Search for Reliable Circulating Biomarkers to Predict Carotid Plaque Vulnerability

Altres ajuts: This research was funded by grants 158/U/2017 from Fundacio La Marato TV3 and from the Instituto de Salud Carlos III (co-financed by the European Regional Development Fund). P.C.R. and E.J.X. are members of RETICS INVICTUS PLUS . S.B. and N.P. aremembers of the Quality Research Group 2017-SGR-1149 from Generalitat de Catalunya, and they are members of the Spanish Atherosclerosis Society Vascular Biology Group.Atherosclerosis is responsible for 20% of ischemic strokes, and the plaques from the internal carotid artery the most frequently involved. Lipoproteins play a key role in carotid atherosclerosis since lipid accumulation contributes to plaque progression and chronic inflammation, both factors leading to plaque vulnerability. Carotid revascularization to prevent future vascular events is reasonable in some patients with high-grade carotid stenosis. However, the degree of stenosis alone is not sufficient to decide upon the best clinical management in some situations. In this context, it is essential to further characterize plaque vulnerability, according to specific characteristics (lipid-rich core, fibrous cap thinning, intraplaque hemorrhage). Although these features can be partly detected by imaging techniques, identifying carotid plaque vulnerability is still challenging. Therefore, the study of circulating biomarkers could provide adjunctive criteria to predict the risk of atherothrombotic stroke. In this regard, several molecules have been found altered, but reliable biomarkers have not been clearly established yet. The current review discusses the concept of vulnerable carotid plaque, and collects existing information about putative circulating biomarkers, being particularly focused on lipid-related and inflammatory molecules

Novel Therapeutic Approaches to Prevent Atherothrombotic Ischemic Stroke in Patients with Carotid Atherosclerosis

Atherothrombotic stroke represents approximately 20% of all ischemic strokes. It is caused by large-artery atherosclerosis, mostly in the internal carotid artery, and it is associated with a high risk of early recurrence. After an ischemic stroke, tissue plasminogen activator is used in clinical practice, although it is not possible in all patients. In severe clinical situations, such as high carotid stenosis (≥70%), revascularization by carotid endarterectomy or by stent placement is carried out to avoid recurrences. In stroke prevention, the pharmacological recommendations are based on antithrombotic, lipid-lowering, and antihypertensive therapy. Inflammation is a promising target in stroke prevention, particularly in ischemic strokes associated with atherosclerosis. However, the use of anti-inflammatory strategies has been scarcely studied. No clinical trials are clearly successful and most preclinical studies are focused on protection after a stroke. The present review describes novel therapies addressed to counteract inflammation in the prevention of the first-ever or recurrent stroke. The putative clinical use of broad-spectrum and specific anti-inflammatory drugs, such as monoclonal antibodies and microRNAs (miRNAs) as regulators of atherosclerosis, will be outlined. Further studies are necessary to ascertain which patients may benefit from anti-inflammatory agents and how

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

Automated scoring of collaterals, blood pressure, and clinical outcome after endovascular treatment in patients with acute ischemic stroke and large-vessel occlusion

Altres ajuts: Ministerio de Ciencia e Innovación; Fondo Europeo de Desarrollo Regional (FEDER).Introduction: We aimed to determine whether the degree of collateral circulation is associated with blood pressure at admission in acute ischemic stroke patients treated with endovascular treatment and to determine its prognostic value. Methods: We evaluated patients with anterior large vessel occlusion treated with endovascular treatment in a single-center prospective registry. We collected clinical and radiological data. Automated and validated software (Brainomix Ltd., Oxford, UK) was used to generate the collateral score (CS) from the baseline single-phase CT angiography: 0, filling of ≤10% of the occluded MCA territory; 1, 11-50%; 2, 51-90%; 3, >90%. When dichotomized, we considered that CS was good (CS = 2-3), or poor (CS = 0-1). We performed bivariate and multivariable ordinal logistic regression analysis to predict CS categories in our population. The secondary outcome was to determine the influence of automated CS on functional outcome at 3 months. We defined favorable functional outcomes as mRS 0-2 at 3 months. Results: We included 101 patients with a mean age of 72.1 ± 13.1 years and 57 (56.4%) of them were women. We classified patients into 4 groups according to the CS: 7 patients (6.9%) as CS = 0, 15 (14.9%) as CS = 1, 43 (42.6%) as CS = 2 and 36 (35.6%) as CS = 3. Admission systolic blood pressure [aOR per 10 mmHg increase 0.79 (95% CI 0.68-0.92)] and higher baseline NIHSS [aOR 0.90 (95% CI, 0.84-0.96)] were associated with a worse CS. The OR of improving 1 point on the 3-month mRS was 1.63 (95% CI, 1.10-2.44) favoring a better CS (p = 0.016). Conclusion: In acute ischemic stroke patients with anterior large vessel occlusion treated with endovascular treatment, admission systolic blood pressure was inversely associated with the automated scoring of CS on baseline CT angiography. Moreover, a good CS was associated with a favorable outcome

