Dissertations / Theses on the topic 'Vascular event'

This thesis proposes a multidirectional methodological framework for a comprehensive ergonomic analysis and modelling of workflow for multi-modal vascular image-guided procedures (IGPs). Two approaches are employed to analyse the workflow: Discrete Event Simulation (DES) and purpose-oriented physical models. In contrast to previous studies, the proposed methodology looks in detail the actions carried out within the intervention rooms and the clinical experience during the procedures with three main objectives: to provide a deeper understanding of vascular procedures, to predict the impact of protocol modifications and to offer a framework to develop new image-guided protocols for the alternative use of Magnetic Resonance (MR) imaging in comparison with X-Ray Digital Subtraction Angiography (DSA). The methodological framework includes an assessment of commercial simulation software packages to evaluate their fitness to the specific requirements of this research. The novel methodology is applied to several cases studies of common vascular IGPs. In addition, a case of MR – guided focused ultrasound intervention demonstrates how it is possible to extend the framework to study non-vascular IGPs. The multi-disciplinary methodological framework described opens a new way to understand IGPs that could be used in prospective applications such as medical education and medical devices regulations.

La malaltia cardiovascular suposa un problema de salut mundial amb gran morbimortalitat associada. L’arteriosclerosi, que la ocasiona, és una malaltia inflamatòria sistèmica en la que hi influencien diversos factors de risc cardiovasculars: edat, gènere, hipertensió arterial (HTA), dislipèmia, tabac, diabetis mellitus (DM), obesitat i malaltia renal crònica (MRC). Altres factors com la fibril·lació auricular (FA) i la malaltia vascular prèvia (MVP) hi influencien. En ocasions es produeixen canvis en la placa d’ateroma que condueixen a l’infart, sigui en territori coronari, cerebrovascular o arterial perifèric. El per què es desenvolupen en unes artèries o unes altres no és del tot conegut però els pacients tendeixen a repetir esdeveniments en el mateix territori. La hipòtesi: Els factors de risc cardiovascular influencien d’una manera diferent que un accident vascular agut es presenti en un territori arterial o en un altre (Síndrome coronària aguda (SCA), accident cerebrovascular (AVC) o malaltia arterial perifèrica crítica (MAP)). S’han descrit les característiques d’una població de 2993 pacients consecutius que han ingressat a urgències d’un hospital general per SCA, AVC o MAP durant tres anys comparant els tres motius d’ingrés. La població estudiada presenta una elevada prevalença de factors de risc clàssic, té menys dones i més edat que d’altres poblacions descrites a la literatura. Els pacients estudiats presenten: 74.2 anys (62.9;81.4), 70.7% són homes, 75.6% HTA, 59% DLP, 20.2% DLP-aterogènica, 18.4% FA, 23% MRC, >35.7% MVP, DM en un 40%, i disglicèmia en 30.3%, diagnòstic de nou d’HTA en 7%. Determinar la HbA1C és una eina fàcil d’implementar i millora la detecció de nous casos de DM en pacients que ingressen per accident vascular agut. S’han diagnosticat 7.2% de DM de nou. Hi ha marge de millora en la prevenció secundària i el grau de control tant en SCA, AVC com en MAP. Destaca el menor ús de fàrmacs antihipertensius en el grup que ingressa per AVC. Un 6.6% dels pacients són èxitus durant l’ingrés, moren més els que ingressen per MAP i menys els SCA. Els factors que predisposen a reingressar per un nou accident vascular són: presència de MVP, MRC, DM i tabac. En canvi en els >75 anys aquests factors són: MVP i DM. En la població estudiada la dislipèmia, l’obesitat l’exposició al tabac (fumadors i exfumadors) i la MRC són els factors que més pesen a l’hora de presentar un primer SCA en comptes d’AVC o MAP. L’edat avançada, la HTA i la FA són els factors que més influencien a l’hora de presentar un AVC en comptes de SCA o MAP. L’edat avançada i la DM són els factors que influencien més a l’hora de presentar una MAP en comptes d’un accident vascular agut en forma de SCA o AVC. En els pacients amb DM el pes dels altres factors de risc per a presentar un accident en un determinat territori en comptes d’un altre s’atenua, mantenint-se la HTA i FA com a factors de major pes per patir un primer AVC respecte SCA i MAP.
Cardiovascular disease (CVD) represents a global health problem with high morbidity and mortality. Atherosclerosis, the cause of CVD, is a systemic inflammatory disease that is influenced by traditional cardiovascular risk factors: age, gender, high blood pressure (HBP), dyslipidaemia (DLP), smoking, diabetes mellitus (DM), obesity and chronic kidney disease ( CKD), as Atrial fibrillation (AF) and prior vascular disease (PVD) are also contributing factors to CVD. Changes in the atherosclerotic plaque can lead to an acute vascular event in different territories: acute coronary syndrome (ACS), cerebrovascular (stroke) or peripheral arterial critical limb disease (PAD). The development of a clinical atherosclerotic event in one arterial vascular territory is not fully understood, but patients tend to repeat events in the same territory. This thesis shows that an association between cardiovascular risk factors and the probability of developing an atherosclerotic event in a particular territory can be made. The study group consists on 2993 patients that were admitted consecutively in the emergency room due to an acute vascular event, ACS, CVA or PAD during a 3 years period. Demographic data, CVR factors, previous events (PVD), previous treatments, in hospital readmission and mortality during the study period were collected from the medical record in a data base. The study also included the evaluation lipid and glycaemic control (HvA1c) and renal function by blood samples analysis. The study compared the collected data for the three events. The analysis of data shows that the population included in this study had a high prevalence of classical CV risk factors, there were less proportion of women and first events appeared in older ages than other populations described in the literature. The characteristics of the studied group were: 74.2 years old [62.9; 81.4], 70.7% men, 75.6% HBP, 59% DLP 20.2% DLP-atherogenic, 18.4% FA, 23% MRC,> 35.7% PVD DM 40%, preDM in 30.3% and 7% of patients have been diagnosed of of new onset hypertension. HbA1C helped detecting 7.2% of new onset DM, showing that HbA1c study should be included for all patients diagnosed for an accute vascular event . The study shows that the secondary prevention for the vascular events included needs to be improved. In particular, we detected a lesser use of antihypertensive drugs in the patients admitted due to a first stroke even if they represented higher proportion of HBP. In our series there was 6.6% inhospital mortality. Mortality rate tended to be higher in patients admitted by PAD than by SCA. Predisposing readmission risk factors were: presence of PVD, CKD, DM and tobacco. However in the> 75 years these factors were: PVD and DM. Factors that have a positive influence on presenting ACS instead of the other two vascular accidents were: DLP, obesity, tobacco exposure (smokers and ex-smokers) and CKD. In the cerebrovascular territory predisposing factors are: the elderly, HBP and AF. Older age and DM are factors that influence in presenting PAD instead of an ACV or ACS. In DM patients the influence of other risk factors is attenuated when having the first acute vascular event. HBP and AF mantain their influence in suffering a first stroke in population with DM.

