Predictores de la evolución clínico-radiológica del ictus isquémico agudo tras tratamiento trombolítico

Introducción: El ictus isquémico representa una importante causa de mortalidad y discapacidad en todo el mundo. La trombolisis intravenosa con activador del plasminógeno tisular recombinante (rt-PA) ha demostrado su eficacia en el tratamiento del ictus isquémico agudo, aunque sólo la mitad de los pacientes logran una respuesta clínica favorable. El conocimiento sobre los factores que influyen en la respuesta terapéutica son limitados. Esta Tesis se centra en dos procesos con potencial impacto pronóstico en el ictus isquémico tras la trombolisis: el perfil dinámico de la recanalización arterial y el curso precoz de la presión arterial (PA). Objetivos: 1) Evaluar el impacto de la velocidad de recanalización (VR) tras la trombolisis sobre el crecimiento de la lesión isquémica en difusión (DWI) por resonancia magnética (RM) y sobre la evolución clínica precoz y el pronóstico funcional. 2) Conocer la influencia de los cambios de la PA durante la fase aguda sobre la evolución de la lesión isquémica en DWI y sobre el pronóstico clínico. Métodos: Estudiamos prospectivamente pacientes con un ictus por oclusión aguda de arteria cerebral media tratados con rt-PA. Se realizó una RM con DWI dentro de las primeras 6 horas y a las 36-48 horas desde el inicio de los síntomas. El crecimiento de la lesión isquémica en DWI (crecDWI) se definió como volumen DWI final - inicial. En el primer trabajo se incluyeron 113 pacientes en los que se realizó una monitorización continua por Doppler transcraneal (DTC) durante 2 horas tras el bolus de rt-PA para determinar la VR, clasificándose en súbita (<1 minuto), escalonada (1-29 minutos) y lenta (≥30 minutos), según su duración. Para el segundo trabajo se realizó además en 80 pacientes una monitorización de PA durante las primeras 24 horas y se determinó la recanalización a las 6 horas. La evolución clínica se determinó a las 24 horas y a los 3 meses. Resultados: 1) Del total, 63 (55,7%) pacientes recanalizaron durante las primeras 2 horas tras la trombolisis. La VR fue súbita en 20,6%, escalonada en 50,8% y lenta en 28,6%. La VR se correlacionó con el crecDWI (r=0.52; p<0.001). La recanalización súbita fue el patrón asociado a menor crecDWI (3.23±10.5 cm3), comparado con el patrón escalonado (24.9±37 cm3) y lento (46.3±38 cm3) y con la ausencia de recanalización (51.7±34 cm3). La recanalización lenta se asoció a mayor crecDWI (P=0.003), peor evolución clínica precoz (P=0.021) y peor pronóstico funcional a los 3 meses (P=0.032), comparable a los que no recanalizaron. 2) La variabilidad de la PA (desviación estándar de la media de 24 horas) se correlacionó con el crecDWI (r=0.46; p=0.0003 para sistólica; r=0.26; p=0.02 para diastólica), la evolución clínica precoz (p=0.06 para sistólica; p=0.01 para diastólica) y el pronóstico funcional (p=0.002 para sistólica; p=0.07 para diastólica). Sin embargo, el significado pronóstico de la variabilidad de PA varió en función de la presencia de recanalización. El aumento de la variabilidad de PA sistólica fue predictor independiente de mayor crecDWI (beta: 6.9; IC 95%: 3.2-10.7; p=0.003) y de peor pronóstico funcional (OR: 11; IC 95%: 2.2-56.1; p=0.004) en pacientes sin recanalización. En cambio, la PA no se relacionó con la evolución clínico-radiológica en pacientes con recanalización. Conclusiones: 1) La identificación de la VR tras la trombolisis intravenosa ayuda a predecir precozmente la evolución de la lesión isquémica y el pronóstico a corto y largo plazo tras el ictus en pacientes tratados con trombolisis intravenosa. 