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Introdução: Estudos pré-clínicos demonstraram que impulsos de alto índice mecânico (IM) de um transdutor de ultrassom diagnóstico durante uma infusão intravenosa de microbolhas (sonotrombólise) podem restaurar o fluxo epicárdico e microvascular no infarto agudo do miocárdio com supradesnivelamento do segmento ST (IAMCSST). Objetivo: Testamos a eficácia clínica da sonotrombólise em pacientes com IAMCSST medindo a taxa de recanalização coronariana precoce, tamanho do infarto do miocárdio por ressonância magnética e ecocardiograma e a evolução do defeito de perfusão e função ventricular esquerda à chegada, após a intervenção coronária percutânea (ICP), 72h a 96h e em um e seis meses de acompanhamento. Métodos: Pacientes com seu primeiro IAMCSST foram prospectivamente randomizados para receberem impulsos de alto IM guiados por ultrassom diagnóstico (grupo terapia) durante a infusão intravenosa de um agente de ultrassom antes e após a ICP ou para um grupo controle que recebeu apenas ICP (n = 50 em cada grupo). Um grupo de referência (n = 203) que chegou fora da janela de randomização também foi analisado. Recanalização angiográfica prévia à ICP, tamanho do infarto (TI) por ressonância magnética e alteração no defeito de perfusão e função sistólica pela ecocardiografia à chegada, após-ICP, 72h a 96h, em um e seis meses foram comparados. Resultados: A média de idade dos pacientes randomizados foi de 59 anos e não houve diferença de sexo, presença de diabetes, hipertensão arterial e dislipidemia entre os grupos estudados. Os tempos porta-balão não foram diferentes entre os grupos analisados (78 ± 32 minutos para o grupo controle versus 77 ± 26 minutos para o grupo terapia, p = 0,42), mas foram mais longos no grupo de referência (96 ± 49 minutos, p < 0,001 comparado aos grupos controle e terapia). A recanalização angiográfica foi de 48% no grupo terapia versus 20% no grupo controle e 21% no grupos de referência (p < 0,001). O TI foi reduzido (29 ± 22 gramas do grupo terapia versus 40 ± 20 gramas do grupo controle, p = 0,026). Da mesma forma, as taxas de fluxo TIMI 3 pré-ICP foram maiores no grupo terapia (32% versus 14% no grupo controle e 16% no grupo de referência, p = 0,02). Após a ICP, fluxo TIMI 3 foi observado no vaso culpado em 37/50 (74%) pacientes no grupo terapia e 30/50 (60%) pacientes do grupo controle. A fração de ejeção do ventrículo esquerdo (FEVE) não foi diferente entre os grupos antes do tratamento (44 ± 11% no grupo terapia versus 43 ± 10% no grupo controle, p = 0,39), mas aumentou imediatamente após a ICP no grupo terapia (p = 0,03) e permaneceu maior aos seis meses (p = 0,015). A correlação entre as medidas do tamanho do infarto (TI) em gramas por ressonância magnética e ecocardiografia com contraste, utilizando o coeficiente de correlação intraclasses foi de 0,672 (p < 0,001). Não houve diferença significativa na % de área acometida pelo infarto pelo ecocardiograma realizado pré-ICP, pós-ICP e durante a internação com 72h a 96h de evolução, mas no seguimento de 1 mês houve consolidação de maior redução da % de área infartada no grupo terapia 20,67 ± 8,99 a 11,87 ± 7,49 quando comparado ao grupo controle 19,16 ± 10,08 a 17,02 ± 10,02 (p = 0,016), mostrando uma diferença comportamental durante as avaliações temporais, com uma maior diminuição no tamanho do infarto no grupo terapia (p < 0,001). Ao comparar a porcentagem média de áreas infartadas naqueles pacientes com artérias coronárias obstruídas na primeira angiografia, houve um menor comprometimento microvascular naqueles do grupo terapia 12,99 ± 6,53 versus 18,87 ± 9,93 do grupo controle (p = 0,015 ). Ainda assim, como consequência das melhorias observadas na % do tamanho do infarto, notamos uma melhora progressiva na fração de ejeção nos pacientes do grupo terapia: 44,0% ± 11,0% para 53,0% ± 10% versus 43 % ± 10% para 48,0% ± 11,0% no grupo controles (p = 0,048) da chegada aos 6 meses de acompanhamento. Conclusões: A sonotrombólise adicionada à ICP melhora as taxas de recanalização e reduz o tamanho do infarto, resultando em melhorias sustentadas na perfusão miocárdica e na função sistólica após o IAMCSST / Background: Pre-clinical studies have demonstrated