Contesto e scopo: La proproteina convertasi subtilisina/kexina di tipo 9 (PCSK9), uno dei principali regolatori del metabolismo del recettore delle LDL, è stata associata allo sviluppo di aterosclerosi. Diversi studi hanno confermato tale associazione attraverso vie lipidiche e non lipidiche. Tuttavia, le relazioni dirette tra PCSK9 circolante e marcatori di aterosclerosi subclinica e clinica sono ancora da chiarire. Pertanto, abbiamo valutato le relazioni tra i livelli plasmatici di PCSK9 ed alcuni indici di aterosclerosi subclinica (marcatori di imaging) e clinica (eventi vascolari; EV). Un altro obiettivo è stato l'identificazione dei determinanti indipendenti di PCSK9, con particolare attenzione ai lipidi e ai biomarcatori infiammatori. Infine, abbiamo anche valutato la relazione tra alcuni marcatori di imaging e quattro SNPs del gene PCSK9, noti per essere associati alla presenza di bassi livelli di colesterolo LDL. Per validare i risultati ottenuti in quest’ultima parte, le analisi genetiche sono state replicate in una coorte indipendente reclutata nel Regno Unito (UK). Metodi: Lo studio è stato realizzato sfruttando le banche dati, biobanche e la banca di immagini dello studio IMPROVE. 3,703 soggetti europei (54-79 anni; 48% uomini), privi di EV al basale e definiti ad alto rischio per la presenza di almeno tre fattori di rischio vascolare, sono stati reclutati e seguiti per 36 mesi. PCSK9 è stata misurata tramite ELISA e trasformata in logaritmo prima delle analisi. I marcatori di imaging convenzionali [spessore medio-intimale carotideo (cIMT, dall’inglese intima-media thickness) e dimensione della placca carotidea] ed emergenti [cambiamento di cIMT nel tempo, ecolucenza dello spessore del complesso medio intimale della carotide comune misurato in zone libere da placca (PF CC-IMTmean), ecolucenza della placca più grande rilevata in tutto l'albero carotideo e punteggio di calcio carotideo (cCS, dall’inglese carotid calcium score)] sono stati misurati su scansioni ultrasonografiche conservate nella banca di immagini. In particolare, l'ecolucenza è stata misurata in termini di mediana della scala dei grigi (GSM, dall’inglese grey scale median) della distribuzione dei pixel di una specifica regione d’interesse, mentre il cCS è stato calcolato come somma delle lunghezze dei coni d’ombra acustici generati dal calcio all'interno delle placche carotidee. I lipidi sono stati misurati con metodi enzimatici (ad eccezione del colesterolo LDL che è stato calcolato con la formula di Friedewald). Tra i marcatori infiammatori, la proteina C reattiva ad alta sensibilità (hs-PCR) è stata misurata con la turbidimetria, mentre il conteggio dei globuli bianchi (WBC, dall’inglese white blood cells) e la formula leucocitaria sono stati misurati localmente. Tutti i soggetti dello studio IMPROVE e della coorte UK (n=22,179; 48 % uomini) sono stati genotipizzati. Risultati: Nell'analisi univariata, PCSK9 correlava positivamente con colesterolo totale, LDL e HDL e con trigliceridi e basofili (tutte le p <0.0001), mentre correlava negativamente con neutrofili ed eosinofili (entrambe le p=0.04). Le correlazioni positive osservate con hs-PCR e con il conteggio dei WBC erano solo vicine alla significatività statistica (p=0.060 e 0.064, rispettivamente). Le terapie con fibrati o statine (positivamente; entrambe le p <0.0001), così come sesso maschile e storia familiare di diabete (negativamente; entrambe le p <0.05) erano i predittori indipendenti più forti dei livelli plasmatici di PCSK9. Nell'analisi non aggiustata, si osservava una correlazione negativa tra PCSK9 e variabili basali di cIMT (IMTmean, IMTmax, IMTmean-max, e PF CC-IMTmean), una correlazione negativa tra PCSK9 e la variazione di cIMT nel tempo (Fastest-IMTmax-progr) e cCS (tutte le p ≤0.01), mentre si osservava un trend positivo tra PCSK9 e GSM sia del PF CC-IMTmean che della placca carotidea (entrambe le p ≤0.0001). Il cCS (positivamente) e il GSM del PF CC-IMTmean (positivamente) erano associati significativamente (o vicini alla significatività) a PCSK9 in diversi modelli multivariati (tutte le p ≤0.064). Tutte le correlazioni osservate all’analisi univariata tra PCSK9 e le variabili basali di cIMT, Fastest-IMTmax-progr e GSM della placca carotidea perdevano la significatività statistica dopo aggiustamento delle stesse per età, sesso, latitudine ed altri potenziali confondenti. Durante il follow-up [mediana (intervallo interquartile): 3.01 (2.98; 3.12) anni], sono stati registrati 215 EV: 125 coronarici, 73 cerebrali e 17 EV periferici. Tra questi, 37 erano eventi hard (infarto miocardico, morte improvvisa ed ictus). Nell'analisi non aggiustata, PCSK9 era associata positivamente ad eventi combinati e coronarici (entrambe le p <0.01), ma non ad eventi cerebrovascolari. Anche in questo caso, tuttavia, tutte le associazioni osservate perdevano la significatività statistica dopo aggiustamento delle analisi per età, sesso e stratificazione per latitudine. La mancanza di associazione con EV era confermata anche nel modello aggiustato per tutti i fattori confondenti considerati e nelle analisi focalizzate sugli eventi hard. Per quanto riguarda il ruolo delle varianti genetiche, nessuno dei quattro SNPs considerati correlava con cIMT (IMTmean, IMTmax, IMTmean-max) quando l'analisi era effettuata nei soggetti reclutati nello studio IMPROVE. La variante rs11591147, invece, correlava negativamente con l’IMTmax misurato nella popolazione UK (p=0.002). Combinando le quattro varianti genetiche in uno score, la relazione con cIMT era non significativa nello studio IMPROVE, mentre era negativa e significativa nella popolazione UK (tutte le p <0.01). Conclusioni: I livelli plasmatici di PCSK9 non sono associati a EV. Per quanto riguarda i marcatori dell'aterosclerosi subclinica, i livelli plasmatici di PCSK9 non sono associati né alla dimensione della lesione, né all'ecolucenza della placca carotidea, ma sono associati all'ecolucenza dello spessore della parete carotidea e al carotid calcium score. Ulteriori studi sono pertanto necessari per comprendere meglio il ruolo di tale proproteina nell'ecolucenza dello spessore della parete carotidea e nel carotid calcium score. La terapia con fibrati o statine, così come il sesso maschile e la storia familiare di diabete sono i predittori indipendenti più forti di PCSK9 circolante. È stata inoltre confermata l'associazione, precedentemente osservata, tra PCSK9 circolante e alcuni marcatori lipidici ed infiammatori. La relazione tra i livelli plasmatici di PCSK9 ed altri marcatori infiammatori (neutrofili, basofili ed eosinofili) merita ulteriori indagini, così come merita ulteriori indagini l’associazione tra le quattro varianti genetiche di PCSK9 selezionate e il cIMT nella coorte britannica, in quanto lascia intravvedere un possibile ruolo di SNPs o polimorfismi genici di PCSK9 nell’aterosclerosi e nelle strategie della sua prevenzione.
Background and purpose: Proprotein convertase subtilisin/kexin type 9 (PCSK9), one of the main regulators of LDL receptor metabolism, has been associated with atherosclerosis development. Several studies have confirmed such association through both lipid and non-lipid pathways. However, the direct relationships between circulating PCSK9 and markers of subclinical and clinical atherosclerosis are still matter of debate. Therefore, we investigated the relationships between plasma PCSK9 levels and some indexes of subclinical (imaging markers) and clinical (vascular events; VEs) atherosclerosis. Another objective was the identification of the independent determinants of PCSK9, with particular attention to lipids and inflammatory biomarkers. Finally, we also assessed the relationship between some imaging markers and four SNPs of the PCSK9 gene, known to be associated with the presence of low levels of LDL-cholesterol. In order to validate the results obtained in this last part, the genetic analyses were replicated in an independent cohort recruited in the United Kingdom (UK). Methods: The study was carried out taking advantage of databases, biobanks and imaging-bank of the IMPROVE study. 3,703 European subjects (54-79 years; 48% men), free of VEs at baseline and defined at high risk for the presence of at least three vascular risk factors, were recruited and followed-up for 36 months. PCSK9 was measured by ELISA and log-transformed prior to analyses. Conventional imaging markers [carotid intima-media thickness (cIMT) and carotid plaque-size], and emerging imaging markers [cIMT change over time, echolucency of the intima-media thickess of common carotid measured in plaque free areas (PF CC-IMTmean), echolucency of the biggest plaque detected in the whole carotid tree, and carotid calcium score (cCS)] were measured on ultrasonographic scans stored in the imaging-bank. In particular, echolucency was measured in terms of grey scale median (GSM) of pixels distribution of a specific region of interest, whereas cCS was calculated as sum of lengths of acoustic shadow cones generated by calcium within carotid plaques. Lipids were measured with enzymatic methods (except for LDL-cholesterol, which was calculated by Friedewald's formula). Among inflammatory markers, high-sensitivity C-reactive protein (hs-CRP) was measured by turbidimetry, whereas white blood cells (WBC) count and the leukocyte formula had already been measured locally. All the IMPROVE study and UK (n=22,179; 48% men) subjects have been genotyped. Results: In the univariate analysis, PCSK9 was positively correlated with total, LDL-, and HDL-cholesterol, and with triglycerides and basophils (all p <0.0001), whereas was negatively correlated with neutrophils and eosinophils (both p=0.04). The positive correlations observed with hs-CRP and WBC count were just close to the statistical significance (p=0.060 and 0.064, respectively). Fibrates or statins therapies (positively; both p <0.0001), as well as male sex and family history of diabetes (negatively; both p <0.05) were the strongest independent predictors of plasma PCSK9 levels. In the unadjusted analysis, a negative correlation was observed between PCSK9 levels and basal cIMT variables (i.e. carotid IMTmean, IMTmax, IMTmean-max, and PF CC-IMTmean), a negative correlation between PCSK9 and cIMT change over time (Fastest-IMTmax-progr) and cCS (all p ≤0.01), whereas a positive trend was observed between PCSK9 and GSM of both PF CC-IMTmean and carotid plaque (both p ≤0.0001). The cCS (positively) and the GSM of PF CC-IMTmean (positively) were significantly (or almost significantly) associated with PCSK9 in several multivariate models (all p ≤0.064). All correlations observed in the univariate analysis between PCSK9 and basal cIMT variables, Fastest-IMTmax-progr and GSM of carotid plaque lost the statistical significance after adjustment for age, sex, latitude, and other potential confounders. During the follow-up [median (interquartile range): 3.01 (2.98; 3.12) years], 215 VEs were recorded: 125 coronary, 73 cerebral and 17 peripheral VEs. Among these, 37 were hard events (i.e. myocardial infarction, sudden death and stroke). In the unadjusted analysis, PCSK9 was positively associated with combined and coronary events (both p <0.01), but not with cerebrovascular events. Also in this case, however, all the associations observed lost the statistical significance after adjustment of the analyses for age, sex, and stratification for latitude. The lack of association with VEs was confirmed also in the model adjusted for all confounding factors considered, and in the analyses focused on hard events. With regard to the role of genetic variants, none of the four SNPs considered was correlated with cIMT (i.e. IMTmean, IMTmax, IMTmean-max) when the analysis was performed in the subjects recruited in the IMPROVE study. The rs11591147 variant, by contrast, was negatively correlated with IMTmax measured in the UK population (p=0.002). By combining the four genetic variants in a score, the relationship with cIMT was not significant in the IMPROVE study, whereas was negative and significant in the UK population (all p <0.01). Conclusions: Plasma PCSK9 levels are not associated with VEs. Regarding markers of subclinical atherosclerosis, PCSK9 levels are associated neither with lesion size, nor with carotid plaque echolucency, but are associated with echolucency of carotid wall thickness and with carotid calcium score. Therefore, further studies are needed to better understand the role of such circulating proprotein in carotid wall thickness echolucency and in carotid calcium score. Fibrates or statins therapies, as well as male sex and family history of diabetes are the strongest independent predictors of PCSK9 levels. The associations, previously observed, between circulating PCSK9 and some lipid and inflammatory markers have been confirmed. The relationship between plasma levels of PCSK9 and other inflammatory markers (neutrophils, basophils and eosinophils) deserves further investigation, as does the association between the four selected PCSK9 variants and cIMT in the UK cohort, as it suggests a possible role of PCSK9 SNPs or gene polymorphisms in atherosclerosis and in its preventive strategies.