2) La variabilidad de PA durante la fase aguda del ictus se asocia al grado de crecimiento de la lesión isquémica y el curso clínico. Sin embargo, su impacto pronóstico depende de la ausencia de recanalización tras la trombolisis.Background: Ischemic stroke is one of the leading causes of death and disability worldwide. There is evidence that intravenous (IV) thrombolysis with recombinant tisular plasminogen activator (rt-PA) is an effective treatment in acute ischemic stroke. However, only half of rt-PA treated patients achieve a good clinical outcome. Information on factors influencing the response to intravenous rt-PA is limited. This Thesis focuses on two processes that may have a relevant prognostic impact on ischemic stroke after thrombolysis: the dynamic profile of arterial recanalization and the early blood pressure (BP) course. Objectives: 1) To evaluate the impact of the speed of recanalization (SR) on the acute ischemic lesion evolution using diffusion-weighted imaging (DWI) and on outcome in stroke patients treated with intravenous rt-PA). 2) To investigate the influence of early BP changes on DWI lesion evolution and clinical outcome after thrombolysis. Methods: Consecutive IV rt-PA-treated stroke patients with middle cerebral artery occlusion were studied. All patients underwent magnetic resonance imaging studies including DWI within the first 6 hours and at 36-48 hours after symptom onset. DWI lesion evolution was assessed as the difference between final and initial DWI. In the first study, we evaluated 113 patients who were continuously monitored with transcranial Doppler (TCD) during the first 2 hours after tPA administration. The SR was defined as sudden (<1 minute), stepwise (1 to 29 minutes), or slow (≥30 minutes). In the second study we included 80 patients who underwent BP monitoring during 24 hours after admission and assessment of recanalization on TCD at 6 hours of stroke onset. Clinical evaluation was performed at 24 hours and 3 months. Results: 1) Sixty-three (55,7%) patients recanalized during TCD monitoring. Of them, 20,6% recanalized suddenly, 50,8% in a stepwise manner, and 28,6% recanalized slowly. SR was significantly correlated with DWI lesion growth at 36-48 hours (r=0.52; p<0.001). Sudden recanalization was associated with smaller DWI lesion growth (3.23±10.5 cm3) compared with stepwise (24.9±37 cm3), slow (46.3±38 cm3), and no (51.7±34 cm3) recanalization. The slow pattern was associated with greater DWI growth (P=0.003), lesser degree of clinical improvement (P=0.021) and worse 3-month outcome (P=0.032), comparable to the non-recanalization group. 2) BP variability, estimated as the SD of the 24h-mean, was associated with DWI lesion growth (r=0.46, p=0.0003 for systolic BP and r=0.26, p=0.02 for diastolic BP), early clinical course (p=0.06 for systolic BP and p=0.01 for diastolic BP), and functional outcome (p=0.002 for systolic BP and p=0.07 for diastolic BP). However, the prognostic significance of BP changes differed depending on the presence of recanalization: systolic BP variability emerged as an independent predictor of DWI lesion growth (beta: 6.9; 95% CI, 3.2 to 10.7, p=0.003) and worse stroke outcome (OR: 11;95%; CI: 2.2 to 56.1; p=0.004) in patients without recanalization, but not in recanalized patients. Conclusions: 1) The identification of the SR allows the early prediction of DWI lesion evolution and clinical outcome in acute stroke patients treated with intravenous thrombolysis

