Elevated circulating metalloproteinase 7 predicts recurrent cardiovascular events in patients with carotid stenosis: a prospective cohort study.

BACKGROUND: Major adverse cardiovascular events are the main cause of morbidity and mortality over the long term in patients undergoing carotid endarterectomy. There are few reports assessing the prognostic value of markers of inflammation in relation to the risk of cardiovascular disease after carotid endarterectomy. Here, we aimed to determine whether matrix metalloproteinases (MMP-1, MMP-2, MMP-7, MMP-9 and MMP-10), tissue inhibitor of MMPs (TIMP-1) and in vivo inflammation studied by 18F-FDG-PET/CT predict recurrent cardiovascular events in patients with carotid stenosis who underwent endarterectomy. METHODS: This prospective cohort study was carried out on 31 consecutive patients with symptomatic (23/31) or asymptomatic (8/31) severe (> 70%) carotid stenosis who were scheduled for carotid endarterectomy between July 2013 and March 2016. In addition, 26 healthy controls were included in the study. Plasma and serum samples were collected 2 days prior to surgery and tested for MMP-1, MMP-2, MMP-7, MMP-9, MMP-10, TIMP-1, high-density lipoprotein, low-density lipoprotein, high-sensitivity C-reactive protein and erythrocyte sedimentation rate. 18F-FDG-PET/CT focusing on several territories' vascular wall metabolism was performed on 29 of the patients because of no presurgical availability in 2 symptomatic patients. Histological and immunohistochemical studies were performed with antibodies targeting MMP-10, MMP-9, TIMP-1 and CD68. RESULTS: The patients with carotid stenosis had significantly more circulating MMP-1, MMP-7 and MMP-10 than the healthy controls. Intraplaque TIMP-1 was correlated with its plasma level (r = 0.42 P = .02) and with 18F-FDG uptake (r = 0.38 P = .05). We did not find any correlation between circulating MMPs and in vivo carotid plaque metabolism assessed by 18F-FDG-PET. After a median follow-up of 1077 days, 4 cerebrovascular, 7 cardiovascular and 11 peripheral vascular events requiring hospitalization were registered. Circulating MMP-7 was capable of predicting events over and above the traditional risk factors (HR = 1.15 P = .006). When the model was associated with the variables of interest, the risk predicted by 18F-FDG-PET was not significant. CONCLUSIONS: Circulating MMP-7 may represent a novel marker for recurrent cardiovascular events in patients with moderate to severe carotid stenosis. MMP-7 may reflect the atherosclerotic burden but not plaque inflammation in this specific vascular territory.

[Perception of physicians on factors that influence the choice of a dicoumarin or a new oral anticoagulant in patients with non-valvular atrial fibrillation]. / Percepción de los médicos sobre los factores que influyen en la elección de un dicumarínico o de un nuevo anticoagulante oral en pacientes con fibrilación auricular no valvular.

AIMS: Recent studies have demonstrated the efficacy and safety of new oral anticoagulant drugs for the prevention of thromboembolic events in patients with non-valvular atrial fibrillation. Our aim was to evaluate the factors that can influence physicians in their choice between a classic and a new anticoagulant in these patients. DESIGN: Several variables of interest were discussed and analysed using a WorkmatTM methodology. SITES: Six regional meetings were held in Spain (East, Catalonia, Andalusia-Extremadura, Madrid, North-east, and North of Spain). PARTICIPANTS: Meetings were attended by 39 specialists (cardiologists, neurologists, haematologists, internists, and emergency and Primary Care physicians). MEASUREMENTS: Each participant graded their level of agreement, with a score from 1 to 10, on every analysed variable. RESULTS: A new anticoagulant drug was preferred in patients with previous failure of dicoumarin therapy (9.7±0.5), high haemorrhagic risk (8.7±1), prior bleeding (7.8±1.5), and high thrombotic risk (7.7±1.2). Dicoumarins were preferred in cases of severe (1.2±0.4) or moderate (4.2±2.5) kidney failure, good control with dicoumarins (2.3±1.5), cognitive impairment (3.2±3), and low haemorrhagic risk (4.3±3). Age, sex, weight, cost of drug, polymedication, and low thrombotic risk achieved intermediate scores. There were no differences between the different specialists or Spanish regions. CONCLUSIONS: The presence of a high thrombotic or haemorrhagic risk and the failure of previous dicoumarin therapy lead to choosing a new oral anticoagulant in patients with non-valvular atrial fibrillation, while kidney failure, cognitive impairment, good control with dicoumarins, and a low bleeding risk predispose to selecting a classic dicoumarin anticoagulant.