that high mechanical index (MI) impulses from a diagnostic ultrasound transducer during an intravenous microbubble infusion (sonothrombolysis) can restore epicardial and microvascular flow in acute ST-segment elevation myocardial infarction (STEMI). Objective: We tested the clinical effectiveness of sonothrombolysis in patients with STEMI by measuring early coronary recanalization rate, size of myocardial infarction by MRI and echocardiography and the evolution of the perfusion defect and left ventricular function at arrival, after PCI, 72h to 96h and at one- and six-months follow-up. Methods: Patients with their first STEMI were prospectively randomized to either diagnostic ultrasound-guided high MI impulses (therapy group) during an intravenous ultrasound agent infusion prior to, and following emergent percutaneous coronary intervention (PCI), or to a control group that received PCI only (n = 50 in each group). A reference group (n = 203) who arrived outside the randomization window was also analyzed. Angiographic recanalization prior to PCI, infarct size (IS) by magnetic resonance imaging, and change in perfusion defect and systolic function by echocardiography at arrival, post PCI, 72h to 96h, one and six months were compared. Results: The mean age of the randomized patients was 59 years and there was no difference in gender, presence of diabetes, arterial hypertension and dyslipidemia between the groups studied. Door to balloon times were not different between groups (78 ± 32 minutes for control versus 77 ± 26 minutes for therapy groups, p = 0.42), but were longer in the reference group (96 ± 49 minutes, p < 0.001 compared to control and therapy groups). Angiographic recanalization was 48% in therapy group versus 20% in control group and 21% in the reference group (p < 0.001). IS was reduced (29 ± 22 grams in therapy group versus 40 ± 20 grams in control group, p = 0.026). Likewise, pre-PCI TIMI 3 flow rates were higher in the therapy group (32% versus 14% in control group and 16% in the reference group, p = 0.02). After PCI, the TIMI 3 flow was observed in the culprit vessel in 37/50 (74%) patients in therapy group and 30/50 (60%) in patients in the control group. Left ventricular ejection fraction (LVEF) was not different between groups before treatment (44 ± 11% in therapy group versus 43 ± 10% in control group, p = 0.39), but increased immediately after PCI in the therapy group (p = 0.03) and remained higher at six months (p = 0.015). The correlation between the measurements of infarct size (IS) in grams by magnetic resonance and contrast echocardiography, using the intra-class correlation coefficient was 0.672 (p < 0.001). There was no significant difference in the % area affected by the infarction on echocardiography performed pre-PCI, post-PCI and during hospital stay with 72h to 96h of evolution, but in the follow-up of 1 month there was a consolidation of greater reduction of the % infarcted area in the therapy group 20.67 ± 8.99 to 11.87 ± 7.49 when compared to control group 19.16 ± 10.08 to 17.02 ± 10.02 (p = 0.016), showing a behavioral difference during the temporal evaluations, with a greater decrease in infarct size in the therapy group (p < 0.001). When comparing the mean % of infarcted areas in those patients with occluded coronary arteries at the first angiography, there was a lower microvascular impairment in those in the therapy group 12.99 ± 6.53 versus 18.87 ± 9,93 in control group (p = 0.015). Still, as a consequence of the improvements observed in the % of infarct size, we noticed a progressive improvement in the ejection fraction in patients in the therapy group 44.0% ± 11.0% to 53.0% ± 10% versus 43% ± 10% to 48.0% ± 11,0% in the control group (p = 0.048) from arrival to 6-month follow-up. Conclusions: Sonothrombolysis added to PCI improves recanalization rates and reduces infarct size, resulting in sustained improvements in myocardial perfusion and systolic function after STEMI