Transcranial diffuse optical assessment of the microvascular reperfusion after thrombolysis for acute ischemic stroke

In this pilot study, we have evaluated bedside diffuse optical monitoring combining diffuse correlation spectroscopy and near-infrared diffuse optical spectroscopy to assess the effect of thrombolysis with an intravenous recombinant tissue plasminogen activator (rtPA) on cerebral hemodynamics in an acute ischemic stroke. Frontal lobes of five patients with an acute middle cerebral artery occlusion were measured bilaterally during rtPA treatment. Both ipsilesional and contralesional hemispheres showed significant increases in cerebral blood flow, total hemoglobin concentration and oxy-hemoglobin concentration during the first 2.5 hours after rtPA bolus. The increases were faster and higher in the ipsilesional hemisphere. The results show that bedside optical monitoring can detect the effect of reperfusion therapy for ischemic stroke in real-time.Peer ReviewedPostprint (published version

Clinical and radiological characteristics and outcome of wake-up intracerebral hemorrhage

There is little information on the characteristics of patients with wake-up intracerebral hemorrhage (WU-ICH). We aimed to evaluate frequency and relevant differences between WU-ICH and while-awake (WA) ICH patients. This is a retrospective study of a prospective database of consecutive patients with spontaneous ICH, who were classified as WU-ICH, WA-ICH or UO-ICH (unclear onset). We collected demographic, clinical and radiological data, prognostic and therapeutic variables, and outcome [(neurological deterioration, mortality, functional outcome (favorable when modified Rankin scale score 0-2)]. From a total of 466 patients, 98 (25.8%) were classified as UO-ICH according to the type of onset and therefore excluded. We studied 368 patients (mean age 73.9 ± 13.8, 51.4% men), and compared 95 (25.8%) WU-ICH with 273 (74.2%) WA-ICH. Patients from the WU-ICH group were significantly older than WA-ICH (76.9 ± 14.3 vs 72.8 ± 13.6, p = 0.01) but the vascular risk factors were similar. Compared to the WA-ICH group, patients from the WU-ICH group had a lower GCS score or a higher NIHSS score and a higher ICH score, and were less often admitted to a stroke unit or intensive care unit. There were no differences between groups in location, volume, rate of hematoma growth, frequency of intraventricular hemorrhage and outcome. One in five patients with spontaneous ICH are WU-ICH patients. Other than age, there are no relevant differences between WU and WA groups. Although WU-ICH is associated with worse prognostic markers vital and functional outcome is similar to WA-ICH patients

The H-ATOMIC Criteria for the Etiologic Classification of Patients with Intracerebral Hemorrhage

Background and Purpose There are no generally accepted criteria for the etiologic classification of intracerebral hemorrhage (ICH). For this reason, we have developed a set of etiologic criteria and have applied them to a large number of patients to determine their utility. Methods The H-ATOMIC classification includes 7 etiologic categories: Hypertension, cerebral Amyloid angiopathy, Tumour, Oral anticoagulants, vascular Malformation, Infrequent causes and Cryptogenic. For each category, the etiology is scored with three degrees of certainty: Possible(3), Probable(2) and Definite(1). Our aim was to perform a basic study consisting of neuroimaging, blood tests, and CT-angio when a numerical score (SICH) suggested an underlying structural abnormality. Combinations of >1 etiologic category for an individual patient were acceptable. The criteria were evaluated in a multicenter and prospective study of consecutive patients with spontaneous ICH. Results Our study included 439 patients (age 70.8 ± 14.5 years; 61.3% were men). A definite etiology was achieved in 176 (40.1% of the patients: Hypertension 28.2%, cerebral Amyloid angiopathy 0.2%, Tumour 0.2%, Oral anticoagulants 2.2%, vascular Malformation 4.5%, Infrequent causes 4.5%). A total of 7 patients (1.6%) were cryptogenic. In the remaining 58.3% of the patients, ICH was attributable to a single (n = 56, 12.7%) or the combination of 2 (n = 200, 45.5%) possible/probable etiologies. The most frequent combinations of etiologies involved possible hypertension with possible CAA (H3A3, n = 38) or with probable CAA (H3A2, n = 29), and probable hypertension with probable OA (H2O2, n = 27). The most frequent category with any degree of certainty was hypertension (H1+2+3 = 80.6%) followed by cerebral amyloid angiopathy (A1+2+3 = 30.9%). Conclusions According to our etiologic criteria, only about 40% patients received a definite diagnosis, while in the remaining patients ICH was attributable to a single possible/probable etiology or to more than one possible/probable etiology. The use of these criteria would likely help in the management of patients with ICH.This work was supported by Ministery of Health-Instituto de Salud Carlos III: RETICS (Redes temáticas de Investigación Cooperativa) INVICTUS RD012/0014 (JM-F, PC-R, AM-D, LP-S, RD-M), FEDER (Fondo Europeo de Desarrollo Regional)

Association of High Serum Levels of Growth Factors with Good Outcome in Ischemic Stroke : a Multicenter Study