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)

Effect of Intra-arterial Alteplase vs Placebo Following Successful Thrombectomy on Functional Outcomes in Patients With Large Vessel Occlusion Acute Ischemic Stroke: The CHOICE Randomized Clinical Trial.

Importance: It is estimated that only 27% of patients with acute ischemic stroke and large vessel occlusion who undergo successful reperfusion after mechanical thrombectomy are disability free at 90 days. An incomplete microcirculatory reperfusion might contribute to these suboptimal clinical benefits. Objective: To investigate whether treatment with adjunct intra-arterial alteplase after thrombectomy improves outcomes following reperfusion. Design, setting, and participants: Phase 2b randomized, double-blind, placebo-controlled trial performed from December 2018 through May 2021 in 7 stroke centers in Catalonia, Spain. The study included 121 patients with large vessel occlusion acute ischemic stroke treated with thrombectomy within 24 hours after stroke onset and with an expanded Treatment in Cerebral Ischemia angiographic score of 2b50 to 3. Interventions: Participants were randomized to receive intra-arterial alteplase (0.225 mg/kg; maximum dose, 22.5 mg) infused over 15 to 30 minutes (n = 61) or placebo (n = 52). Main outcomes and measures: The primary outcome was the difference in proportion of patients achieving a score of 0 or 1 on the 90-day modified Rankin Scale (range, 0 [no symptoms] to 6 [death]) in all patients treated as randomized. Safety outcomes included rate of symptomatic intracranial hemorrhage and death. Results: The study was terminated early for inability to maintain placebo availability and enrollment rate because of the COVID-19 pandemic. Of 1825 patients with acute ischemic stroke treated with thrombectomy at the 7 study sites, 748 (41%) patients fulfilled the angiographic criteria, 121 (7%) patients were randomized (mean age, 70.6 [SD, 13.7] years; 57 women [47%]), and 113 (6%) were treated as randomized. The proportion of participants with a modified Rankin Scale score of 0 or 1 at 90 days was 59.0% (36/61) with alteplase and 40.4% (21/52) with placebo (adjusted risk difference, 18.4%; 95% CI, 0.3%-36.4%; P = .047). The proportion of patients with symptomatic intracranial hemorrhage within 24 hours was 0% with alteplase and 3.8% with placebo (risk difference, -3.8%; 95% CI, -13.2% to 2.5%). Ninety-day mortality was 8% with alteplase and 15% with placebo (risk difference, -7.2%; 95% CI, -19.2% to 4.8%). Conclusions and relevance: Among patients with large vessel occlusion acute ischemic stroke and successful reperfusion following thrombectomy, the use of adjunct intra-arterial alteplase compared with placebo resulted in a greater likelihood of excellent neurological outcome at 90 days. However, because of study limitations, these findings should be interpreted as preliminary and require replication. Trial registration: ClinicalTrials.gov Identifier: NCT03876119; EudraCT Number: 2018-002195-40

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

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

Nous marcadors de vulnerabilitat de l'ateroesclerosi carotídia en pacients amb ictus isquèmic