Diabetes in all its forms imposes unacceptably high human, social and economic costs on all countries and at all income levels, with Type 2 diabetes (T2D) consistently growing due to increasing rates of obesity, sedentary lifestyle and hypercaloric diets. The major cause of morbidity and premature mortality in people with diabetes is not so much the presence of diabetes itself, but the development of chronic diabetic complications, causing loss of vision, renal failure, amputations, coronary artery disease and stroke. In addition to hyperglycaemia, hypertension, dyslipidaemia and obesity, the related processes of inflammation, oxidative stress; and disturbed-angiogenesis, are important factors implicated in the development and progression of diabetic micro and macrovascular complications. These factors are also key therapeutic targets. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study is a landmark study of 9795 adults with T2D aged (at baseline) 50‐75 years from Australia, New Zealand and Finland. The double blinded randomised placebo controlled FIELD study demonstrated that the oral lipid lowering drug fenofibrate reduces the occurrence of serious vascular and new complications of T2D over 5-years, including sight-threatening diabetic retinopathy by 37%, nephropathy by 15%, and lower limb amputations by 36%; and also significant reductions in some types of cardiovascular disease. Interestingly, except for some of the renoprotection, the clinical benefits were independent of fenofibrate changes to traditional lipid levels. We propose that the pleiotropic effects of fenofibrate, such as related to growth factors, inflammation and oxidative stress may contribute to fenofibrate’s effects. We conducted a clinical research project to explore this hypothesis, with an emphasis on two growth factors, Pigment Epithelium Derived Factor (PEDF) and Kallistatin. Recent literature has identified two SERPIN growth factors, PEDF and Kallistatin, to have anti-angiogenic, anti-oxidant, and anti-inflammatory effects, and small cross-sectional studies have shown promising results for their involvement in vascular function and chronic diabetes complications. The overall aims of this research project were to investigate the T2D FIELD study cohort, to determine whether plasma PEDF and Kallistatin levels were associated with T2D and its vascular and neurologic complications, their correlations with traditional and novel vascular risk factors, and if and how they are changed by fenofibrate. This thesis consists of six chapters. Chapter one is an introduction and literature review related to diabetes and risk factors; and the FIELD study and PEDF and kallistatin. Chapter two describes the FIELD study, the substudy design, and the materials and methods for both PEDF and kallistatin analyses (by ELISA). Chapter three details an issue with the identification of suboptimal quantity of the batch to batch variation of the commercially available PEDF kits and the problem resolution. Chapter four outlines the study and results of the PEDF analysis. Mean PEDF levels were significantly higher in women than men. Baseline plasma PEDF levels significantly correlated positively, however weakly, with traditional and novel vascular risk factors, including HbA1c, BMI, insulin resistance, renal dysfunction, inflammation and oxidative stress, and inversely with HDL-C levels, and with eGFR. In addition, higher PEDF levels significantly predicted the development of on-trial composite macrovascular and microvascular complications, including nephropathy and amputations. Higher baseline PEDF was also associated with a reduced risk for retinopathy development. This data suggests a role for PEDF as a potential marker to evaluate future vascular health risk and as a potential therapeutic target and agent. Plasma PEDF levels are also significantly increased by fenofibrate. We suggest that some of fenofibrate’s clinical benefits may be via its effects on PEDF; and PEDF may be a therapeutic target. Chapter five outlines the study and results of kallistatin analysis in the FIELD study T2D subjects. Baseline plasma kallistatin levels significantly correlated positively, however weakly, with traditional and novel vascular risk factors, including HbA1c, TG, total cholesterol, HDL-C, abnormal apolipoprotein profiles, and renal dysfunction. Kallistatin was also found to inversely correlate with circulating levels of markers of inflammation, MPO, and cystatin C. Significant independent determinants of baseline plasma kallistatin levels were HDL-C, TG, systolic BP, HbA1c and BMI. Unlike PEDF levels, kallistatin levels were not found to significantly correlate with vascular complications at baseline, and on-trial. Kallistatin correlated with PEDF at baseline (r=0.15), and in response to fenofibrate, circulating kallistatin levels significantly decreased, opposite to that seen in PEDF. Chapter six is a thesis summary, summarising the key findings of each chapter, and suggests research directions to extend and enhance the study findings.

