<p>This dissertation aims to demonstrate the feasibility of direct infarct visualization using 3D medical ultrasound. The dissertation proceeds by providing the first ever demonstration of fully-sampled 3D ultrasonic speckle tracking using raw B-Mode data of the heart. The initial demonstration uses a Cramer-Rao lower bound limited displacement estimator. The dissertation then proceeds to develop an implementable method for biased time-delay estimation. Biased time-delay estimation is shown to surpass the traditional limits described by the Cramer-Rao lower bound in a mean square error sense. Additional characterization of this new class of estimator is performed to demonstrate that with easily obtainable levels of prior information it is possible to estimate displacements that do surpass the Cramer-Rao lower bound. Finally, using 2D and 3D realizations of biased displacement estimation (Bayesian speckle tracking) the passive strain induced in the ventricle walls during atrial systole is shown to be sufficient to distinguish healthy and chronically infarcted myocardium.</p> / Dissertation

According to the theory of Traditional Chinese Medicine, the main etiology of stroke results from blood stasis. Ligustic Rhizoma (LR), a Chinese herb, is considered to stimulate stasis-dispelling. As Tetramethyl Pyrazine (TMP) is a major component of LR, the aim of the present study is to investigate the effects of TMP on cerebral infarct. We establish an animal model of cerebral infarct by occluding the both common carotid arteries and right middle cerebral artery for 90 minutes, then reperfusing for 24 hrs. Effects of TMP on cerebral infarct are evaluated by the ratio of infarction areas and modified neurologica severity scale (mNSS). In addition, we observe the changes of ED1, tumor necrosis factor-£\ (TNF-£\) and interleukin-1£] (IL-1£]) immuno-reacting cells in the infarction region. The founding indicate that pre-treatment with TMP 100 mg/kg, 120 mg/kg and 140 mg/kg, and post-treatment with TMP 100 mg/kg will decrease the ratio of cerebral infarction area and the neurological deficit. Moreover, pre-treatment TMP 100 mg/kg also decreases ED1, TNF-£\ and IL-1£] immuno-reacting cell. In conclusion, TMP can decrease cerebral infarction area and neurological deficit. The effects of TMP, at least in part, are closely related to microglia, TNF-£\ and IL-1£], suggesting that TMP can be used to treat stroke in human.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2002. / Härtill 4 uppsatser.

Submitted by Nadir Basilio (nadirsb@uninove.br) on 2018-06-21T18:29:06Z No. of bitstreams: 1 Eduardo Tadeu Santana.pdf: 3781492 bytes, checksum: 5fb6eff774c2c39d42bab565b9e807ef (MD5) / Made available in DSpace on 2018-06-21T18:29:06Z (GMT). No. of bitstreams: 1 Eduardo Tadeu Santana.pdf: 3781492 bytes, checksum: 5fb6eff774c2c39d42bab565b9e807ef (MD5) Previous issue date: 2015-12-18 / The ligation of the anterior descending coronary artery is the most commonly used experimental model to induce myocardial infarction (MI) in rodents. A high mortality in the acute phase and the heterogeneity of the size of the MI obtained are drawbacks recognized in this model. In an attempt to solve the problem, our group recently developed a new MI experimental model which is based on application of myocardial ablation radio-frequency currents (AB-RF) that yielded MI with homogeneous sizes and significantly reduce acute mortality. In addition, cardiac structural and functional changes aroused by AB-RF were similar to those seen in animals with MI induced by coronary artery ligation. Herein, we evaluated modifications of gene expression that govern post-MI milieu in occlusion and ablation models. We analyzed 48 mRNA expressions of 9 different signal transduction pathways (signs of cell survival and metabolism, matrix extracellular, cell cycle, oxidative stress, apoptosis, calcium signaling, hypertrophy markers, angiogenesis and inflammation) in rat left ventricle 1 week after MI promoted by either coronary occlusion and AB-RF. Furthermore, high-throughput miRNA analysis was also assessed after either MI procedures. Interestingly, mRNA expression levels and miRNA expressions were similar in both models after MI, with few specificities in each model. This study reports for the first time the global changes in rat cardiac mRNA and miRNA contents after two different MI procedures and identifies key signaling regulators modulating the pathophysiology of these two models that might culminate in heart failure. Furthermore, these analyses would enhance our present knowledge regarding altered pathophysiology of these two different MI models. / A ligadura da artéria coronariana descendente anterior é o modelo experimental mais comumente usado para induzir o infarto do miocárdio (IM) em roedores. Entretanto, uma elevada taxa de mortalidade na fase aguda e a heterogeneidade do tamanho do IM obtidos são desvantagens reconhecidas neste modelo. Em uma tentativa de resolver o problema, o nosso grupo desenvolveu recentemente um novo modelo experimental de insuficiência cardíaca que se baseia na aplicação de correntes de radiofrequência ablação do miocárdio (AB-RF), produzindo IM com tamanhos homogêneos e com significativamente redução da mortalidade aguda. Além disso, alterações estruturais e funcionais do coração deste modelo foram semelhantes aos observados em animais com infarto induzido por ligação da artéria coronária. Aqui, nós avaliamos modificações da expressão de RNA mensageiro (RNAm) de genes após IM induzido por oclusão e ablação. Foram analisadas as expressões de 48 RNAm de 9 diferentes vias de transdução de sinal (sinais de sobrevivência celular e metabolismo, matriz extracelular, ciclo celular, estresse oxidativo, apoptose, sinalização de cálcio, marcadores de hipertrofia, angiogênese e inflamação) no ventrículo esquerdo de ratos uma semana após o IM promovido por oclusão coronária e AB-RF. Além disso, a análise de alto rendimento de miRNA também foi avaliada após ambos procedimentos de IM. Curiosamente, os níveis de expressão de RNAm e expressão de miRNA foram semelhantes em ambos os modelos após o IM, com algumas especificidades em cada modelo. Este estudo relata pela primeira vez as mudanças globais nos conteúdos de RNAm e miRNA após dois procedimentos de IM diferentes e identifica reguladores que podem modular a fisiopatologia desses dois modelos, culminando em insuficiência cardíaca.

Opioids are considered as a dangerous addictive substances which are widely used in medicine for their strong analgetic effects. Opioids (such as morphine and methadon) may nevertheless play an important role in the resistance of the heart to ischemia by reducing the rate of cell damage. This protective effect is well understood about morphine but we don't know almost nothing about effects of methadone on the myocardium. The main aim of this thesis was to find out how chronic methadone treatment affects ischemic tolerance of rat hearts. For our experiments we used Wistar rats in two series. In the first series we administered morphine (10 mg/kg/day, i.m.) or methadone (2 mg/kg/day, i.m.) for 10 days. In the second experiment series we administered methadon for 28 days (2 mg/kg/day, i.m.). For analysis of the ischemic heart tolerance we used the isolated perfused heart method. Incidence and severity of ischemia and reperfusion arrhythmias were analyzed during the 50 min of ischemia and early reperfusion. Infarct size was analyzed histochemically, using tetrazolium salts and KMnO4 1 h after reperfusion and was determined by planimetric method. In the first series of experiments analyzing the effect of 10-day administration of both opioids on the resistance of the heart to ischemia we did not find a...

Current evidence regarding the effect of intravenous morphine administration on reperfusion injury and/or cardioprotection in patients with myocardial infarction is conflicting. The aim of this study was to evaluate the impact of morphine administration, on infarct size and reperfusion injury assessed by cardiac magnetic resonance imaging (CMR) in a large multicenter ST-elevation myocardial infarction (STEMI) population. In total, 734 STEMI patients reperfused by primary percutaneous coronary intervention <12 h after symptom onset underwent CMR imaging at eight centers for assessment of myocardial damage. Intravenous morphine administration was recorded in all patients. CMR was completed within one week after infarction using a standardized protocol. The clinical endpoint of the study was the occurrence of major adverse cardiac events (MACE) within 12 months after infarction. Intravenous morphine was administered in 61.8% (n = 454) of all patients. There were no differences in infarct size (17%LV, interquartile range [IQR] 8–25%LV versus 16%LV, IQR 8–26%LV, p = 0.67) and microvascular obstruction (p = 0.92) in patients with versus without morphine administration. In the subgroup of patients with early reperfusion within 120 min and reduced flow of the infarcted vessel (TIMI-flow ≤2 before PCI) morphine administration resulted in significantly smaller infarcts (12%LV, IQR 12–19 versus 19%LV, IQR 10–29, p = 0.035) and reduced microvascular obstruction (p = 0.003). Morphine administration had no effect on hard clinical endpoints (log-rank test p = 0.74) and was not an independent predictor of clinical outcome in Cox regression analysis. In our large multicenter CMR study, morphine administration did not have a negative effect on myocardial damage or clinical prognosis in acute reperfused STEMI. In patients, presenting early ( ≤120 min) morphine may have a cardioprotective effect as reflected by smaller infarcts; but this finding has to be assessed in further well-designed clinical studies

No description available.