Premi Extraordinari de Doctorat concedit pels programes de doctorat de la UAB per curs acadèmic 2019-2020L'ateroesclerosi causa el 20% dels ictus isquèmics, essent les plaques d'ateroma de l'artèria caròtida interna les que més freqüentment es veuen implicades en la gènesi de l'ictus. L'elevat risc de recurrència d'aquest tipus d'ictus justifica valorar en cada cas la necessitat d'un tractament de revascularització de la caròtida, per eliminar o excloure aquestes plaques de la circulació. Actualment aquesta decisió es fa tenint en compte el grau d'estenosi de les plaques, que és l'únic marcador de risc de recurrència validat en assaigs clínics. No obstant, el grau d'estenosi per si sol no és suficient per prendre decisions en algunes situacions clíniques relativament freqüents. Per aquest motiu és necessari l'estudi de nous marcadors de vulnerabilitat de les plaques carotídies que ajudin a millorar la selecció de pacients que es beneficien dels tractaments de revascularització. En aquesta tesi presentem els resultats d'un estudi de cohorts prospectiu de pacients amb ictus isquèmic i ateroesclerosi carotídia en el que s'ha estudiat el valor pronòstic de dos potencials nous marcadors de vulnerabilitat: la Tomografia per Emissió de Positrons (PET) amb Fluorodesoxiglucosa 18F (18FDG), que permet mesurar la inflamació de les plaques d'ateroma, i el dúplex amb contrast, que permet la detecció de neovascularització a l'interior de les plaques. En aquest estudi hem inclòs 91 pacients i els hem seguit durant una mitjana de 12,7 mesos registrant un total de 16 recurrències durant el seguiment, a més de vuit pacients que havien presentat símptomes abans de l'ingrés (recurrències prèvies). Hem observat que tant la inflamació de les plaques mesurada mitjançant PET (HR de tenir una recurrència durant el seguiment per cada increment de 1g/ml de SUV=4,57 IC 95% 1,49-13,96, p=0,008) com la neovascularització detectada mitjançant dúplex amb contrast (HR de presentar una recurrència si la placa presenta neovascularització difusa=6,54 IC 95% 1,66-26,01, p=0,007), s'associen amb el risc de recurrència d'ictus isquèmic. Aquesta associació és independent del grau d'estenosi i d'altres factors de risc vascular coneguts. A més, en el cas de la PET, els resultats del nostre estudi s'han replicat en dues cohorts internacionals diferents i independents, i s'ha fet una anàlisi conjunta. Finalment, hem creat i validat una escala de risc de recurrència (SCAIL score) que per primera vegada integra la informació derivada del grau d'estenosi i de la inflamació mesurada amb PET. La puntuació d'aquesta escala varia entre el 0 i el 5 i hem observat que puntuacions de baix risc (0, 1) s'associen amb un risc de recurrència del 0% (IC 95% 0-18,5%), mentre que puntuacions d'alt risc (4, 5) s'associen amb un risc de recurrència del 51,9% (IC 95% 32,0-71,3%). En definitiva, els resultats d'aquesta tesi mostren nous marcadors de vulnerabilitat de l'ateroesclerosi carotídia que aporten informació complementària al grau d'estenosi, i que en un futur es podrien utilitzar a la pràctica clínica per seleccionar millor els pacients candidats a tractaments de revascularització de la caròtida.La aterosclerosis causa el 20% del total de ictus isquémicos, siendo las placas de ateroma de la arteria carótida interna las que más frecuentemente se ven implicadas en la génesis del ictus. El elevado riesgo de recurrencia de este tipo de ictus justifica valorar en cada caso la necesidad de un tratamiento de revascularización de la carótida, con el objetivo de eliminar o excluir estas placas de la circulación. Actualmente esta decisión se toma teniendo en cuenta el grado de estenosis de las placas, el único marcador de riesgo de recurrencia que ha sido validado en ensayos clínicos. No obstante, el grado de estenosis por sí solo no es suficiente para tomar decisiones en algunas situaciones clínicas relativamente frecuentes. Por este motivo es necesario el estudio de nuevos marcadores de vulnerabilidad de las placas de ateroma carotídeas que ayuden a mejorar la selección de pacientes que se pueden beneficiar de los tratamientos de revascularización. En esta tesis doctoral presentamos los resultados de un estudio de cohortes prospectivo de pacientes con ictus isquémico y aterosclerosis carotídea en el cual se ha estudiado el valor pronóstico de dos potenciales nuevos marcadores de vulnerabilidad: la Tomografía por Emisión de Positrones (PET) con Fluorodesoxiglucosa 18F (18FDG), que permite medir la inflamación de las placas de ateroma, y el dúplex con contraste, que permite la detección de neovascularización en el interior