Fabry (FD) and Gaucher (GD) disease are lysosomal storage disorders, caused by single enzyme deficiencies on the glycosphingolipid degradation pathway as a result of genetic mutations in the GLA and GBA genes respectively. These result in a functional enzyme deficiency within the lysosome and accumulation of un-degraded substrate. GD is characterised by a bleeding tendency and bone infarction. Patients with FD suffer from a vasculopathy with strokes, proteinuric renal failure and cardiac conduction defects, but both disorders are highly heterogeneous. Abnormal cytokine profiles and a pro-inflammatory state have been found in both FD and GD, leading to the hypothesis that abnormalities at the blood-endothelial interface affecting coagulation and leucocyte adhesion contribute to the pathology of these disorders. This thesis demonstrates the importance of vascular manifestations in the presentation of both GD and FD with failure to identify the underlying cause of these manifestations resulting in delays between the onset of clinical manifestations and arrival at the correct diagnosis. Abnormalities at the blood-endothelial interface identified in GD include up-regulation of adhesion molecules on lymphocytes that may be of importance in the pathogenesis of bone disease, and increased thrombin generation in an endothelial cell model of GD. In FD, whilst cardiac and renal manifestations occur at earlier onset and with greater severity in men, cerebrovascular disease seems to affect both sexes to a similar degree. Monocytes from females with FD exhibit an age-dependent increase in adhesion mimicking the age-dependent increase in cardiac and renal disease seen in these patients but the mechanisms underlying cerebrovascular disease remain uncertain. Initial investigations of platelet prothrombinase activity suggest this may be enhanced in FD. Further investigation of these abnormalities at the cellular level may shed new insights on, and open up new therapeutic options, for the management of the vascular complications of these disorders.

What is known and objective: Although non-steroidal anti-inflammatory drugs (NSAIDs) have been studied in randomized, controlled trials and meta-analyses in an effort to determine their cardiovascular (CV) risks, no consensus has been reached. These studies continue to raise questions, including whether cyclooxygenase-2 (COX-2) selectivity plays a role in conferring CV risk. We performed a meta-analysis of current literature to determine whether COX-2 selectivity leads to an increased CV risk. Methods: We utilized randomized, controlled trials and prospective cohort studies. We selected eight NSAIDs based on popularity and COX selectivity and conducted a search of the MEDLINE, EMBASE, and Cochrane databases. Primary endpoints included any myocardial infarction (MI), any stroke, CV death, and a combination of all three (composite CV outcomes). Twenty-six studies were found that met inclusion and exclusion criteria. Comparisons were made between all included drugs, against placebo, and against non-selective NSAIDs (nsNSAIDs). Drugs were also compared against COX-2 selective inhibitors (COXIBs) with and without inclusion of rofecoxib. Results and discussion: Incidence of MI was increased by rofecoxib in all comparison categories [all NSAIDs (OR: 1·811, 95% CI: 1·379-2·378), placebo (OR: 1·655: 95% CI: 1·029-2·661), nsNSAIDs (OR: 2·155, 95% CI: 1·146-4·053), and COXIBs (OR: 1·800, 95% CI: 1·217-2·662)], but was decreased by celecoxib and naproxen in the COXIB comparison [(OR: 0·583, 95% CI: 0·396-0·857) and (OR: 0·609, 95% CI: 0·375-0·989, respectively]. Incidence of stroke was increased by rofecoxib in comparisons with all NSAIDs and other COXIBs [(OR: 1·488, 95% CI: 1·027-2·155) and (OR: 1·933, 95% CI: 1·052-3·549), respectively]. Incidence of stroke was decreased by celecoxib when compared with all NSAIDs, nsNSAIDs, and COXIBs [(OR: 0·603, 95% CI: 0·410-0·887), (OR: 0·517, 95% CI: 0·287-0·929), and (OR: 0·509, 95% CI: 0·280-0·925), respectively]. No NSAID reached statistical significance in regard to CV death. Incidence of the composite endpoint was increased by rofecoxib when compared against all NSAIDs, placebo, and other COXIBs [(OR: 1·612, 95% CI: 1·313-1·981), (OR: 1·572, 95% CI: 1·123-2·201) and (OR: 1·838, 95% CI: 1·323-2·554), respectively]. Incidence of composite endpoint was decreased by celecoxib in the all NSAIDs and COXIBs comparisons [(OR: 0·805, 95% CI: 0·658-0·986) and (OR: 0·557, 95% CI: 0.404-0.767), respectively]. When rofecoxib was removed from the COXIBs group, no difference was found with any comparison, suggesting rofecoxib skewed the data. What is new and conclusion: This instead of the meta-analysis suggests that COX-2 selectivity may not play a role in the CV risk of NSAIDs. Rofecoxib was the only drug to demonstrate harm and skewed the data of the COX-2 selective group.

La población española es considerada una población de bajo riesgo cardiovascular (RCV), a pesar de los eventos vasculares (EV) son una de las principales causes de muerte. Los eventos coronarios (EC) han sido la principal causa de muerte seguida de los eventos cerebrales (ECe). Objetivo: Determinar la incidencia de EV en una población mediterránea de bajo RCV después de 9 años de seguimiento, así como la influencia de los diferentes factores de riesgo vascular (FRV), en especial la arteriopatía periférica (AP) y la aparición de recurrencia. Material y métodos: El grupo ARTPER es un estudio poblacional prospectivo observacional iniciado en el ano 2006 y con un seguimiento hasta la actualidad, con una muestra inicial de 3.786 sujetos mayores de 49 anos, reclutados bajo muestreo simple aleatorio de diferentes centros de Atención Primaria. Se recogieron los datos socio-demográficos y las variables de RCV [Hipertensión arterial (HTA), Diabetes Mellitus (DM), Dislipemia (DSLP), tabaquismo, obesidad y AP]. Los EV y la morbi-mortalidad fueron las variables principales del estudio. Resultados: Los sujetos con AP presentan mayor incidencia de EV. El riesgo de mortalidad vascular es hasta 7 veces superior en individuos con AP respecto a los sanos. El riesgo de EC y ECe es mayor de 4 veces y 3 veces, respectivamente, en sujetos con AP, en relación con individuos con índice tobillo brazo (ITB) normal. Los sujetos con calcificación arterial (CA) no presentan diferencias en la incidencia de EV respecto a los sanos, excepto en ECe. La recurrencia de EV, independientemente de la etiología, es mayor en el grupo de AP (42%) respecto a los sanos (31%). La odds ratio (OR) de recurrencia de ECe de AP respecto a los sanos, tras ajustar por los FRV, es de 1,77. Conclusiones: La presencia de AP aumenta la incidencia de EV independientemente de FRV, así como el riesgo de recurrencia, especialmente en lo que se refiere a los ECe.
Spanish population is considered a low cardiovascular risk population although vascular events are the principal cause of death. Coronary events were ranked as the first in number of deaths in the general population, followed by cerebrovascular events. Objective: the aim of our study is to determine the incidence of vascular events in lowcardiovascular-risk general population after 9 years follow-up, as well as the influence of vascular risk factors, with a special interest in peripheral arterial disease patients and future events. Methods: ARTPER is an ongoing prospective observational population cohort study with 3786 subjects over 49 years old recruited (simple random sampling) from Primary Health Care Centers. We obtained demographic variables, different vascular risk scores, the presence of principal cardiovascular risk factors (hypertension, diabetes mellitus, hypercholesterolemia, smoking habit, obesity, abdominal obesity and peripheral arterial disease). Vascular events or morbi-mortality (vascular and non-vascular cause) were classified as end points. Results: Patient with peripheral arterial disease present higher incidence of vascular events. The risk of vascular mortality is up to 7 times higher in individuals with peripheral arterial disease than healthy population. The risk of coronary events and cerebrovascular events is greater than 4 times and 3 times respectively in subjects with peripheral arterial disease in contrast with healthy population. Subjects with arterial calcification do not present differences in the incidence of vascular events compared to healthy subjects, except in cerebrovascular events. The recurrence of vascular events independently of etiology is greater in in peripheral arterial disease (42%) compared to healthy group (31%). The Odds Ratio of recurrence of cerebrovascular events for patients with peripheral arterial disease vs healthy patients after adjusting for cardiovascular risk factor is 1.77. Conclusions: The presence of peripheral arterial disease increases the incidence of vascular evens independently of other vascular risk factors, as well as the risk of recurrence, especially in cerebrovascular events.