Basilar branch occlusion.

OPINION STATEMENT: During the past few years, the branch syndromes have been ascribed to pontine lesions, and the development of neuroimaging techniques has renewed the interest in exploring their clinical-radiological correlation. Brain imaging via MRI has helped in the diagnosis and accurate localization of lesions. From classic studies it is now accepted that the pathogenic mechanism of lacunar pontine infarction (LPI) is perforating small arterial disease or microangiopathy caused by lipohyalinosis, whereas paramedian pontine infarction (PPI) are caused by paramedian or circumferential basilar branch disease due to atheromatous branch occlusion. The importance of basilar artery disease not only in severe posterior circulation infarcts but also in minor brainstem strokes is known from previous reports. The mechanism of PPI is probably local occlusion of the mouths of paramedian perforators through the atheromatous basilar artery (basilar branch occlusion). Infrequent basilar artery diseases such as dissection, aneurysm and hypoplasia, dolichoectatic basilar artery, embolism, or vasospasms are known to block the orifices of penetrating branch arteries and cause an infarct in the territory of the obstructed branches. An association between basilar artery branch disease and isolated pontine infarction exists; moreover, the enlargement of pontine lesion seems to be associated with neurologic worsening and fluctuating symptoms, but we know little about stroke mechanisms in patients with fluctuating symptoms and about the role of branch atherosclerotic disease. The treatment remains controversial, even in acute cases. Implementation of new neuroimaging techniques, such as high-resolution MRI, could be helpful in identifying pathogenetic mechanisms of isolated pontine infarction, thus improving therapeutic strategy and secondary prevention.

RNU6-1 in circulating exosomes differentiates GBM from non-neoplastic brain lesions and PCNSL but not from brain metastases.

BACKGROUND: Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Circulating biomarkers may assist in the processes of differential diagnosis and response assessment. GBM cells release extracellular vesicles containing a subset of proteins and nucleic acids. We previously demonstrated that exosomes isolated from the serum of GBM patients had an increased expression of RNU6-1 compared to healthy subjects. In this exploratory study, we investigated the role of this small noncoding RNA as a diagnostic biomarker for GBM versus other brain lesions with some potential radiological similarities. METHODS: We analyzed the expression of RNU6-1 in circulating exosomes of GBM patients (n = 18), healthy controls (n = 30), and patients with subacute stroke (n = 30), acute/subacute hemorrhage (n = 30), acute demyelinating lesions (n = 18), brain metastases (n = 21), and primary central nervous system lymphoma (PCNSL; n = 12) using digital droplet PCR. RESULTS: Expression of RNU6-1 was significantly higher in GBM patients than in healthy controls (P = .002). RNU6-1 levels were also significantly higher in exosomes from GBM patients than from patients with non-neoplastic lesions (stroke [P = .05], hemorrhage [P = .01], demyelinating lesions [P = .019]) and PCNSL (P = .004). In contrast, no significant differences were found between patients with GBM and brain metastases (P = .573). Receiver operator characteristic curve analyses supported the role of this biomarker in differentiating GBM from subacute stroke, acute/subacute hemorrhage, acute demyelinating lesions, and PCNSL (P < .05), but again not from brain metastases (P = .575). CONCLUSIONS: Our data suggest that the expression of RNU6-1 in circulating exosomes could be useful for the differentiation of GBM from non-neoplastic brain lesions and PCNSL, but not from brain metastases.