de las placas. En este estudio hemos incluído 91 pacientes y los hemos seguido durante una media de 12,7 meses registrando un total de 16 recurrencias durante el seguimiento, además de ocho pacientes que habían tenido síntomas antes del ingreso (recurrencias previas). Hemos observado que tanto la inflamación de las placas medida mediante PET (HR de tener una recurrencia durante el seguimiento por cada incremento de 1g/ml de SUV=4,57 IC 95% 1,49-13,96, p=0,008) como la neovascularización detectada mediante dúplex con contraste (HR de presentar una recurrencia si la placa presenta neovascularización difusa=6,54 IC 95% 1,66-26,01, p=0,007), se asocian con el riesgo de recurrencia de ictus isquémico. Esta asociación es independiente del grado de estenosis y de otros factores de riesgo vascular conocidos. Además, en el caso de la PET, los resultados de nuestro estudio se han replicado en dos cohortes internacionales diferentes e independientes, y se ha hecho un análisis conjunto. Finalmente, hemos creado y validado una escala de riesgo de recurrencia (SCAIL score) que por primera vez integra la información derivada del grado de estenosis y de la inflamación medida con PET. La puntuación de esta escala varía entre 0 y 5 y hemos observado que puntuaciones de bajo riesgo (0, 1) se asocian con un riesgo de recurrencia del 0% (IC 95% 0-18,5%), mientras que puntuaciones de alto riesgo (4, 5) se asocian con un riesgo de recurrencia del 51,9% (IC 95% 32,0-71,3%). En definitiva, los resultados de esta tesis doctoral muestran nuevos marcadores de vulnerabilidad de la aterosclerosis carotídea que aportan información complementaria al grado de estenosis y que en un futuro se podrían utilizar en la práctica clínica para seleccionar mejor los pacientes candidatos a tratamientos de revascularización de la carótida.Atherosclerosis is responsible for approximately 20% of all ischemic strokes, being plaques from the internal carotid artery (ICA) the most frequently involved in stroke pathogenesis. Atherosclerosis-related strokes present high risk of recurrence and thus, revascularization therapies of the ICA should be considered in the setting of this stroke subtype. Currently, the decision of performing a revascularization therapy depends solely on the degree of stenosis of the carotid plaque, which is the only marker of risk of recurrence validated on clinical trials. However, the degree of stenosis alone, is not sufficient to decide on the best treatment in some frequent clinical situations. Therefore, there is a need for new biomarkers of carotid plaque vulnerability, which may help identifying patients who benefit from carotid revascularization. In this doctoral thesis, we present the results of a propective cohort study of patients with a recent ischemic stroke and carotid atherosclerosis, in whom we tested the prognostic value of two new vulnerability biomarkers: inflammation of the plaques measured with 18F-Fluorodeoxyglucose Positron-Emission Tomography (18FDG-PET), and neovascularization detected with Contrast-Enhanced Ultrasound (CEUS). We included 91 patients and we followed them during a mean of 12,7 months. We registered 16 stroke recurrences during the follow-up and eight patients had presented symptoms before admission (pre-hospitalization recurrences). We observed that both markers, inflammation measured with 18FDG-PET (HR for stroke recurrence for 1g/ml increase in the SUV of the plaque=4,57 CI 95% 1,49-13,96, p=0,008) and neovascularization assessed with CEUS (HR for stroke recurrence if the plaque presents diffuse neovascularization=6,54 CI 95% 1,66-26,01, p=0,007), are associated with the early risk of stroke recurrence. This association is independent from the degree of stenosis and other known vascular risk factors. In addition, we replicated the prognostic value of the carotid PET in two international independent cohorts and we performed a pooled analysis of the three studies. Finally, we have created and validated the first stroke risk score (SCAIL score) that gathers the information derived from the PET and the degree of stenosis. This score ranges from 0 to 5 and we observed that low-risk scores (0, 1) were associated with a risk of stroke recurrence of 0% (CI 95% 0-18,5%), while high-risk scores predicted a risk of reccurrence of 51,9% (CI 95% 32,0-71,3%). In conclusion, the results presented in this doctoral thesis demonstrate new markers of carotid plaque vulnerability which add complementary information to the degree of stenosis. This information might be used in the near future to better select patients who can benefit from carotid revascularization