Methods: OXVASC is a population-based study of all acute vascular events (TIA, stroke, ACS and PVE) and those interventions for vascular disease in Oxfordshire. The pilot study covered a population of 90542 in 9 general practices. Summary of main findings: 1. The methods used in OXVASC achieved near-complete ascertainment. However, my analyses suggested that differences in case definition and ascertainment strategies between studies could each lead to differences in measured stroke incidence of up to 20%. 2. The early risk of recurrence can very twofold depending on which definition is used. The 90 day risks (95%CI) of recurrent stroke with a 24 hour definition of recurrence were 18.3%(10.8-25.8) in OXVASC and 14.5%(11.5-17.5) in OCSP. The equivalent risks using a 28 day definition of recurrence were 5.9%(1.0-10.9) in OXVASC and 4.8%(2.8-6.7) in OCSP. Recurrences occurring after 24 hours should be used as the standard to avoid underestimation and to allow valid comparison between studies. 3. In OXVASC the risks of stroke at 7 days after a TIA and minor stroke were 8.0% (95%CI=2.3-13.7) and 11.5%(95%CI=4.8-11.2) respectively. This is much higher than commonly quoted. 4. Recurrent stroke risk varies significantly between aetiological (TOAST) subtypes (p<0.001). Large artery atherosclerosis strokes have the highest odds of recurrence at 7 days (OR=3.3, 95%CI=1.5-7.0). They account for 37% of recurrences within 7 days highlighting the importance of urgent carotid imaging and avoiding delays before endarterectomy. 5. Incident stroke cases and their brain imaging were reviewed with the original OCSP principal investigator and neuroradiologist. 6. In OXVASC, acute cerebrovascular events accounted for 41.2% of all incident acute vascular events.

INTRODUÇÃO: O Acidente Vascular Cerebral Isquêmico (AVCI) é o evento mais freqüente dentre os AVCs, sendo caracterizado pela interrupção da irrigação sanguínea ao cérebro, a qual pode acarretar em lesão celular e alterações nas funções neurológicas. As manifestações clínicas desta doença podem incluir alterações das funções motoras, sensitivas, cognitivas, perceptivas, da linguagem entre outras. Sendo assim, é extremamente importante que sejam identificadas possíveis alterações nas vias auditivas, periférica e central, as quais podem prejudicar a qualidade de vida destes indivíduos. OBJETIVO: caracterizar os achados das avaliações comportamentais, eletroacústicas e eletrofisiológicas da audição em indivíduos destros com lesão isquêmica do hemisfério cerebral direito, bem como compará-los aos obtidos em indivíduos normais da mesma faixa etária. MÉTODOS: foram realizadas audiometria tonal, logoaudiometria, medidas de imitância acústica, potencial evocado auditivo de tronco encefálico (PEATE), potencial evocado auditivo de média latência (PEAML) e potencial cognitivo (P300) em 17 indivíduos com lesão do hemisfério direito (grupo pesquisa) e 25 normais (grupo controle), com idades entre 20 e 70 anos. RESULTADOS: Na análise dos dados qualitativos não foram encontradas alterações na avaliação comportamental da audição para os dois grupos. Ambos os grupos apresentaram alterações nos resultados do PEATE e do PEAML, sendo que houve diferença estatisticamente significante entre os grupos, para esses dois potenciais, nas quais o grupo pesquisa apresentou maior ocorrência de alterações. No PEATE a alteração mais freqüente foi do tipo tronco encefálico baixo, sendo que, entre os grupos, houve diferença estatisticamente significante, na qual o grupo pesquisa mostrou maior ocorrência dessa alteração. No PEAML a alteração predominante foi do tipo ambas (efeito orelha e efeito eletrodo ocorrendo concomitantemente) para o grupo pesquisa, e do tipo efeito eletrodo para o grupo controle. Na análise dos dados quantitativos (realizada apenas para os potenciais evocados auditivos) verificou-se, no PEATE, que ocorreu diferença estatisticamente significante entre os grupos com relação às latências das ondas III e V e interpicos I-III e I-V. Para o PEAML, a diferença estatisticamente significante entre os grupos ocorreu apenas para a latência da onda Na na posição C3/A1. Para o P300, ocorreu diferença entre os grupos com relação à latência da onda P300, sendo que o grupo pesquisa apresentou tempo médio de latência maior; além disso, houve uma tendência estatisticamente significante entre as orelhas direita e esquerda dentro do grupo pesquisa, mostrando aumento de latência da onda P300 na orelha direita. CONCLUSÃO: Indivíduos destros com lesão de hemisfério direito apresentaram limiares auditivos dentro da normalidade na avaliação comportamental da audição, entretanto, apresentaram resultados indicativos de déficit no sistema nervoso auditivo central, nas avaliações eletrofisiológicas da audição. Foram observados comprometimentos em tronco encefálico baixo, bem como nas regiões subcorticais e corticais. Dificuldades auditivas não foram percebidas pelos indivíduos, sugerindo que, provavelmente tal sinal possa estar relacionado à uma heminegligência auditiva. Tornam-se necessários mais estudos que avaliem a via auditiva central destes indivíduos para uma melhor caracterização dos achados eletrofisiológicos
INTRODUCTION: The ischemic cerebral stroke (ICS) is the most frequent event among cerebral strokes. It is characterized by the interruption of blood supply to the brain, which can lead to cell damage and alterations in neurological functions. The clinical manifestations of this disease may include alterations in motor, sensory, cognitive, perceptual and language functions among others. Therefore, the identification of possible alterations in both peripheral and central auditory pathways that may impair the quality of life of these individuals is extremely important. OBJECTIVE: To characterize the findings of behavioral, electrophysiological and electroacoustic hearing evaluations in right-handed individuals with right hemisphere ischemic lesion, and to compare such data to those obtained in normal individuals with the same age. METHODS: Pure tone audiometry, speech audiometry, acoustic immittance measures, brainstem auditory evoked potential (BAEP), Auditory Middle-Latency Response (AMLR) and cognitive potential (P300) were carried out in 17 subjects with right hemisphere lesions (research group) and 25 normal individuals (control group), aged between 20 and 70 years. RESULTS: No alterations were found on the qualitative data analysis of the hearing behavioral assessment of both groups. Both groups showed alterations in the BAEP and AMLR results, with statistically significant differences between groups for both potentials and a higher occurrence of alterations in the research group. The lower brainstem was the most frequent alteration type in the BAEP, and a statistically significant difference between groups was observed, with higher occurrence of such alteration in the research group. With regards the AMLR, the alteration predominantly observed was the Both type one (ear effect and electrode effect occurring concurrently) for the research group, and the electrode effect type one for the control group. In the analysis of quantitative data (performed only for the auditory evoked potentials), a statistically significant difference between groups was observed with respect to the BAEP latencies of waves III, V and interpeaks I-III and I-V. Regarding the AMLR measures, a statistically significant difference between groups was observed only for the Na wave latency in the C3/A1 position. For the P300, a difference between groups was observed, with higher mean latencies for the research group. In addition, there was a trend to statistically significant difference between right and left ears in the research group, which showed increased latency of P300 wave in the right ear. CONCLUSION: Right-handed individuals with right hemisphere lesion showed hearing thresholds within normal limits in the behavioral hearing assessment. However, they presented results indicative of central auditory nervous system deficits on the electrophysiological assessment of hearing. Alterations were observed in lower brainstem and in sub-cortical and cortical regions. Hearing difficulties were not perceived by these individuals, suggesting that this signal can probably be related to an auditory hemineglect. Further studies that evaluate the central auditory pathway of individuals with ICS are needed to better characterize the electrophysiological findings

Objectives. Evaluate differences in depressive symptoms, compare sociodemographic and health-related variables associated with depressive symptoms and report level of impact of depressive symptoms on daily activities. Methods. Cross-sectional study using a self-administered questionnaire and Patient Health Questionnaire-9 (PHQ-9) diagnostic survey on 1115 patients aged 60–93 years who attended a primary care clinic in Korea, Russia or USA. Results. At least mild depression (PHQ-9 score of ≥5) occurred in 28% of Koreans, 65% of Russian and 27% of US participants. Russians scored more depressed on all PHQ-9 items (P < 0.01) and more suicidal thoughts (P < 0.001), while Koreans had less feelings of worthlessness (P < 0.001). Depression predictors included poorer self-rated health [odds ratio (OR) 2.47, 95% confidence interval (CI) 1.84–3.33, P < 0.0001], chronic diseases (OR 1.34, CI 1.21–1.48, P < 0.0001), female gender (OR 1.56, CI 1.15–2.12, P = 0.0046) and religious attendance (OR 0.88, CI 0.79–0.97, P = 0.0099) for all subjects. Being employed was protective in Korea (OR 0.41, CI 0.21–0.77, P = 0.0061) and being married (OR 0.42, CI 0.27–0.66, P = 0.0002) and of older age (OR 0.95, CI 0.93–0.98, P = 0.0006) protective in US participants. Vascular disease was associated with depressive symptoms in Russia (OR 3.47, CI 1.23–9.80, P = 0.0187). In regression analyses stratified by country for a given level of depressive symptoms, the Russian sample had less impact on daily activities (Russia R2 = 0.107 versus Korea R2 = 0.211 and US R2 = 0.419) P = 0.029. Conclusions. Depressive symptoms were more common in Russia than in Korea and USA but had less impact on daily functioning. Cultural or environmental factors may account for this finding.