<p>Cerebrovascular disease (stroke), especially ischemic stroke, is a major cause of death and neurological disability in adults. Because of its clinical heterogeneity, stroke is considered as a multi-factorial and polygenic disorder. Most current genetic studies of ischemic stroke focus on genetic susceptibility rather than factors determining stroke outcome. The genetic components of ischemic stroke outcome are difficult to study in humans due to environmental factors and medical intervention. Thus, we proposed to use a surgically induced, permanent, focal cerebral ischemic stroke mouse model to investigate genetic factors of ischemic stroke outcome measured by infarct volume. This model is the middle cerebral artery occlusion (MCAO) model. First, we screened infarct volumes across 32 inbred mouse strains. The infarct volume varies between strains, and this strongly suggests that infarct volume is genetically determined. To identify these genetic factors, we used genome-wide association study [Efficient Mixed-Model Association (EMMA) analysis] on infarct volume from 32 inbred mouse strains. Using the EMMA analysis, we identified 11 infarct volume-associated loci; however, most loci were mapped with missing alleles. This suggests that these loci might be false positives. Thus, we used specifically designed scripts of EMMA analysis with updated mouse SNP database to correct for potential false positives. The loci identified by the updated EMMA analyses will led us to the identification of genes involved in ischemic stroke outcome. </p><p> There are two major mechanisms were proposed to be determinants of infarct volume, the extent of native collateral circulation and neuroprotection. Using the infarct volume screening panel from 32 inbred strains, we observed that infarct volume is inversely correlated with the native collateral vessel number. However, among these inbred strains, we also observed several strains differ significantly in infarct volumes but harbor similar collateral numbers. In order to identify genetic factors determining infarct volume in a collateral-independent manner (neuroprotection), we used quantitative trait locus (QTL) mapping on mouse strains that exhibit the most difference in infarct volumes but the least difference in collateral numbers (C57BL/6J and C3H/HeJ). From the F2 B6 x C3H cross, we mapped 4 loci determining infarct volume (cerebral infarct volume QTL 4 to 7, Civq4 to Civq7). The Civq4 locus is the strongest locus (LOD 9.8) that contributes 21% of phenotypic variance in infarct volume. We also used a parallel F2 B6 x C3H cross to perform a QTL mapping on collateral vessel traits to further verify these collateral-independent loci. Among these 4 loci, the Civq4 and Civq7 loci appear to be truly collateral-independent. Based on strain-specific sequence variants and mRNA expression differences, we proposed Msr1 and Mtmr7 are the potential candidate genes of the Civq4 locus. Identification of the collateral-independent genetic factors will help to understand the genetic architecture, disease pathophysiology and potential therapeutic targets for of ischemic stroke</p> / Dissertation