Nous marcadors de vulnerabilitat de l’ateroesclerosi carotídia en pacients amb ictus isquèmic

L’ateroesclerosi causa el 20% dels ictus isquèmics, essent les plaques d’ateroma de l’artèria caròtida interna les que més freqüentment es veuen implicades en la gènesi de l’ictus. L’elevat risc de recurrència d’aquest tipus d’ictus justifica valorar en cada cas la necessitat d’un tractament de revascularització de la caròtida, per eliminar o excloure aquestes plaques de la circulació. Actualment aquesta decisió es fa tenint en compte el grau d’estenosi de les plaques, que és l’únic marcador de risc de recurrència validat en assaigs clínics. No obstant, el grau d’estenosi per si sol no és suficient per prendre decisions en algunes situacions clíniques relativament freqüents. Per aquest motiu és necessari l’estudi de nous marcadors de vulnerabilitat de les plaques carotídies que ajudin a millorar la selecció de pacients que es beneficien dels tractaments de revascularització. En aquesta tesi presentem els resultats d’un estudi de cohorts prospectiu de pacients amb ictus isquèmic i ateroesclerosi carotídia en el que s’ha estudiat el valor pronòstic de dos potencials nous marcadors de vulnerabilitat: la Tomografia per Emissió de Positrons (PET) amb Fluorodesoxiglucosa 18F (18FDG), que permet mesurar la inflamació de les plaques d’ateroma, i el dúplex amb contrast, que permet la detecció de neovascularització a l’interior de les plaques. En aquest estudi hem inclòs 91 pacients i els hem seguit durant una mitjana de 12,7 mesos registrant un total de 16 recurrències durant el seguiment, a més de vuit pacients que havien presentat símptomes abans de l’ingrés (recurrències prèvies). Hem observat que tant la inflamació de les plaques mesurada mitjançant PET (HR de tenir una recurrència durant el seguiment per cada increment de 1g/ml de SUV=4,57 IC 95% 1,49-13,96, p=0,008) com la neovascularització detectada mitjançant dúplex amb contrast (HR de presentar una recurrència si la placa presenta neovascularització difusa=6,54 IC 95% 1,66-26,01, p=0,007), s’associen amb el risc de recurrència d’ictus isquèmic. Aquesta associació és independent del grau d’estenosi i d’altres factors de risc vascular coneguts. A més, en el cas de la PET, els resultats del nostre estudi s’han replicat en dues cohorts internacionals diferents i independents, i s’ha fet una anàlisi conjunta. Finalment, hem creat i validat una escala de risc de recurrència (SCAIL score) que per primera vegada integra la informació derivada del grau d’estenosi i de la inflamació mesurada amb PET. La puntuació d’aquesta escala varia entre el 0 i el 5 i hem observat que puntuacions de baix risc (0, 1) s’associen amb un risc de recurrència del 0% (IC 95% 0-18,5%), mentre que puntuacions d’alt risc (4, 5) s’associen amb un risc de recurrència del 51,9% (IC 95% 32,0-71,3%). En definitiva, els resultats d’aquesta tesi mostren nous marcadors de vulnerabilitat de l’ateroesclerosi carotídia que aporten informació complementària al grau d’estenosi, i que en un futur es podrien utilitzar a la pràctica clínica per seleccionar millor els pacients candidats a tractaments de revascularització de la caròtida.La aterosclerosis causa el 20% del total de ictus isquémicos, siendo las placas de ateroma de la arteria carótida interna las que más frecuentemente se ven implicadas en la génesis del ictus. El elevado riesgo de recurrencia de este tipo de ictus justifica valorar en cada caso la necesidad de un tratamiento de revascularización de la carótida, con el objetivo de eliminar o excluir estas placas de la circulación. Actualmente esta decisión se toma teniendo en cuenta el grado de estenosis de las placas, el único marcador de riesgo de recurrencia que ha sido validado en ensayos clínicos. No obstante, el grado de estenosis por sí solo no es suficiente para tomar decisiones en algunas situaciones clínicas relativamente frecuentes. Por este motivo es necesario el estudio de nuevos marcadores de vulnerabilidad de las placas de ateroma carotídeas que ayuden a mejorar la selección de pacientes que se pueden beneficiar de los tratamientos de revascularización. En esta tesis doctoral presentamos los resultados de un estudio de cohortes prospectivo de pacientes con ictus isquémico y aterosclerosis carotídea en el cual se ha estudiado el valor pronóstico de dos potenciales nuevos marcadores de vulnerabilidad: la Tomografía por Emisión de Positrones (PET) con Fluorodesoxiglucosa 18F (18FDG), que permite medir la inflamación de las placas de ateroma, y el dúplex con contraste, que permite la detección de neovascularización en el interior de las placas. En este estudio hemos