This thesis was undertaken to investigate the cost-effectiveness of various antiplatelet regimens used in the secondary prevention of vascular events in adults undergoing percutaneous coronary intervention (PCI). Analyses include the first economic evaluation to evaluate three antiplatelet regimens (clopidogrel + ASA, ticlopidine + ASA, and ASA alone) for the PCI indication from the perspective of the Canadian provincial/territorial healthcare payer, budget impact analyses investigating potential consequences of changing prescribing patterns, and a value of information analysis indicating future research priorities. Results demonstrate that, for a population of patients undergoing PCI at age 60, one year of antiplatelet therapy with ticlopidine + ASA, followed by lifetime ASA therapy, dominates clopidogrel + ASA therapy due to lower costs and better health outcomes (ICER = $523.44 vs. ASA alone). The clinical effectiveness of ticlopidine is proven to be the most uncertain variable in the model, and further clinical research is recommended.

La Enfermedad Vascular Cerebral (EVC) isquémica es una de las entidades más frecuentes a la que se enfrenta en la práctica diaria tanto el neurólogo como el médico general. En el Perú, esta entidad se va constituyendo cada vez más en una de las principales causas de morbi-mortalidad en la población. Según los reportes del año 2001, de la Oficina General de Epidemiología del Ministerio de Salud, en el Perú la EVC representa la cuarta causa de mortalidad general y en la provincia del Callao la tercera causa. (1,2) El impacto de esta entidad trasciende al paciente, llegando a constituir un problema familiar, social, laboral y económico. Las terapias trombolíticas que se usan en la etapa aguda del EVC, que constituyen una herramienta farmacológica poderosa contra esta entidad y que están ampliamente difundidas en los países desarrollados desde hace casi una década; lamentablemente aún no están disponibles para la gran mayoría de la población en un país como el nuestro, debido fundamentalmente al factor económico. Por eso, en nuestra realidad, no nos queda sino otra cosa que prevenir la enfermedad, dado que poco o casi nada podemos hacer para revertirla cuando la observamos en su fase aguda. Para dicha prevención es necesario conocer los factores de riesgos para una EVC isquémica, fundamentalmente los modificables, pues son sobre los cuales podemos actuar a tiempo.
Tesis de segunda especialidad

Contexte : Les hémorragies intracérébrales spontanées (HIC) présentent une mortalité élevée et un pronostic fonctionnel sombre. Les survivants sont à haut risque d’évènements vasculaires majeurs mais les données concernant le pronostic au long terme des HIC sont limitées. L’objectif principal de ce travail était d’étudier le pronostic vasculaire cérébral et extra-cérébral au long cours.Méthodes : Nous avons inclus les patients de la cohorte prospective et observationnelle PITCH (Prognosis of Intra Cerebral Haemorrhage), qui a recruté de façon consécutive tous les patients admis au CHU de Lille pour une HIC spontanée entre 2004 et 2009.Nous avons étudié (i) l’incidence des évènements vasculaires majeurs, ischémiques ethémorragiques, ainsi que leurs facteurs prédictifs cliniques et neuroradiologiques ; (ii)la prévalence de la sidérose superficielle corticale (SSc) et les facteurs cliniques et radiologiques associés ; (iii) l’impact des micro hémorragies cérébrales sur le risque de récidive hémorragique.Résultats : Nous avons mis en évidence qu’il existait un risque élevé d’évènements vasculaires majeurs, cérébraux et extra-cérébraux, chez les patients ayant souffert d’une HIC. Au long cours, le risque d’évènements ischémiques dépasse le risque hémorragique, en particulier chez les patients avec une hémorragie profonde.Concernant le risque hémorragique cérébral, nous avons montré qu’au sein de notre cohorte, un patient sur cinq avait de la SSc sur l’IRM cérébrale réalisée à l’admission et que la présence de SSc est un facteur neuroradiologique prédictif majeur de récidive hémorragique, suggérant l’implication de l’angiopathie amyloïde cérébrale. Un nombre élevé de microhémorragies cérébrales est par ailleurs associé à un risque de récidive hémorragique plus importante.Conclusion : Les résultats de ce travail ont un impact clinique important, ils suggèrent l’indication d’un suivi au long cours et multidisciplinaire des patients ayant présenté une HIC. Ils apportent des informations nouvelles sur le risque extra-cérébral et sur les prédicteurs de récidive hémorragique
Background: Spontaneous (non-traumatic) intracerebral hemorrhage (ICH) is the mostdramatic type of stroke being responsible for the majority of mortality and stroke related disability. Survivors are at high risk of major vascular events, nevertheless, data on long-term prognosis after ICH are scarce. The main objective was to study long term cerebral and extra-cerebral vascular prognosis after ICH.Methods: We included patients from the PITCH (Prognosis of Intra Cerebral Haemorrhage) cohort which is a prospective and observational study that included consecutive adults admitted at the Lille University Hospital for spontaneous ICH between 2004 and 2009. We aimed to determine (i) cumulative incidence of major ischemic and hemorrhagic vascular events and their clinical and radiological predictors;(ii) the prevalence of cortical superficial siderosis (cSS) and its associated factors; (iii) the impact of cerebral microbleeds on ICH recurrence.Results: We showed that ICH survivors are at high risk of major cerebral and extracerebralvascular events. Ischemic risk overwhelmed the hemorrhagic one on long term,particularly in deep index ICH. Concerning recurrent ICH, we found that in our cohort,one out of five patients had cSS on baseline MRI and its presence was a strong predictorof recurrent ICH, suggesting the implication of underlying cerebral amyloid angiopathy.Global burden of microbleeds was also associated with higher rate of ICH recurrence.Conclusion: These findings have immediate clinical relevance and suggest that ICH survivors should benefit of a long-term and multidisciplinary follow-up. These results may also provide additional information on the risk of major ischemic and hemorrhagicevents after ICH and on radiological predictors of recurrence risk

Endotelio funkcijos sutrikimas (disfunkcija) - būklė, apibūdinama padidėjusia adhezijos molekulių ekspresija, padidėjusia prouždegiminių veiksnių ir protrombotinių faktorių sinteze bei sutrikusia kraujagyslių tono reguliacija - yra mirties dėl kardiovaskulinės patologijos, miokardo infarkto bei poreikio revaskuliarizacijos procedūroms išsivystymo rizikos veiksnys. Darbo tikslas buvo nustatyti endotelio pažeidimą atspindinčių žymenų, hs-CRP, sVCAM-1 ir sICAM-1 reikšmę, nuspėjant kardiovaskulines komplikacijas po aortos vainikinių jungčių suformavimo operacijos, atliktos dirbtinės kraujo apytakos sąlygomis. Nustatėme, kad didesnės priešoperacinės hs-CRP ir sVCAM-1 koncentracijos buvo nepriklausomi didesnės kardiovaskulinių komplikacijų po aortos vainikinių jungčių suformavimo operacijų rizikos žymenys. Po aortos vainikinių jungčių suformavimo operacijos nustatyta reikšmingai didesnė hs-CRP, sVCAM-1 ir sICAM-1 koncentracija, palyginus su priešoperaciniu koncentracijos lygiu. Patikimos žymenų koreliacijos su aortos užspaudimo, dirbtinės kraujo apytakos bei operacijos trukme neradome. Pacientams po aortos vainikinių jungčių suformavimo operacijos koreliacijos tarp pooperacinio sICAM-1, sVCAM-1 bei hs-CRP koncentracijos lygio ir kardiovaskulinių komplikacijų išsivystymo rizikos nebuvo nenustatyta.
The endothelial cell damage/dysfunction is associated with increased expression of adhesion molecules, synthesis of proinflammatory, prothrombotic factors and abnormal modulation of vascular tone. A growing body of evidence suggests that endothelial dysfunction is associated with future cardiovascular events including cardiac death, myocardial infarction and the need for revascularization procedures. The aim of the study was to evaluate the impact of markers of endothelial damage as predictors of cardiovascular events after on-pump coronary artery bypass grafting surgery. We found that higher concentrations preoperatively of hs-CRP and sVCAM-1 were independent markers for higher risk of cardiovascular events after coronary artery bypass grafting surgery. Concentration of hs-CRP, sVCAM-1 and sICAM-1 increased significantly after on-pump coronary artery bypass grafting surgery compared to preoperative level. However correlation between the duration of aortic cross-clamp, cardiopulmonary bypass or surgery and markers of endothelial damage was not found. Correlation between postoperative concentration of hs-CRP, sVCAM-1 and sICAM-1 and risk for cardiovascular events after coronary artery bypass grafting surgery was not found.