Altres ajuts: This project was partially supported by grants from Xunta de Galicia (Consellería Educación: GRC2014/027 and IN607A2018/3), Spanish Research Network on Cerebrovascular Diseases RETICS-INVICTUS PLUS (RD16/0019), and by the European Union FEDER program.The main objective of this research work was to study the association of serum levels of growth factors (GF) and SDF-1α with the functional outcome and reduction of lesion volume in ischemic stroke patients. In this multicenter study, 552 patients with non-lacunar stroke (male, 62.1%; mean age, 68.2 ± 11.4) were included within 24 h from symptom onset. The main outcome variable was good functional outcome (modified Rankin Scale [mRS] ≤ 2) at 12 months. Secondary outcome variable was infarct volume (in mL) after 6 ± 3 months. Serum levels of VEGF, Ang-1, G-CSF, BDNF, and SDF-1α were measured by ELISA at admission, 7 ± 1 days, at 3 ± 1 months, and 12 ± 3 months. Except for BDNF, all GF and SDF-1α serum levels showed a peak value at day 7 and remained elevated during the first 3 months (all p < 0.01). High serum levels at day 7 of VEGF (OR, 19.3), Ang-1 (OR, 14.7), G-CSF (OR, 9.6), and SDF-1α (OR, 28.5) were independently associated with good outcome at 12 months (all p < 0.0001). On the other hand, serum levels of VEGF (B, − 21.4), G-CSF (B, − 14.0), Ang-1 (B, − 13.3), and SDF-1α (B, − 44.6) measured at day 7 were independently associated with lesion volume at 6 months (p < 0.01). In summary, high serum levels of VEGF, Ang-1, G-CSF, and SDF-1α at day 7 and 3 months after ischemic stroke are associated with good functional outcome and smaller residual lesion at 1 year of follow-up

Single nucleotide variations in ZBTB46 are associated with post-thrombolytic parenchymal haematoma

Haemorrhagic transformation is a complication of recombinant tissue-plasminogen activator treatment. The most severe form, parenchymal haematoma, can result in neurological deterioration, disability, and death. Our objective was to identify single nucleotide variations associated with a risk of parenchymal haematoma following thrombolytic therapy in patients with acute ischaemic stroke. A fixed-effect genome-wide meta-analysis was performed combining two-stage genome-wide association studies (n = 1904). The discovery stage (three cohorts) comprised 1324 ischaemic stroke individuals, 5.4% of whom had a parenchymal haematoma. Genetic variants yielding a P-value < 0.05 1 x 10(-5) were analysed in the validation stage (six cohorts), formed by 580 ischaemic stroke patients with 12.1% haemorrhagic events. All participants received recombinant tissue-plasminogen activator; cases were parenchymal haematoma type 1 or 2 as defined by the European Cooperative Acute Stroke Study (ECASS) criteria. Genome-wide significant findings (P < 5 x 10(-8)) were characterized by in silica functional annotation, gene expression, and DNA regulatory elements. We analysed 7 989 272 single nucleotide polymorphisms and identified a genome-wide association locus on chromosome 20 in the discovery cohort; functional annotation indicated that the ZBTB46 gene was driving the association for chromosome 20. The top single nucleotide polymorphism was rs76484331 in the ZBTB46 gene [P = 2.49 x 10(-8); odds ratio (OR): 11.21; 95% confidence interval (CI): 4.82-26.55]. In the replication cohort (n = 580), the rs76484331 polymorphism was associated with parenchymal haematoma (P = 0.01), and the overall association after meta-analysis increased (P = 1.61 x 10(-8), OR: 5.84; 95% CI: 3.16-10.76). ZBTB46 codes the zinc finger and BTB domain-containing protein 46 that acts as a transcription factor. In silica studies indicated that ZBTB46 is expressed in brain tissue by neurons and endothelial cells. Moreover, rs76484331 interacts with the promoter sites located at 20q13. In conclusion, we identified single nucleotide variants in the ZBTB46 gene associated with a higher risk of parenchymal haematoma following recombinant tissue-plasminogen activator treatment.Peer reviewe

