Molecular magnetic resonance imaging discloses endothelial activation after transient ischaemic attack.

SEE SUN ET AL DOI101093/AWW306 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: About 20% of patients with ischaemic stroke have a preceding transient ischaemic attack, which is clinically defined as focal neurological symptoms of ischaemic origin resolving spontaneously. Failure to diagnose transient ischaemic attack is a wasted opportunity to prevent recurrent disabling stroke. Unfortunately, diagnosis can be difficult, due to numerous mimics, and to the absence of a specific test. New diagnostic tools are thus needed, in particular for radiologically silent cases, which correspond to the recommended tissue-based definition of transient ischaemic attack. As endothelial activation is a hallmark of cerebrovascular events, we postulated that this may also be true for transient ischaemic attack, and that it would be clinically relevant to develop non-invasive in vivo imaging to detect this endothelial activation. Using transcriptional and immunohistological analyses for adhesion molecules in a mouse model, we identified brain endothelial P-selectin as a potential biomarker for transient ischaemic attack. We thus developed ultra-sensitive molecular magnetic resonance imaging using antibody-based microparticles of iron oxide targeting P-selectin. This highly sensitive imaging strategy unmasked activated endothelial cells after experimental transient ischaemic attack and allowed discriminating transient ischaemic attack from epilepsy and migraine, two important transient ischaemic attack mimics. We provide preclinical evidence that combining conventional magnetic resonance imaging with molecular magnetic resonance imaging targeting P-selectin might aid in the diagnosis of transient ischaemic attack.

Copeptin and Long-Term Risk of Recurrent Vascular Events After Transient Ischemic Attack and Ischemic Stroke: Population-Based Study.

BACKGROUND AND PURPOSE: Copeptin, the c-terminal portion of provasopressin, is a useful prognostic marker in patients after myocardial infarction and heart failure. More recently, high levels of copeptin have also been associated with worse functional outcome and increased mortality within the first year after ischemic stroke and transient ischemic attack (TIA). However, to date, there are no published data on whether copeptin predicts long-term risk of vascular events after TIA and stroke. METHODS: We measured copeptin levels in consecutive patients with TIA or ischemic stroke in a population-based study (Oxford Vascular Study) recruited from 2002 to 2007 and followed up to 2014. Associations with risk of recurrent vascular events were determined by Cox-regression. RESULTS: During ≈6000 patient-years in 1076 patients, there were 357 recurrent vascular events, including 174 ischemic strokes. After adjustment for age, sex, and risk factors, copeptin was predictive of recurrent vascular events (adjusted hazard ratio per SD, 1.47; 95% confidence interval, 1.31-1.64; P=0.0001), vascular death (1.85; 1.60-2.14; P<0.0001), all-cause death (1.75; 1.58-1.93; P<0.0001), and recurrent ischemic stroke (1.22; 1.04-1.44; P=0.017); and improved model-discrimination significantly: net reclassification improvement for recurrent vascular events (32%; P<0.0001), vascular death (55%; P<0.0001), death (66%; P<0.0001), and recurrent stroke (16%; P=0.044). The predictive value of copeptin was largest in patients with cardioembolic index events (adjusted hazard ratio, 1.84; 95% confidence interval, 1.53-2.20 versus 1.31, 1.14-1.50 in noncardioembolic stroke; P=0.0025). In patients with cardioembolic stroke, high copeptin levels were associated with a 4-fold increased risk of vascular events within the first year of follow-up (adjusted hazard ratio, 4.02; 95% confidence interval, 2.13-7.70). CONCLUSIONS: In patients with TIA and ischemic stroke, copeptin predicted recurrent vascular events and death, particularly after cardioembolic TIA/stroke. Further validation is required, in particular, in studies using more extensive cardiac evaluation.

Biomarkers and mortality after transient ischemic attack and minor ischemic stroke: population-based study.

BACKGROUND AND PURPOSE: Premature death after transient ischemic attack or stroke is more often because of heart disease or cancer than stroke. Previous studies found blood biomarkers not usefully predictive of nonfatal stroke but possibly of all-cause death. This association might be explained by potentially treatable occult cardiac disease or cancer. We therefore aimed to validate the association of a panel of biomarkers with all-cause death, particularly cardiac death and cancer death, despite the absence of associations with risk of nonfatal vascular events. METHODS: Fifteen biomarkers were measured in 929 consecutive patients in a population-based study (Oxford Vascular Study), recruited from 2002 and followed up to 2013. Associations were determined by Cox regression. Model discrimination was assessed by c-statistic and the integrated discrimination improvement. RESULTS: During 5560 patient-years of follow-up, none of the biomarkers predicted risk of nonfatal vascular events. However, soluble tumor necrosis factor α receptor-1, von Willebrand factor, heart-type fatty-acid-binding protein, and N-terminal pro-B-type natriuretic peptide were independently predictive of all-cause death (n=361; adjusted hazard ratio per SD, 95% confidence interval: heart-type fatty-acid-binding protein: 1.31, 1.12-1.56, P=0.002; N-terminal pro-B-type natriuretic peptide: 1.34, 1.11-1.62, P=0.002; soluble tumor necrosis factor α receptor-1: 1.45, 1.26-1.66, P=0.02; von Willebrand factor: 1.19, 1.04-1.36, P=0.01). The independent contribution of the four biomarkers taken together added prognostic information and improved model discrimination (integrated discrimination improvement=0.028, P=0.0001). N-terminal pro-B-type natriuretic peptide was most predictive of vascular death (adjusted hazard ratio=1.80, 95% confidence interval, 1.34-2.41, P<0.0001), whereas heart-type fatty-acid-binding protein predicted cancer deaths (1.64, 1.26-2.12, P=0.0002). Associations were strongest in patients without known prior cardiac disease or cancer. CONCLUSIONS: Several biomarkers predicted death of any cause after transient ischemic attack and minor stroke. N-terminal pro-B-type natriuretic peptide and heart-type fatty-acid-binding protein might improve patient selection for additional screening for occult cardiac disease or cancer, respectively. However, our results require validation in future studies.