As doenças cardiovasculares continuam sendo a primeira causa de morte no Brasil (32%) representando a terceira maior causa de internação hospitalar. Apesar dos avanços terapêuticos das últimas décadas, estudos epidemiológicos consideram o infarto agudo do miocárdio (AMI) uma das maiores causas de morbidade e mortalidade, sendo a maioria, ligados a realização de terapias não adequadas, dos quais 50% das mortes ocorrem nas primeiras 2 horas do ocorrido e 14% morrem antes de receber atendimento médico. O objetivo deste estudo foi de avaliar a técnica de infusão transpericárdica de células mononucleares de medula óssea (CMMO) em suínos. Três suínos fêmeas, pesando 25Kg foram induzidas ao AMI, com auxilio de cateter balão colocado no 1° ramo diagonal da artéria coronária interventricular por 45 minutos, seguido por infusão de 1x108 CMMO marcadas com Hoechst® pela via transpericárdica. O grupo controle foi composto por 3 animais, os quais receberam infusão de 1x108 CMMO marcadas com Hoechst® através da mesma técnica. Os resultados revelaram distribuição homogênea das CMMO no miocárdio, concentrando-se especialmente na área infartada, enquanto que o grupo controle apresentou distribuição homogênea ao longo do miocárdio. Nós concluímos que a técnica transpericárdica é viável para infusão de CMMO em processos de isquemia cardíaca. / Cardiovascular illnesses continue to be the first cause of death in Brazil (32%), representing the third major reason of hospital internment. Although the therapeutics advances in the last decades, epidemiologic studies considered the acute myocardium infarct (AMI) to be one of the most causes of morbidity and mortality (30%), most of, related to the institution of non-adequate therapy, thereby 50% of deaths in the early two hours of the event and 14% dying before any medical assistance. Currently therapies include stent angioplasty, Thrombolytic medication and aortic-coronary venous grafting; while in experimental area the cellular therapy has been largely investigated being the cells infusion technique investigation the most enthusiastic issue. This study aimed to evaluate the transepicardic infusion technique of bone marrow mononuclear cells (BMMC) in swine. Three female swine, averaging 25 kg, were induced to AMI, with the aid of a balloon catheter displaced on the first interventricular diagonal branch of the coronary artery for 45 minutes, following to the infusion of 1x108 BMMC stained with Hoescht® by the transepicardic technique. Sham operation was carried out in three animals (Control group), which received infusion of 1x108 BMMC stained with Hoescht® by the same technique. The results revealed an inhomogeneous distribution of the BMMC in the myocardium, being more concentrated in the infarcted area, while the control group presented a homogeneous distribution along the myocardium. We concluded the transpericardic technique would be acceptable to the infusion of BMMC in cardiac ischemic processes.

Dans ce travail de thèse, nous avons montré l'importance de l'imagerie, en sus de la clinique, et plus particulièrement de la localisation de la lésion ischémique, pour la prédiction de l'évolution d'un patient après un infarctus cérébral. Pour cela, nous avons utilisé une cohorte de 428 patients victimes d'un infarctus cérébral sus-tentoriel datant de 24 à 72 heures. Ces patients ont eu une évaluation clinique et un examen en imagerie par résonance magnétique à l'inclusion et ont été suivis à trois mois et à un an après l'ictus. À partir de cette cohorte, nous avons montré que la localisation précise de l'infarctus cérébral, définie à l'échelle du voxel avec la méthode Voxel-Based Lesion-Symptom Mapping, améliorait significativement le pronostic cognitif global évalué à trois mois après l'infarctus cérébral, et ce indépendamment des variables consensuelles comme la sévérité initiale, l'âge et le volume de la lésion. Par ailleurs, l'analyse de l'intégrité du faisceau cortico-spinal (CST) en tenseur de diffusion à la phase aigüe de l'infarctus cérébral a permis d'identifier un marqueur précoce de la dégénérescence wallérienne : le ratio du nombre de fibres initial (iFNR), défini comme le nombre de fibres du CST du côté ipsilatéral à l'infarctus cérébral normalisé par le nombre de fibres du CST du côté controlatéral. L'iFNR améliorait significativement la prédiction de la récupération motrice chez les patients ayant un déficit moteur initial sévère, alors que le score clinique initial seul ne le permettait pas. / In this thesis works, we address the question of early outcome prediction after a cerebral infarct. In addition to clinical assessment, early MR Imaging of stroke location in eloquent regions and neuron fibers quantification improved the outcome prediction of cognitive functions and motor functions respectively. In that purpose, we used a large population of 428 patients with a supratentorial ischemic stroke between 24 and 72 hours after stroke onset. These patients were assessed with a magnetic resonance imaging and a clinical evaluation at baseline and were followed at three months and one year post-stroke. Using this stroke population, we demonstrated that an accurate stroke location, defined on a voxel basis with the Voxel-Based Lesion-Symptom Mapping method, significantly improved the prediction of global cognitive outcome assessed at three months post-stroke and was independent from classic predictors such as initial stroke severity, age and stroke volume. Furthermore, the analysis of corticospinal tract (CST) integrity using diffusion tensor imaging at the acute phase allowed to identify an early surrogate marker of wallerian degeneration : the initial fiber number ratio (iFNR) defined as the number of CST fibers from the ipsilateral side of stroke normalized by the number of CST fibers from the contralateral side. The iFNR significantly improved the prediction of motor recovery in stroke patients with an initial severe motor impairment, whereas initial clinical score alone could not.