HINTERGRUND UND ZWECK: Das Penumbra System ist ein innovatives, neuartiges mechanisches Instrument für die Rekanalisierung von langstreckigen Gefäßverschlüssen der Hirnarterien durch Thrombus-Aspiration. Zweck dieser Studie ist die Beurteilung der Effektivität der Gefäßrekanalisation und des neurologischen Endergebnisses von Patienten, die infolge eines akuten ischämischen Schlaganfalls mit dem Penumbra System therapiert wurden. MATERIAL UND METHODEN: Insgesamt 91 Patienten mit akutem ischämischen Schlaganfall aufgrund eines Verschlusses hirnversorgender Arterien wurden mit dem Penumbra System behandelt und in diese retrospektive Studie aufgenommen. In 14 Fällen kam dabei allein das Penumbra System zum Einsatz, bei weiteren 77 Patienten wurde die mechanische Rekanalisation mit intraarterieller und/oder intravenöser Thrombolyse kombiniert. Das klinische Endergebnis wurde anhand des modified Rankin Scale (mRS) bewertet; die Rekanalisation wurde mit dem Thrombolysis in Cerebral Infarction Score (TICI Score) beurteilt. ERGEBNISSE: Das durchschnittliche Patientenalter betrug 62 ± 19,4 Jahre; der mittlere NIH Stroke Scale (NIHSS) bei Krankenhausaufnahme war 17. Eine erfolgreiche Rekanalisation konnte bei 77 % der Patienten erreicht werden. Durchschnittlich vergingen 49 Minuten von arterieller Punktion bis zur Gefäßrekanalisation (Quartillen 31 - 86). In der Verlaufskontrolle zeigten 36 % der Patienten eine NIHSS-Verbesserung von ≥ 10 Punkten und 34 % der Patienten mit einem Verschluss in der vorderen Zirkulation hatten einen mRS ≥ 2, während nur 7 % der Patienten mit einem Gefäßverschluss in der hinteren Zirkulation ein gutes Endergebnis im Nachbeobachtungszeitraum vorwiesen. Insgesamt 20 Patienten verstarben während des Krankenhausaufenthaltes; kein Todesfall war auf den Einsatz des Penumbra Systems zurückzuführen. FAZIT: Zusammenfassend bestätigen die in dieser Arbeit dargestellten Ergebnisse einer retrospektiven Single-Center-Studie die Effektivität des Penumbra Systems für die mechanische Rekanalisation von ischämischen Schlaganfallpatienten. Eine erfolgreiche und schnelle Rekanalisation mithilfe des Penumbra Systems ist dabei assoziiert mit einer signifikanten Verbesserung des funktionellen-klinischen Endergebnisses bei Patienten mit akutem ischämischen Schlaganfall aufgrund eines Gefäßverschlusses der hirnversorgenden Gefäße.Der erweiterte klinische Nutzen der mechanischen Thrombektomie, im Vergleich zur medikamentösen Standardtherapie, muss in der Zukunft durch eine prospektive, randomisierte und kontrollierte Studie belegt werden.

La reperfusion complète et précoce est le moyen le plus efficace pour limiter l'extension de l'infarctus cérébral et les séquelles neurologiques. Le traitement de l'infarctus cérébral a été révolutionné par la thrombectomie mécanique intra-artérielle en permettant une recanalisation dans plus de 70% des cas et une réduction significative de la morbidité comparativement à la thrombolyse seule pour le territoire carotidien. Le pronostic des occlusions basilaires reste dramatique et aucun essai n'a démontré le bénéfice de l'approche intra-artérielle à l'heure actuelle. Dans la première partie du travail, nous avons réalisé une méta-analyse sur la thrombectomie par «stent-retriever» des occlusions basilaires, à partir des résultats publiés dans MEDLINE entre novembre 2010 et avril 2014: recanalisation angiographique (TICI≥2b)=81% (IC 95%: 73-87); hémorragie cérébrale symptomatique à 24 heures=4% (IC 95%: 2-8); évolution neurologique favorable (mRS≤2 à 3 mois)=42% (IC 95%: 36-48); mortalité=30% (IC 95%: 25-36). L'approche intra-artérielle ouvre une nouvelle ère thérapeutique, cependant un modèle animal adapté et pertinent est nécessaire pour l'évaluation pré-clinique. Dans la deuxième partie du travail, nous avons caractérisé l'évolution spatio-temporelle précoce de l'infarctus par IRM multimodale dans un modèle d'ischémie cérébrale focale transitoire réalisé par occlusion sélective intra-artérielle de l'artère cérébrale moyenne chez le rat adulte. Une occlusion complète de l'artère cérébrale moyenne proximale était observée dans 75% des 16 rats opérés, et un mismatch diffusion/perfusion dans 77% des cas. Le volume ischémique durant l'occlusion artérielle, définie sur la séquence de diffusion, était de 90±64 mm3 et de 57±67 mm3 à 24 heures sur la séquence T2. La recanalisation artérielle s'associe à une reperfusion tissulaire dans 36% des cas. L'hypoperfusion persistait chez la majorité des animaux 3 heures après recanalisation. L'infarctus était de localisation cortical dans 31%, striatale dans 25%, et cortico-striatale dans 44%. Tous les animaux étaient en vie à 24 heures confirmant le caractère mini-invasif de ce modèle. Bien que la reperfusion sauve incontestablement une partie du parenchyme ischémique, elle s'accompagne également de lésions irréversibles spécifiques, dites de reperfusion, s'ajoutant aux lésions initiales. Limiter l'importance des lésions de reperfusion représente un objectif thérapeutique majeur. Dans la troisième partie, nous avons testé l'effet neuroprotecteur de la Cyclosporine A sur la réduction du volume de l'infarctus cérébral et sur le pronostic clinique. Une procédure d'ischémie reperfusion cérébrale de 60 minutes a été réalisée chez 48 animaux, puis ont été randomisés en quatre groupes (groupe témoin, pré-conditionnement, postconditionnement intraveineux et intra-artériel avec la Cyclosporine A à la dose de 10 mg/kg dans les 30 secondes suivant la reperfusion). Sur les 43 animaux inclus dans l'analyse, il n'a pas été observé de réduction du volume ischémique ni une amélioration du pronostic après injection intraveineuse ou intra-artérielle de Cyclosporine A. La Cyclosporine A ne permet pas non plus de limiter l'extension des lésions de reperfusion au sein de la zone à risque à 24 heures de la reperfusion cérébrale / Early and complete reperfusion is the most effective therapy to limit the extent of brain infarction. The treatment of acute anterior ischemic stroke has been revolutionized by the intra-arterial mechanical thrombectomy allowing a 70% recanalization rate and a significant reduction of morbidity compared with thrombolysis alone. The prognosis of basilar artery occlusion remains catastrophic, and to date any trial has demonstrated the benefit of intra-arterial approach. In the first part of the work, we conducted a systematic review and meta-analysis of all previous studies of stent retriever thrombectomy in basilar artery occlusion patients between November 2010 and April 2014: recanalization (TICI≥2b)=81% (95% CI: 73-87); symptomatic intracranial haemorrhage at 24 hours=4% (95% CI 2-8); favorable neurological outcome (mRS≤2 at 3 months)=42% (95% CI: 36-48); mortality=30%(95% CI 25-36). Intra-arterial approach opens new avenues for the developement of treatments for brain infarction, but a relevant animal model of acute ischemic stroke is required for preclinical evaluation. In the second part of the work, we evaluated the spatiotemporal evolution of cerebral ischemia by sequential multimodal MRI in a new minimally invasive model of transient focal ischemia by selective intra-arterial occlusion of the middle cerebral artery in rat. A complete occlusion of the proximal portion of the middle cerebral artery was observed in 75% of 16 operated rats, and a mismatch diffusion/perfusion in 77% of cases. Acute stroke volume during arterial occlusion was 90±64 mm3 on diffusion-weighted imaging, and 57±67 mm3 at 24 hours on T2-weighted imaging. Recanalization is associated with tissue reperfusion in 36% of cases. The hypoperfusion persisted in the majority of animals 3 hours after recanalization. Brain infarction was cortical in 31%, striatal in 25%, and corticalstriatal in 44% of cases. All animals were alive at 24 hours, confirming the minimally invasive nature of the model. Although reperfusion saves a portion of ischemic tissue, it also carries specific irreversible damage, called reperfusion injury, in addition to initial damage caused by ischemia. Limiting the size of infarction is a major objective. In the third part, we tested the neuroprotective effect of Cyclosporine A in reducing the lesion volume and functional outcome. A total of 48 adult rats underwent the intra-arterial ischemia reperfusion procedure, and were randomly assigned to four treatment groups (control, preconditioning, intravenous and intra-arterial postconditioning with Cyclosporine A). Intravenous or intra arterial injection of Cyclosporine A at reperfusion does not either reduce the volume of stroke or improve the neurological outcome. Administation of Cyclosporin A at reperfusion does not limit the extension of reperfusion injuries within the ischemic risk area at 24 hours