Méthodes et principaux résultats. Dans une revue systématique des études sur les facteurs déclenchants des infarctus cérébraux, nous n’avons identifié qu’une seule étude, négative, consacrée aux événements de vie. Nous avons montré, dans une étude prospective portant sur 247 patients admis pour un infarctus cérébral, qu’une exposition à au moins 1 évènement de vie était plus fréquente dans le mois précédant l’infarctus cérébral que dans les 5 périodes témoins (OR=2,96 ; IC à 95% 2,19-4,00). L’exposition à des évènements de vie était aussi un facteur prédictif des dépressions survenant dans les 6 mois suivant un infarctus cérébral. Les autres facteurs prédictifs de dépression post-AVC étaient un score de Rankin > 2, un antécédent de dépression, une lésion caudée et/ou lenticulaire gauche, le sexe féminin et des pleurs pathologiques. Conclusion et perspectives. Ce travail de thèse apporte des arguments en faveur d’un rôle des évènements de vie d’une part, dans la survenue à court terme d’un infarctus cérébral, d’autre part dans la survenue d’une dépression dans les 6 mois suivant un AVC. Il souligne aussi les difficultés spécifiques de l’étude des événements de vie concernant leur définition, l’évaluation de leur sévérité, les biais de rappel et la définition de la période à risque. Nos résultats doivent être confirmés et précisés avant d’évaluer le bénéfice d’une stratégie préventive
Methods and main results. In our systematic review of potential triggers of ischemic stroke, the only study that examined stressful life events didn’t show any association with stroke onset. In a prospective study of 247 consecutive patients admitted for ischemic stroke, exposure to at least one stressful life event was significantly more common during the first month preceding stroke onset than during the five control periods (OR=2.96 ; 95% CI 2.19-4.00). Stressful life events exposure also predicted depression occurring within six months after ischemic stroke onset. The other predictors of post-stroke depression were a modified Rankin score > 2, a prior history of depression, a left caudate and/or lenticular lesion, the female sex and pathologic crying.Conclusion and perspectives. Our results support the role of stressful life events as triggers of ischemic stroke and predictors of post-stroke depression. Our research also highlights the difficulty of studying stressful life events, due to potential influence of memory biases and lack of precise definitions of stressful life events, severe vs. minor events and hazard period durations. These preliminary results should be confirmed in order to assess benefits of preventive strategies

Background: Previous studies that have examined functional status in relation to vascular events have focused on the short term after events and have measured functional status a limited number of times. The trajectories of functional status before and after vascular events are not well characterized, and the factors influencing these trajectories are not well known. Methods: A comprehensive, structured, narrative review was performed on the topic of trajectories of disability and cognition surrounding vascular events. Then using 2 large population-based epidemiologic cohorts, the Northern Manhattan Study (NOMAS) and the Cardiovascular Health Study (CHS), trajectories of functional status were examined. In Analysis A, in NOMAS, the effect of inflammatory biomarkers (interleukin-6 [IL6], tumor necrosis factor receptor-1 [TNFR1], C-reactive protein [CRP], and lipoprotein-associated phospholipase-A2 [LpPLA2]) on the intercept and slope of functional status was determined over a median of 13 years, measured with yearly assessments by the Barthel index. In Analysis B, in NOMAS, a similar modeling strategy was used to examine whether subclinical ischemic disease on brain MRIs, measured by subclinical brain infarct (SBI) and white matter hyperintensity volume (WMHV), was associated with functional trajectories. In Analysis C, in CHS, participants had yearly assessments of disability with a combined activities of daily living (ADL) and instrumental ADL scale. The slope of change in disability was compared before and after vascular events (stroke and myocardial infarction [MI]). Results: In Analysis A, CRP (-0.41 BI points per 1 SD increase, 95% CI -0.82 to 0.002) and LpPLA2 (-0.40, 95% CI -0.75 to -0.04) were associated with baseline BI but not change over time. TNFR1 was associated with baseline BI (-0.93, 95% CI -1.59 to -0.26) and change over time (-0.36 BI points per year, 95% CI -0.69 to -0.03). In Analysis B, functional change was -0.85 BI points per year (95%CI -1.01 to -0.69); among those with SBI there were -0.88 additional points annually (-1.44 to -0.32). In WMHV models, annual functional change was -1.04 points (-1.2 to -0.88), with -0.74 additional points annually per SD WMHV increase (-0.99 to -0.49). In Analysis C, stroke (0.88, 95% CI 0.57-1.20, p<0.0001) was associated with a greater acute increase in disability than MI (0.20, 0.06-0.35, p=0.006). The annual increase in disability before stroke (0.06 points per year, 0.002-0.12, p=0.04) more than tripled after stroke (0.15 additional points per year, 0.004-0.30, p=0.04). The annual increase in disability before MI (0.04 points per year, 0.004-0.08, p=0.03) did not change significantly after MI (0.02 additional points per year, -0.07-0.11, p=0.7). Conclusions: In these large population-based studies with repeated measures of functional status and disability over long-term follow-up, several trajectories were found. In Analysis A, TNFR1 predicted worse overall functional status as well as accelerated decline over time. In Analysis B, both SBI and WMHV were associated with accelerated decline. In Analysis C, there was a steeper decline in function after stroke but not MI. These findings help to elucidate the course and potential etiologies of long-term functional decline related to vascular events, and they suggest directions for future research in this area.

碩士
國立成功大學
臨床醫學研究所
103
Acute myocardial infarction (AMI) is a leading cause of death of cardiovascular disease (CVD) in the world. It can be triggered by thrombin, which promotes thrombosis and causes coronary artery occlusion. In early CVD, monocyte and macrophage play major role in atherosclerosis and promote plaque formation partially via Rho kinase (ROCK) signal pathway. However, it remained unknown how ROCK signaling or its associated pathways play the role on monocytes and macrophages functions during the AMI development process. Previous studies have shown that galectin-3 could promote inflammation cell migration and macrophage phagocytosis. It is possible that galectin-3 may play as the mechanism between activation of macrophages or monocytes under thrombin stimulation thus facilitate ROCK activation. Therefore, our aim is to test the interaction between galectin-3 and Rho protein signal pathway in macrophages. To investigate the ROCK activity, ROCK expression and galectin-3 secretion in macrophages, thrombin was used for the activation of THP-1 macrophage cell line. After stimulation of thrombin in macrophages, we studied the relationship between ROCK and galectin-3 secretion by western blots. Then, we tested the galectin-3 secretion among macrophage with ROCK inhibitor after thrombin stimulation. Flow cytometry and migration assay were applied to detect the M1/M2 macrophage expression distribution and migration functional changes after thrombin treatment. Finally, to prove that ROCK is important in human acute thrombotic event, we detected the phosphor-ezrin/radixin/moesin (pERM), which are the downstream molecules of ROCK, and galectin-3 expression in macrophages isolated from AMI patient and also healthy donors. We found that galectin-3 secretion was activated in macrophage after thrombin treatment peaking at 24 hours. Interestingly, Rho-associated pathway protein expressions increased after thrombin treatment earlier at 12 hours. After Rho-kinase inhibitor treatment, the expression of galectin-3 decreased in the activated macrophage. Regarding functional assay, more percentage of THP-1-derived macrophages were prone to become M1 type macrophage after thrombin treatment in flow cytometry and had greater migration ability after thrombin treatment. Finally, we proved that pERM and galectin-3 expression in AMI patient’s macrophages were higher than healthy donor’s macrophages. In conclusion, thrombin treatment can stimulate macrophage to M1 type and their migration ability, thus promote Rho-kinase signal pathway expression and galectin-3 secretion.

碩士
高雄醫學大學
藥學系碩士在職專班
104
Background: Saxagliptin is an oral hypoglycemic agent that can control blood sugar by inhibiting the metabolism of incretin. Several research studies recently showed that saxagliptin may increase the risk of cardiovascular events recetently. The aims of our study were to evaluate the risk of cardio-cerebral vascular events in patients who received saxagliptin and explore the precipitating risk factors of cardio-cerebral vascular events. Methods: There were two parts in our study. First, a systemic review and meta-analysis of randomized controlled studies of comparing saxagliptin to placebo with cardio-cerebral vascular events was conducted. Databases were searched for relevant published articles. Second, a retrospective cohort study was performed based on medical records of a medical center in southern Taiwan. Data such as patient’s basic information, medication records, lab data and diagnostic records were extracted and used to explore the risk factors of cardio-cerebral vascular events. Results: Six randomized controlled studies were included in the meta-analysis. Compared to control, treatment with saxagliptin significantly increased the risk of heart failure (RR=1.25, 95%CI：1.05-1.48；p value=0.01). Saxagliptin did not increase the risk of myocardial infarction and angina. The result of subgroup stratified by cardiovascular history showed that treatment with saxagliptin increased risk of heart failure (RR=1.26, 95%CI：1.06-1.49；p value=0.009) in the subgroup with CV history. Retrospective cohort study explored the significant risk factors of developing cardio-cerebral vascular events in patients who used saxagliptin were heart failure history (OR=3.395, 95%CI：1.118-10.305；p value=0.031) and atherosclerosis disease history OR=2.936, 95%CI： 1.017-8.481; p value=0.047). Conclusions: Our study showed that the usage of saxagliptin may increase the risk of heart failure in type 2 diabetes patients with history of cardiovascular disease. We found that the heart failure history and atherosclerosis disease history were important risk factors for developing cardio-cerebral vascular events.

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2021
Contextualização. A fibrilhação auricular pós-operatória (POAF) é uma das complicações mais frequentes após cirurgia. Apesar de ter sido vista como uma situação benigna por muito tempo, vários estudos têm demonstrado que a POAF tem consequências importantes para a morbimortalidade a longo prazo, por aumentar o risco de eventos tromboembólicos. No entanto, não existem estudos que avaliem a eficácia e segurança da anticoagulação oral (ACO) na redução de eventos tromboembólicos e mortalidade em doentes com POAF. Métodos. Pesquisa sistemática no CENTRAL e MEDLINE de RCTs e estudos observacionais. Os dados foram selecionados e extraídos por dois revisores independentes. O risco de viés foi avaliado pela ferramenta ROBINS-I. Realizámos um modelo de efeitos aleatórios para estimar os Odds Ratios (OR) combinados com intervalos de confiança a 95% (IC), e a heterogeneidade foi avaliada pela estatística I2. O outcome primário considerado foi tromboembolismo. Resultados. Sete estudos observacionais incluindo 177,141 doentes com POAF foram incluídos na meta-análise. O uso de ACO foi associado a um menor risco de eventos tromboembólicos (OR = 0,67; IC 95% 0,46-0,99; I2 = 65%). O efeito da ACO não foi estatisticamente significativo na análise conjunta de mortalidade (OR = 0,73; IC 95% 0,49 a 0,50; I2 = 95%) e de hemorragia (OR = 2,18; IC 95% 0,55 a 8,66; I2 = 0%). Conclusão. A ACO foi associada a um menor risco de eventos tromboembólicos em pacientes com POAF após cirurgia cardíaca.
Background. Post-operative atrial fibrillation (POAF) is one of the most frequent complications after surgery. Although it was thought to be a benign situation for a long time, several studies have shown that POAF has important consequences for long-term morbidity and mortality, by increasing the risk of thromboembolic events. However, there is no study evaluating the efficacy and safety of oral anticoagulation (OAC) in reducing thromboembolic events and mortality in patients with POAF. Methods. We searched CENTRAL and MEDLINE for RCTs and observational studies. Data were screened and extracted by two independent reviewers. The risk of bias was evaluated by ROBINS-I tool. We performed a random-effects model to estimate the pooled Odds Ratios (OR) with 95% Confidence Intervals (CI), and heterogeneity was evaluated by I2 statistics. The primary outcome was thromboembolic events. Results. Seven observational studies including 177,141 patients with POAF were included in the meta-analysis. OAC use was associated with lower risk of thromboembolic events (OR = 0.67; 95% CI 0.46 to 0.99; I2 = 65%). The effect of OAC was not statistically significant in a pooled analysis of all-cause mortality (OR = 0.73; 95% CI 0.49 to 0.50; I2 = 95%) and bleeding (OR = 2.18; 95% CI 0.55 to 8.66; I2 = 0%). Conclusion. Oral anticoagulation was associated with a lower risk of thromboembolic events in patients with POAF following cardiac surgery.

Trabalho Final do Mestrado Integrado em Medicina apresentado à Faculdade de Medicina
Background: Up to a third of all ischaemic strokes are rendered cryptogenic or of undetermined aetiology. AF monitoring is recommended as part of the systematic investigation of potential causes. However, the most effective way of undertaking AF screening has not been established, particularly concerning the method and the duration of monitoring. Recent evidence demonstrated that an algorithm including the Apple Watch® and the Heart study app® is feasible for AF screening. This way, the Apple Watch® may prove to be a widely applicable approach for AF detection in stroke patients, likely increasing its yield. Detection of AF after incidental stroke has important therapeutic implications, since oral anticoagulation therapy would then be recommended for secondary prevention. Study design: The Apple Watch stroke study is a multicentre, prospective, randomized and controlled trial designed to evaluate the performance of the Apple Watch® and its associated smartphone application as a long-term monitoring method for AF detection after a stroke otherwise regarded as cryptogenic. Five hundred patients will be enrolled and randomized in a 1:1 fashion to standard arrhythmia monitoring, as proposed by international scientific societies (control arm), or Apple Watch® monitoring (experimental arm).Outcomes: The primary endpoint is AF detection rate within 12 months after stroke. Secondary endpoints further include recurrent stroke and rehospitalization incidence, antiarrhythmic and oral anticoagulation drug usage and a multidimensional quality of life assessment. The clinical follow-up period will be at least 12 months. Study completion date is expected at the end of 2024.
Introdução: Até um terço dos AVCs são classificados como criptogénicos ou de etiologia indeterminada. Neste contexto, o rastreio de FA faz parte da avaliação etiológica de rotina. No entanto, a duração e o método ideais para a sua monitorização continuam por esclarecer. Recentemente, um algoritmo envolvendo o Apple Watch® e a Heart study app® foi validado enquanto método de rastreio de FA. Especula-se que o emprego sistemático deste método possa incrementar a probabilidade de deteção desta arritmia em doentes com AVC. A deteção de FA após um AVC tem implicações terapêuticas importantes, recomendando-se, idiossincrasicamente, a anticoagulação oral como estratégia de prevenção secundária preferencial.Desenho do estudo: O Apple Watch stroke study é um estudo multicêntrico, prospetivo, aleatorizado e controlado que visa avaliar a performance do Apple Watch® e da respetiva aplicação para smartphone enquanto método de monitorização prolongada para detecção de FA após AVC agudo de outra forma considerado criptogénico. Quinhentos doentes serão incluídos e aleatorizados num rácio 1:1 para a monitorização cardíaca de rotina por ora recomendada por sociedades científicas internacionais (grupo controlo) ou monitorização com recurso ao Apple Watch® (grupo experimental).Outcomes: O endpoint primário é a taxa de detecção de FA 12 meses após o AVC. Endpoints secundários incluem, ainda, a incidência de AVC recorrente e de re-hospitalização, o uso de farmacoterapia antiarrítmica ou anticoagulante e uma avaliação multidimensional da qualidade de vida. O período de follow-up clínico mínimo será de 12 meses. A data esperada para a conclusão do estudo é 2024.