Table_3_A Polygenic Risk Score Based on a Cardioembolic Stroke Multitrait Analysis Improves a Clinical Prediction Model for This Stroke Subtype.DOCX

[Background] Occult atrial fibrillation (AF) is one of the major causes of embolic stroke of undetermined source (ESUS). Knowing the underlying etiology of an ESUS will reduce stroke recurrence and/or unnecessary use of anticoagulants. Understanding cardioembolic strokes (CES), whose main cause is AF, will provide tools to select patients who would benefit from anticoagulants among those with ESUS or AF. We aimed to discover novel loci associated with CES and create a polygenetic risk score (PRS) for a more efficient CES risk stratification.[Methods] Multitrait analysis of GWAS (MTAG) was performed with MEGASTROKE-CES cohort (n = 362,661) and AF cohort (n = 1,030,836). We considered significant variants and replicated those variants with MTAG p-value < 5 × 10−8 influencing both traits (GWAS-pairwise) with a p-value < 0.05 in the original GWAS and in an independent cohort (n = 9,105). The PRS was created with PRSice-2 and evaluated in the independent cohort.[Results] We found and replicated eleven loci associated with CES. Eight were novel loci. Seven of them had been previously associated with AF, namely, CAV1, ESR2, GORAB, IGF1R, NEURL1, WIPF1, and ZEB2. KIAA1755 locus had never been associated with CES/AF, leading its index variant to a missense change (R1045W). The PRS generated has been significantly associated with CES improving discrimination and patient reclassification of a model with age, sex, and hypertension.[Conclusion] The loci found significantly associated with CES in the MTAG, together with the creation of a PRS that improves the predictive clinical models of CES, might help guide future clinical trials of anticoagulant therapy in patients with ESUS or AF.Peer reviewe

Multi-ancestry GWAS reveals excitotoxicity associated with outcome after ischaemic stroke

During the first hours after stroke onset, neurological deficits can be highly unstable: some patients rapidly improve, while others deteriorate. This early neurological instability has a major impact on long-term outcome. Here, we aimed to determine the genetic architecture of early neurological instability measured by the difference between the National Institutes of Health Stroke Scale (NIHSS) within 6 h of stroke onset and NIHSS at 24 h. A total of 5876 individuals from seven countries (Spain, Finland, Poland, USA, Costa Rica, Mexico and Korea) were studied using a multi-ancestry meta-analyses. We found that 8.7% of NIHSS at 24 h of variance was explained by common genetic variations, and also that early neurological instability has a different genetic architecture from that of stroke risk. Eight loci (1p21.1, 1q42.2, 2p25.1, 2q31.2, 2q33.3, 5q33.2, 7p21.2 and 13q31.1) were genome-wide significant and explained 1.8% of the variability suggesting that additional variants influence early change in neurological deficits. We used functional genomics and bioinformatic annotation to identify the genes driving the association from each locus. Expression quantitative trait loci mapping and summary data-based Mendelian randomization indicate that ADAM23 (log Bayes factor = 5.41) was driving the association for 2q33.3. Gene-based analyses suggested that GRIA1 (log Bayes factor = 5.19), which is predominantly expressed in the brain, is the gene driving the association for the 5q33.2 locus. These analyses also nominated GNPAT (log Bayes factor = 7.64) ABCB5 (log Bayes factor = 5.97) for the 1p21.1 and 7p21.1 loci. Human brain single-nuclei RNA-sequencing indicates that the gene expression of ADAM23 and GRIA1 is enriched in neurons. ADAM23, a presynaptic protein and GRIA1, a protein subunit of the AMPA receptor, are part of a synaptic protein complex that modulates neuronal excitability. These data provide the first genetic evidence in humans that excitotoxicity may contribute to early neurological instability after acute ischaemic stroke. Ibanez et al. perform a multi-ancestry meta-analysis to investigate the genetic architecture of early stroke outcomes. Two of the eight genome-wide significant loci identified-ADAM23 and GRIA1-are involved in synaptic excitability, suggesting that excitotoxicity contributes to neurological instability after ischaemic stroke.Peer reviewe

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries