, n = 200) and two longitudinal (study 3, n = 74; study 4, n = 332) studies were analyzed separately. CCL23 levels in the blood and/or cerebrospinal fluid (CSF) of each study were measured by immunoassays. Globally, our results suggest a predictive role of CCL23 protein levels both in the plasma in study 3 (hazard ratio (HR) = 2.5 (confidence interval (CI) 95% : 1.2-5.3), p = 0.02) and in the CSF in study 4 (HR = 3.05 (CI 95% : 1.02-5), p = 0.04) in cases of MCI that progress to AD. Moreover, we observed that the APOEɛ4 allele was associated with higher levels of CCL23 in study 2 (470.33 pg/mL (interquartile range (IQR): 303.33-597.76) versus 377.94 pg/mL (IQR: 267.16-529.19), p = 0.01) (APOE genotypes were available in studies 2 and 4). Together, these findings support the role of CCL23 in neuroinflammation in the early stages of AD, suggesting that CCL23 might be a candidate blood biomarker for MCI to AD progression.

12.
J Investig Med ; 68(3): 807-810, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31852749

RESUMO

Previous studies have shown the potential of microRNAs (miRNA) in the pathological process of stroke and functional recovery. Bone marrow mononuclear cell (BM-MNC) transplantation improves recovery in experimental models of ischemic stroke that might be related with miRNA modifications. However, its effect on circulating miRNA has not been described in patients with stroke. We aimed to evaluate the circulating levels of miRNAs after autologous BM-MNC transplantation in patients with stroke. We investigate the pattern of miRNA-133b and miRNA-34a expression in patients with ischemic stroke included in a multicenter randomized controlled phase IIb trial (http://www.clinicaltrials.gov; unique identifier: NCT02178657). Patients were randomized to 2 different doses of autologous intra-arterial BM-MNC injection (2×106/kg or 5×106/kg) or control group within the first 7 days after stroke onset. We evaluate plasma concentration of miRNA-113b and miRNA-34a at inclusion and 4, 7, and 90 days after treatment. Thirteen cases (8 with 2×106/kg BM-MNC dose and 5 with 5×106/kg dose) and 11 controls (BM-MNC non-treated) were consecutively included. Mean age was 64.1±12.3 with a mean National Institutes of Health Stroke Scale score at inclusion of 14.5. Basal levels of miRNA were similar in both groups. miR-34a-5p and miR-133b showed different expression patterns. There was a significant dose-dependent increase of miRNA-34a levels 4 days after BM-MNC injection (fold change 3.7, p<0.001), whereas miRNA-133b showed a significant increase in the low-dose BM-MNC group at 90 days. Intra-arterial BM-MNC transplantation in patients with ischemic stroke seems to modulate early circulating miRNA-34a levels, which have been related to precursor cell migration in stroke and smaller infarct volumes.

13.
Neurosci Lett ; 714: 134580, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31672489

RESUMO

Patients' outcome prediction after ischemic stroke is still challenging. Aquaporin-4 (AQP4) is a water channel that is up-regulated in the brain after the ischemic event, but its presence in bloodstream of stroke patients has not been previously studied. The aim of this pilot study was to investigate circulating AQP4 levels after stroke and its correlation with infarct growth and neurological outcome. AQP4 level was determined by ELISA in serum from 42 t-PA-treated ischemic stroke patients at admission (before t-PA) and 13 healthy subjects. To assess infarct growth, serial brain diffusion-weighted magnetic resonance images were performed at hospital admission and 1-3 days after. Neurological improvement was defined as a ≥4-point decrease in NIHSS score compared to baseline score. Despite stroke patients and healthy controls had similar baseline circulating AQP4 levels, among strokes AQP4 level negatively correlated with NIHSS score at admission (R= -0.34, p = 0.029) and with infarct growth after 1-3 days of stroke onset (R=-0.36; p = 0.018). Furthermore, baseline AQP4 level was higher in those stroke patients showing a neurological improvement 48 h after stroke onset (p = 0.030) and at hospital discharge (p = 0.037). Baseline AQP4 levels also resulted to be an independent predictor of good neurological outcome at both studied time points (ORadj: 14.33[1.82-112.92], p = 0.012 at 48 h; ORadj: 4.86[0.98-24.12], p = 0.053 at discharge) in logistic regression analysis, adjusted by age, sex, baseline NIHSS and significant variables in the univariate analysis. Overall, we have explored circulating AQP4 levels, and our data suggest that AQP4 could be used as a biomarker of neurological recovery in the acute-subacute phase of ischemic stroke.

14.
Circulation ; 140(22): 1834-1850, 2019 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-31765261

RESUMO

Cardiac thromboembolism attributed to atrial fibrillation (AF) is responsible for up to one-third of ischemic strokes. Stroke may be the first manifestation of previously undetected AF. Given the efficacy of oral anticoagulants in preventing AF-related ischemic strokes, strategies of searching for AF after a stroke using ECG monitoring followed by oral anticoagulation (OAC) treatment have been proposed to prevent recurrent cardioembolic strokes. This white paper by experts from the AF-SCREEN International Collaboration summarizes existing evidence and knowledge gaps on searching for AF after a stroke by using ECG monitoring. New AF can be detected by routine plus intensive ECG monitoring in approximately one-quarter of patients with ischemic stroke. It may be causal, a bystander, or neurogenically induced by the stroke. AF after a stroke is a risk factor for thromboembolism and a strong marker for atrial myopathy. After acute ischemic stroke, patients should undergo 72 hours of electrocardiographic monitoring to detect AF. The diagnosis requires an ECG of sufficient quality for confirmation by a health professional with ECG rhythm expertise. AF detection rate is a function of monitoring duration and quality of analysis, AF episode definition, interval from stroke to monitoring commencement, and patient characteristics including old age, certain ECG alterations, and stroke type. Markers of atrial myopathy (eg, imaging, atrial ectopy, natriuretic peptides) may increase AF yield from monitoring and could be used to guide patient selection for more intensive/prolonged poststroke ECG monitoring. Atrial myopathy without detected AF is not currently sufficient to initiate OAC. The concept of embolic stroke of unknown source is not proven to identify patients who have had a stroke benefitting from empiric OAC treatment. However, some embolic stroke of unknown source subgroups (eg, advanced age, atrial enlargement) might benefit more from non-vitamin K-dependent OAC therapy than aspirin. Fulfilling embolic stroke of unknown source criteria is an indication neither for empiric non-vitamin K-dependent OAC treatment nor for withholding prolonged ECG monitoring for AF. Clinically diagnosed AF after a stroke or a transient ischemic attack is associated with significantly increased risk of recurrent stroke or systemic embolism, in particular, with additional stroke risk factors, and requires OAC rather than antiplatelet therapy. The minimum subclinical AF duration required on ECG monitoring poststroke/transient ischemic attack to recommend OAC therapy is debated.

15.
Epilepsy Behav ; : 106549, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31677998

RESUMO

INTRODUCTION: Blood biomarkers have not been widely studied in stroke-related seizures. In this study, we aimed to describe clinical factors and biomarkers present during acute stroke and to analyze their association with early-onset seizures. METHODS: We retrospectively evaluated a panel of 14 blood biomarkers in 1115 patients with ischemic and hemorrhagic stroke. Biomarkers were normalized and standardized using Z scores. We also recorded stroke and epilepsy-related variables, including stroke severity (National Institute of Health Stroke Scale [NIHSS] scores), type, and causes, time from onset of stroke to occurrence of early seizures, and type of seizure. Adjusted logistic regression models were built to identify clinical variables and biomarkers independently associated with early seizures. RESULTS: Mean ±â€¯standard deviation (SD) age was 72.3 ±â€¯13.2 years, and 56.8% of the patients were men. Thirty-eight patients (3.9%) developed early seizures with a median time to onset of 1 day (interquartile range (IQR), 0-4). A higher NIHSS score (odds ratio [OR] = 1.046; 95% confidence interval (CI): 1.001-1.094; p = 0.044) and hemorrhagic stroke (OR = 2.133; 95% CI: 1.010-4.504; p = 0.047) were independently associated with a greater risk of early seizures. Independent blood biomarkers predictive of early seizures were lower levels of tumor necrosis factor receptor 1 (TNF-R1) (<0.013) (p = 0.006; OR = 3.334; 95% CI: 1.414-7.864) and higher levels of neural cell adhesion molecule (NCAM) (>0.326) (p = 0.009; OR = 2.625; 95% CI: 1.271-5.420). The predictive power of the regression model was greater when clinical variables were combined with blood biomarkers (73.5%; 95% CI: 65.1%-81.9%) than when used alone (64%; 95% CI: 55%-72.9%). CONCLUSION: Higher NCAM and lower TNF-R1 levels may help predict the occurrence of early seizures. The combined use of these biomarkers and clinical variables could be useful for identifying patients at risk of seizures. "This article is part of the Special Issue "Seizures & Stroke".

16.
J Stroke ; 21(3): 276-289, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31590472

RESUMO

Stroke is a complex disease and one of the main causes of morbidity and mortality among the adult population. A huge variety of factors is known to influence patient outcome, including demographic variables, comorbidities or genetics. In this review, we expound what is known about the influence of clinical variables and related genetic risk factors on ischemic stroke outcome, focusing on acute and subacute outcome (within 24 to 48 hours after stroke and until day 10, respectively), as they are the first indicators of stroke damage. We searched the PubMed data base for articles that investigated the interaction between clinical variables or genetic factors and acute or subacute stroke outcome. A total of 61 studies were finally included in this review. Regarding the data collected, the variables consistently associated with acute stroke outcome are: glucose levels, blood pressure, presence of atrial fibrillation, prior statin treatment, stroke severity, type of acute treatment performed, severe neurological complications, leukocyte levels, and genetic risk factors. Further research and international efforts are required in this field, which should include genome-wide association studies.

18.
Stroke ; 50(12): 3618-3621, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31587654

RESUMO

Background and Purpose- Immune cells play a key role in the first 24h poststroke (acute phase), being associated with stroke outcome. We aimed to find genetic risk factors associated with leukocyte counts during the acute phase of stroke. Methods- Ischemic stroke patients with leukocyte counts data during the first 24h were included. Genome-wide association study and gene expression studies were performed. Results- Our genome-wide association study, which included 2064 (Discovery) and 407 (Replication) patients, revealed a new locus (14q24.3) associated with leukocyte counts. After Joint analysis (n=2471) 5 more polymorphisms reached genome-wide significance (P<5×10-8). The 14q24.3 locus was associated with acute stroke outcome (rs112809786, P=0.036) and with ACOT1 and PTGR2 gene expression. Previous polymorphisms associated with leukocyte counts in general-population did not show any significance in our study. Conclusions- We have found the first locus associated with leukocyte counts in ischemic stroke, also associated with acute outcome. Genetic analysis of acute endophenotypes could be useful to find the genetic factors associated with stroke outcome. Our findings suggested a different modulation of immune cells in stroke compared with healthy conditions.

19.
Artigo em Inglês | MEDLINE | ID: mdl-31504375

RESUMO

AIMS: Clopidogrel is prescribed for the prevention of atherothrombotic events. While investigations have identified genetic determinants of inter-individual variability in on-treatment platelet inhibition (e.g. CYP2C19*2), evidence that these variants have clinical utility to predict major adverse cardiovascular events remains controversial. METHODS AND RESULTS: We assessed the impact of 31 candidate gene polymorphisms on ADP-stimulated platelet reactivity in 3,391 clopidogrel-treated coronary artery disease patients of the International Clopidogrel Pharmacogenomics Consortium (ICPC). The influence of these polymorphisms on cardiovascular events (CVE) was tested in 2,134 ICPC patients (N = 129 events) in whom clinical event data were available. Several variants were associated with on-treatment ADP-stimulated platelet reactivity (CYP2C19*2, P = 8.8x10-54; CES1 G143E, P = 1.3x10-16; CYP2C19*17, P = 9.5x10-10; CYP2B6 1294 + 53C>T, P = 3.0x10-4; CYP2B6 516G>T, P = 1.0x10-3; CYP2C9*2, P = 1.2x10-3; and CYP2C9*3, P = 1.5x10-3). While no individual variant was associated with CVEs, generation of a pharmacogenomic polygenic response score (PgxRS) revealed that patients who carried a greater number of alleles that associated with increased on-treatment platelet reactivity were more likely to experience CVEs (ß = 0.17, SE 0.06, P = 0.01) and cardiovascular-related death (ß = 0.43, SE 0.16, P = 0.007). Patients who carried 8 or more risk alleles were significantly more likely to experience CVEs (OR = 1.78, 95%CI 1.14-2.76, P = 0.01) and cardiovascular death (OR = 4.39, 95%CI 1.35-14.27, P = 0.01) compared to patients who carried 6 or fewer of these alleles. CONCLUSION: Several polymorphisms impact clopidogrel response and PgxRS is a predictor of cardiovascular outcomes. Additional investigations that identify novel determinants of clopidogrel response and validating polygenic models may facilitate future precision medicine strategies.

20.
Transl Stroke Res ; 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31475302

RESUMO

An accurate etiological classification is key to optimize secondary prevention after ischemic stroke, but the cause remains undetermined in one third of patients. Several studies pointed out the usefulness of circulating gene expression markers to discriminate cardioembolic (CE) strokes, mainly due to atrial fibrillation (AF), while only exploring them in small cohorts. A systematic review of studies analyzing high-throughput gene expression in blood samples to discriminate CE strokes was performed. Significantly dysregulated genes were considered as candidates, and a selection of them was validated by RT-qPCR in 100 patients with defined CE or atherothrombotic (LAA) stroke etiology. Longitudinal performance was evaluated in 12 patients at three time points. Their usefulness as biomarkers for AF was tested in 120 cryptogenic strokes and 100 individuals at high-risk for stroke. Three published studies plus three unpublished datasets were considered for candidate selection. Sixty-seven genes were found dysregulated in CE strokes. CREM, PELI1, and ZAK were verified to be up-regulated in CE vs LAA (p = 0.010, p = 0.003, p < 0.001, respectively), without changes in their expression within the first 24 h after stroke onset. The combined up-regulation of these three biomarkers increased the probability of suffering from CE stroke by 23-fold. In cryptogenic strokes with subsequent AF detection, PELI1 and CREM showed overexpression (p = 0.017, p = 0.059, respectively), whereas in high-risk asymptomatic populations, all three genes showed potential to detect AF (p = 0.007, p = 0.007, p = 0.015). The proved discriminatory capacity of these gene expression markers to detect cardioembolism even in cryptogenic strokes and asymptomatic high-risk populations might bring up their use as biomarkers.

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