Prognostic value of blood glucose in emergency room and glycosylated hemoglobin in patients who have suffered an acute cerebro-vascular event. / Valor pronóstico de la glucemia en urgencias y la hemoglobina glucosilada en pacientes que han sufrido un accidente cerebrovascular agudo.

BACKGROUND AND OBJECTIVE: Stress hyperglycemia has been associated with a worse prognosis in patients hospitalized in critical care units. The aim of this study is to evaluate the impact of blood glucose and glycosylated hemoglobin (HbA1c) levels on the mortality of patients suffering a acute cerebro-vascular event, and to determine if this relationship depends on the presence of diabetes. MATERIAL AND METHODS: A retrospective analysis of 255 patients admitted to the ER for stroke was performed. Venous plasma glucose levels in the emergency room and HbA1c levels within the first 48hours were analyzed. The presence of diabetes was defined in terms of the patients' medical history, as well as their levels of fasting plasma glucose and HbA1c. Mortality was assessed within the first 30 months after the onset of the acute event. RESULTS: 28.2% of patients had diabetes. Higher mortality was observed in patients who had been admitted with plasma glucose levels≥140mg/dl (hazard ratio [HR]=2.22, 95% CI: 1.18-4.16, P=.013) after adjusting for various factors. This relationship was not confirmed in diabetic patients (HR=2.20, 95% CI: 0.66-7.40, P=.201) and was in non-diabetics (HR=2.55, 95% CI: 1.11-5.85, P=.027). In diabetics, HbA1c≥7% was not associated with poor prognosis (HR=0.68, 95% CI: 0.23-1.98, P=.475), whereas non-diabetics with admission levels of HbA1c falling within the pre-diabetes range (5.7% -6.4%) had a higher mortality (HR=2.62, 95% CI: 1.01-6.79, P=.048). CONCLUSION: Admission hyperglycemia is associated with a worse prognosis in patients without diabetes admitted for stroke, but this relationship was not seen in diabetics. In non-diabetic patients, HbA1c levels in the pre-diabetes range is associated with higher mortality.

[Urgent stroke care in hospitals with a stroke unit. Quick Project]. / Atención urgente al ictus en hospitales con unidad de ictus. Proyecto Quick.

INTRODUCTION: A stroke is a time-dependent medical emergency. Swiftness in its recognition and in the care received by the patients plays a key role in the prognosis. AIMS: To analyse the medical intervention times, to evaluate possible areas where improvements can be made and to examine the allocation of resources in the centres. PATIENTS AND METHODS: The study was based on a prospective register of patients with suspected stroke and stroke code activation treated in eight experienced Spanish stroke units. Onset-to-door, door-to-computed tomography (CT), door-to-needle, CT-to-needle and onset-to-needle times were collected. Information about the means of transport used to get to the hospital, the type of stroke and reperfusion therapies was also collected. With regard to the structural resources of the centres, data were gathered about the nurse-to-patient ratio, bed monitoring, availability of multimodal CT and magnetic resonance, and doing information or training courses. RESULTS: Altogether 197 patients were included, of whom 181 (151 infarctions and 30 brain haemorrhages) were valid. The medians (p25-p75) in minutes were: onset-to-door, 104 (70-188); door-to-CT, 27 (19-41); CT-to-needle, 30 (21-43); door-to-needle, 64 (49-83); and onset-to-needle, 156 (129-202). Reperfusion therapies were applied in 68 patients (45% of the cerebral infarctions), of which 81% were intravenous thrombolyses; 7%, endovascular treatments; and 12%, a combination of the two. The resources available in the centres were in accordance with those recommended by the clinical guidelines. There was a low percentage of patients who were studied by means of magnetic resonance. CONCLUSION: The percentage of patients treated with thrombolysis was very high and although the times of the in-hospital circuits were good, there is still room for further improvement.