Population-based study of blood biomarkers in prediction of subacute recurrent stroke.

BACKGROUND AND PURPOSE: Risk of recurrent stroke is high in the first few weeks after transient ischemic attack or stroke and clinical risk prediction tools have only limited accuracy, particularly after the hyperacute phase. Previous studies of the predictive value of biomarkers have been small, been done in selected populations, and have not concentrated on the acute phase or on intensively treated populations. We aimed to determine the predictive value of a panel of blood biomarkers in intensively treated patients early after transient ischemic attack and stroke. METHODS: We studied 14 blood biomarkers related to inflammation, thrombosis, atherogenesis, and cardiac or neuronal cell damage in early transient ischemic attack or ischemic stroke in a population-based study (Oxford Vascular Study). Biomarker levels were related to 90-day risk of recurrent stroke as hazard ratio (95% confidence interval) per decile increase, adjusted for age and sex. RESULTS: Among 1292 eligible patients, there were 53 recurrent ischemic strokes within 90 days. There were moderate correlations (r=0.40-0.61; P<0.0001) between the inflammatory biomarkers and between the cell damage and thrombotic subsets. Associations with risk of early recurrent stroke were weak, with significant associations limited to interleukin-6 (adjusted hazard ratio, 1.12; 1.01-1.24; P=0.033) and C-reactive protein (adjusted hazard ratio, 1.15; 1.02-1.30; P=0.022) after adjusting for age, sex, hypertension, smoking, and diabetes mellitus although P-selectin seemed to predict stroke after transient ischemic attack (adjusted hazard ratio, 1.28; 1.00-1.63; P=0.046). CONCLUSIONS: In the largest study to date, we found limited predictive use for early recurrent stroke for a panel of inflammatory, thrombotic, and cell damage biomarkers.

Lack of association between aspirin responsiveness and seven candidate gene haplotypes in patients with symptomatic vascular disease.

We studied the effect of prophylactic aspirin (ASA) ingestion on platelet function in 463 patients with stroke, transient ischemic attack (TIA) or acute coronary disease (ACD), using the Platelet Function Analyzer-100 (PFA-100). We correlated ASA responsiveness with haplotypes of seven candidate genes, selected for their documented role in platelet function, namely, the genes for integrins alpha2beta1and alphaIIbbeta3 (ITGA2, ITGA2B, and ITGB3), platelet glycoproteins Ibalpha and VI (GPIBA and GP6), the purinergic receptor P2Y1 (P2RY1), and prostaglandin H synthase 1 (PTGS1 = COX1). Non-responsiveness to ASA was defined as the failure of prior ASA ingestion to prolong the PFA-100 closure time (CT) when blood was perfused through cartridges coated with collagen plus epinephrine (CEPI-CT). ASA non-responsiveness was observed in 114 of 463 patients (24.6 %), but was not associated with haplotypes of any of the seven candidate genes. There was also no association between any haplotypes and the CT when blood was perfused through cartridges coated with collagen plus ADP (CADP-CT). The ASA non-responsive cohort had significantly increased whole blood platelet counts (p = 0.03) and plasma von Willebrand Factor antigen levels (p < 0.001), which likely contributes to resistance to the inhibitory effects of ASA in the PFA-100.

Methods for counting platelets in severe thrombocytopenia.

Accurate platelet counts in severe thrombocytopenia are critical in clinical practice to facilitate decisions at prophylactic platelet-transfusion thresholds. Until recent years, the accuracy of platelet counts has been limited by the reliance of hematology analyzers on calibration material values derived from the manual platelet counting method. The calibration of hematology analyzers in thrombocytopenia and the reduction of variation between instruments have been hindered by a lack of adequate quality control materials, making the accuracy of automated methodologies in routine practice difficult to assess. This situation could now be vastly improved by the use of the International Reference Method (IRM) to assign calibration materials and by further knowledge of the accuracy and limitations of the particular types of automated platelet count available to the clinician. These changes will improve clinical confidence in the accuracy of a platelet count and thus inform clinical decisions at the current level of prophylactic platelet transfusions.