incluído 91 pacientes y los hemos seguido durante una media de 12,7 meses registrando un total de 16 recurrencias durante el seguimiento, además de ocho pacientes que habían tenido síntomas antes del ingreso (recurrencias previas). Hemos observado que tanto la inflamación de las placas medida mediante PET (HR de tener una recurrencia durante el seguimiento por cada incremento de 1g/ml de SUV=4,57 IC 95% 1,49-13,96, p=0,008) como la neovascularización detectada mediante dúplex con contraste (HR de presentar una recurrencia si la placa presenta neovascularización difusa=6,54 IC 95% 1,66-26,01, p=0,007), se asocian con el riesgo de recurrencia de ictus isquémico. Esta asociación es independiente del grado de estenosis y de otros factores de riesgo vascular conocidos. Además, en el caso de la PET, los resultados de nuestro estudio se han replicado en dos cohortes internacionales diferentes e independientes, y se ha hecho un análisis conjunto. Finalmente, hemos creado y validado una escala de riesgo de recurrencia (SCAIL score) que por primera vez integra la información derivada del grado de estenosis y de la inflamación medida con PET. La puntuación de esta escala varía entre 0 y 5 y hemos observado que puntuaciones de bajo riesgo (0, 1) se asocian con un riesgo de recurrencia del 0% (IC 95% 0-18,5%), mientras que puntuaciones de alto riesgo (4, 5) se asocian con un riesgo de recurrencia del 51,9% (IC 95% 32,0-71,3%). En definitiva, los resultados de esta tesis doctoral muestran nuevos marcadores de vulnerabilidad de la aterosclerosis carotídea que aportan información complementaria al grado de estenosis y que en un futuro se podrían utilizar en la práctica clínica para seleccionar mejor los pacientes candidatos a tratamientos de revascularización de la carótida.Atherosclerosis is responsible for approximately 20% of all ischemic strokes, being plaques from the internal carotid artery (ICA) the most frequently involved in stroke pathogenesis. Atherosclerosis-related strokes present high risk of recurrence and thus, revascularization therapies of the ICA should be considered in the setting of this stroke subtype. Currently, the decision of performing a revascularization therapy depends solely on the degree of stenosis of the carotid plaque, which is the only marker of risk of recurrence validated on clinical trials. However, the degree of stenosis alone, is not sufficient to decide on the best treatment in some frequent clinical situations. Therefore, there is a need for new biomarkers of carotid plaque vulnerability, which may help identifying patients who benefit from carotid revascularization. In this doctoral thesis, we present the results of a propective cohort study of patients with a recent ischemic stroke and carotid atherosclerosis, in whom we tested the prognostic value of two new vulnerability biomarkers: inflammation of the plaques measured with 18F-Fluorodeoxyglucose Positron-Emission Tomography (18FDG-PET), and neovascularization detected with Contrast-Enhanced Ultrasound (CEUS). We included 91 patients and we followed them during a mean of 12,7 months. We registered 16 stroke recurrences during the follow-up and eight patients had presented symptoms before admission (pre-hospitalization recurrences). We observed that both markers, inflammation measured with 18FDG-PET (HR for stroke recurrence for 1g/ml increase in the SUV of the plaque=4,57 CI 95% 1,49-13,96, p=0,008) and neovascularization assessed with CEUS (HR for stroke recurrence if the plaque presents diffuse neovascularization=6,54 CI 95% 1,66-26,01, p=0,007), are associated with the early risk of stroke recurrence. This association is independent from the degree of stenosis and other known vascular risk factors. In addition, we replicated the prognostic value of the carotid PET in two international independent cohorts and we performed a pooled analysis of the three studies. Finally, we have created and validated the first stroke risk score (SCAIL score) that gathers the information derived from the PET and the degree of stenosis. This score ranges from 0 to 5 and we observed that low-risk scores (0, 1) were associated with a risk of stroke recurrence of 0% (CI 95% 0-18,5%), while high-risk scores predicted a risk of reccurrence of 51,9% (CI 95% 32,0-71,3%). In conclusion, the results presented in this doctoral thesis demonstrate new markers of carotid plaque vulnerability which add complementary information to the degree of stenosis. This information might be used in the near future to better select patients who can benefit from carotid revascularization.Universitat Autònoma de Barcelona. Programa de Doctorat en Medicin