TITLE: Atencion urgente al ictus en hospitales con unidad de ictus. Proyecto Quick.Introduccion. El ictus es una emergencia medica dependiente del tiempo. La rapidez en su reconocimiento y en la atencion que reciben los pacientes es clave en el pronostico. Objetivos. Analizar los tiempos de actuacion medica, evaluar posibles areas de mejora y estudiar la dotacion de recursos de los centros. Pacientes y metodos. Registro prospectivo de pacientes atendidos en ocho unidades de ictus experimentadas españolas con sospecha de ictus y activacion del codigo ictus. Se recogieron los tiempos inicio-puerta, puerta-tomografia computarizada (TC), puerta-aguja, TC-aguja e inicio-aguja. Tambien se recogieron el metodo de trasporte al hospital, el tipo de ictus y las terapias de reperfusion. En cuanto a la dotacion estructural de los centros, se recogieron la ratio de enfermeria, la monitorizacion de camas, la disponibilidad de TC multimodal y resonancia magnetica, y la realizacion de cursos de informacion o formacion. Resultados. Se incluyeron 197 pacientes, de los cuales fueron validos 181 (151 infartos y 30 hemorragias cerebrales). Las medianas (p25-p75) en minutos fueron: inicio-puerta, 104 (70-188); puerta-TC, 27 (19-41); TC-aguja, 30 (21-43); puerta-aguja, 64 (49-83); e inicio-aguja, 156 (129-202). Se aplicaron terapias de reperfusion en 68 pacientes (el 45% de los infartos cerebrales), de los cuales el 81% fueron trombolisis intravenosas; el 7%, tratamientos endovasculares; y el 12%, una combinacion de ambos. Los recursos de los centros estuvieron de acuerdo con lo recomendado por las guias clinicas. Hubo un bajo porcentaje de pacientes estudiados con resonancia magnetica. Conclusion. El porcentaje de pacientes tratados con trombolisis fue muy elevado y los tiempos de los circuitos intrahospitalarios, aunque buenos, tienen margen de mejora.

Epidemiology of Intracranial Haemorrhages Associated with Vitamin K Antagonist Oral Anticoagulants in Spain: TAC Registry.

BACKGROUND: Vitamin K antagonist oral anticoagulants (VKA-OACs) are effective for primary and secondary prevention of embolic events. The rate of haemorrhagic neurological complications in patients admitted to neurology departments in Spain is not yet known. AIMS: We aimed to determine the clinical and epidemiological characteristics of patients with intracranial haemorrhage secondary to VKA-OACs as well as the incidence of this severe complication. METHODS: We conducted a retrospective, descriptive, multi-centre study using information from the medical records of all patients admitted to neurology departments, diagnosed with spontaneous intracranial haemorrhage, and treated with VKA-OACs within a 1-year period. We collected demographic and care data from centres, patients' medical records [demographic data, medical history, haemorrhage origin, vascular risk factors, concomitant treatment, and National Institutes of Health Stroke Scale (NIHSS) scores], and patients' outcome at 3 months [independence (modified Rankin Scale score <3) and mortality rate]. RESULTS: Twenty-one hospitals serving a population of 8,155,628 inhabitants participated in the study. The total number of cases was 235, the mean age was 78.2 (SD 9.4) years, and the baseline NIHSS score was 11.6 (SD 9.5; median 9; interquartile range 14). The VKA-OACs used were acenocoumarol in 95.3% (224 patients) and warfarin in 4.7% (11 patients). The haemorrhage origin was deep in 29.8%, lobar in 25.5%, intraventricular in 11.5%, extensive in 17.4% (>100 ml), cerebellar in 12.3%, and in the brainstem in 3.4%. The international normalised ratio was within therapeutic ranges at admission (according to indication) in 29.4% (69 patients). The global incidence (cases per 100,000 inhabitants per year) is 2.88. The in-hospital mortality rate was 40%, and 24.3% of the patients were independent at 3 months, while the mortality at 3 months was 42.6%. CONCLUSION: VKA-OAC treatment is associated with a large percentage of all cases of spontaneous intracranial haemorrhage, an event leading to high dependence and mortality rates.

[Current management of antithrombotic treatment in patients with non valvular atrial fibrillation and prior history of stroke or transient ischemic attack]. / Manejo actual del tratamiento antitrombotico en pacientes con fibrilacion auricular no valvular y antecedentes de ictus o ataque isquemico transitorio.

Atrial fibrillation is the most frequent arrhythmia seen in clinical practice and is one of the most important risk factors for suffering a stroke. Strokes associated to atrial fibrillation are more severe, present higher mortality and disability rates, and there is a greater risk of recurrence. Consequently, both primary and secondary prevention of stroke associated to atrial fibrillation by means of suitable antithrombotic treatment is clearly essential in order to lower this risk. Chronic oral anticoagulants are the cornerstone of antithrombotic treatment in patients with non-valvular atrial fibrillation, especially in those who have already had a stroke. Vitamin K antagonists have traditionally been used for this purpose. Yet, these drugs have several important disadvantages (narrow therapeutic window, unpredictable response, numerous interactions with drugs and foods, as well as starting and finishing their action slowly), which limit their use in clinical practice. The new oral anticoagulants not only overcome these disadvantages but also have proved to be at least as effective as warfarin in the prevention of strokes and systemic embolism in patients with non-valvular atrial fibrillation. Additionally, they have been shown to have a better safety profile, especially with an important drop in the risk of intracranial haemorrhage, regardless of the antecedents of stroke or transient ischaemic attack, which makes them first-choice drugs in the treatment of these patients.

TITLE: Manejo actual del tratamiento antitrombotico en pacientes con fibrilacion auricular no valvular y antecedentes de ictus o ataque isquemico transitorio.La fibrilacion auricular es la arritmia mas frecuente en la practica clinica y es uno de los factores de riesgo mas importantes para padecer un ictus. Los ictus asociados a la fibrilacion auricular son mas graves, presentan una mayor mortalidad y discapacidad, y el riesgo de recurrencias es mayor. En consecuencia, la prevencion, tanto primaria como secundaria, del ictus asociado a la fibrilacion auricular mediante el adecuado tratamiento antitrombotico es claramente esencial y crucial para disminuir este riesgo. La anticoagulacion oral cronica supone la piedra angular del tratamiento antitrombotico en el paciente con fibrilacion auricular no valvular, especialmente en el paciente que ya ha tenido un ictus. Para este fin, tradicionalmente se han empleado los antagonistas de la vitamina K. Sin embargo, estos farmacos poseen importantes desventajas (estrecha ventana terapeutica, respuesta impredecible, numerosas interacciones con farmacos y alimentos, asi como un comienzo y final de accion lentos) que limitan su uso en la practica clinica. Los nuevos anticoagulantes orales no solo superan estas desventajas, sino que, ademas, han demostrado ser, al menos, tan eficaces como la warfarina en la prevencion de ictus y embolia sistemica en los pacientes con fibrilacion auricular no valvular, y poseer un mejor perfil de seguridad, en particular con una importante disminucion del riesgo de hemorragia intracraneal, independientemente de los antecedentes de ictus o ataque isquemico transitorio, lo que hace que sean farmacos de primera linea en el tratamiento de estos pacientes.

[Stroke and Takotsubo syndrome: a reciprocal relationship]. / Ictus y síndrome de takotsubo: una relación recíproca.

INTRODUCTION: Takotsubo syndrome is a transient stress cardiomyopathy associated with a distinctive left ventricular contraction pattern. It has been described as a cardioembolic source or as a consequence of stroke. Two patients are reported that illustrate the reciprocal relationship between Takotsubo syndrome and stroke and the physiopathological mechanisms implicated are analyzed. CASE REPORTS: Two women aged 70 and 78 years respectively are described. The first one was admitted with electro-cardiogram ST-segment elevation, slight troponin elevation and stroke symptoms. Ecocardiography and cardiac magnetic resonance findings were consistent with Takotsubo syndrome that was the probable source of cardioembolic stroke. The second patient suffered a Takotsubo syndrome 72 hours after a brain infarction involving the insular cortex that was considered the trigger of Takotsubo syndrome. CONCLUSIONS: Takotsubo syndrome and stroke may have a reciprocal etiological relationship that is suggested by the temporal profile between the two processes. Cardiac magnetic resonance may aid in the establishment of the diagnosis of Takotsubo syndrome.