La genèse d’un anévrysme intracrânien n’est pas uniquement due à un effet mécanique mais à un ensemble d’éléments biologiques. Parmi eux, le thrombus intra-anévrysmal a un rôle majeur car il est le site d’activation de nombreuses métalloprotéinases et d’une protéolyse importante. Cependant, le thrombus du sac anévrysmal est également un substrat indispensable à la cicatrisation des anévrysmes après traitement endovasculaire car il sert de support à la recolonisation de l’anévrysme par des cellules mésenchymateuses. Dans les différents travaux présentés dans cette thèse, nous avons pu analyser une partie des phénomènes biologiques impliqués dans le succès ou l’échec des traitements endovasculaires. Les travaux présentés sont basés sur des expérimentations dans le modèle d’anévrysme à l’élastase chez le lapin et traités par coils, flow-diverters ou dispositifs intra-sacculaires (WEB). Ces travaux permettent de mieux comprendre les mécanismes biologiques mis en jeu par les différents traitements endovasculaires. L’analyse de ces phénomènes est indispensable pour comprendre les causes d’échec, mais aussi afin de développer de nouveaux outils biologiquement actifs pour le traitement des anévrysmes intracrâniens. Nous proposons ainsi le développement de stents flow-diverters biologiquement actifs. Nous proposons également trois approches différentes de thérapie cellulaire par voie endovasculaire, utilisant des cellules souches mésenchymateuses autologues, permettant une recolonisation du thrombus intraanévrysmal et une cicatrisation accélérée de l’anévrysme. Au total, le traitement des anévrysmes intracrâniens ne peut plus être basé uniquement sur des considérations mécaniques. Le développement des futurs dispositifs endovasculaires devra inclure une dimension biologique pour optimiser la cicatrisation complète des anévrysmes intracrâniens. / The genesis of an intracranial aneurysm is not only due to a mechanical effect but to a set of biological elements. Among them, intra-aneurysmal thrombus plays a major role, as it is the site of activation of many metalloproteinases and an important site of proteolysis. However, the thrombus of the aneurysmal sac is also crucial for the healing of the aneurysm after endovascular treatment, because it serves as a support for the recolonization of the aneurysm by mesenchymal cells. In the various works presented in this thesis, we analyzed some of the biological phenomena involved in the success or failure of endovascular treatments. The presented works are based on experiments in the elastase aneurysm model in the rabbit and treated with coils, flow-diverters or intra-saccular devices. This work enables to better understand the biological mechanisms involved in the various endovascular treatments. The analysis of these phenomena is essential to understand the causes of failure, but also to develop new biologically active devices for the treatment of intracranial aneurysms. We propose the development of biologically active flow-diverter stents. We also propose three different approaches of endovascular cell therapy, using autologous mesenchymal stem cells, allowing recolonization of the intra-aneurysmal thrombus and accelerated healing of the aneurysm. The treatment of intracranial aneurysms can no longer be based solely on mechanical considerations. The development of future endovascular devices should include a biological dimension to improve the complete healing of intracranial aneurysms

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22339号 / 医博第4580号 / 新制||医||1042(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 木村 剛, 教授 髙橋 良輔, 教授 小池 薫 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24966号 / 医博第5020号 / 新制||医||1069(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 江木 盛時, 教授 浅野 雅秀, 教授 湊谷 謙司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Understanding the hemodynamics of the cardiovascular system and associated diseases is important for mitigating health risks. We applied flow diagnostic techniques to investigate pulsatile flow characteristics past sidewall cavities, which have implications to two biomedical problems in the cardiovascular system: sidewall aneurysms and the left atrial appendage. Superhydrophobically-coated mesh diverters and synthetic slippery surfaces were studied for their effects on flow diversion and cavity flow enhancements. The study of pulsatile flow over a coated mesh diverter showed that the formation of the primary vortex was prevented which prevents flow stagnation and downwash flow in the cavity. The second study indicates that the healthy heart cycle is essential to reducing flow stasis inside the left atrial appendage. After applying a synthetic slippery surface to the interior of a side wall cavity model, this surface reduced the wall shear stress and allowed vortical flow to reach deeper into the cavity.

L'anévrisme intracrânien est la prédisposition mortelle la plus fréquente chez le sujet jeune. Sa compréhension demeure limitée alors que nous assistons au développement de nouveaux traitements endovasculaires permettant le traitement d'anévrismes de plus en plus complexes. L'essentiel des études sur le sujet repose sur des séries cliniques peu informatives, l'utilisation de méthodes de simulation numérique limitées et cible presque exclusivement les phénomènes mécaniques intrasacculaires sans tenir compte des conséquences de l'anévrisme sur l'artère porteuse. In vitro, l'utilisation d'anévrismes en silicone au sein d'un simulateur cardiovasculaire a permis d'objectiver un impact de l'anévrisme sur l'écoulement au sein du vaisseau porteur caractérisé par une diminution de sa résistance. In vivo, cet effet a été objectivé et mesuré en IRM de flux par l'analyse des courbes de débit volumétrique. Le flux sanguin en aval des anévrismes était caractérisé par une démodulation systolo-diastolique avec diminution des index de résistance et de pulsatilité. Cet effet était fortement corrélé au volume de l'anévrisme. Les stents flow diverters permettaient une « reconstruction hémodynamique » mesurable du vaisseau porteur en restaurant un flux normo-modulé et des index de pulsatilité et de résistance dans les limites de la normale. Une méthode originale pour la segmentation de l'artère carotide interne en IRM en contraste de phase 2D a été proposée. Elle se base sur l'application de la Transformée de Fourier sur les images de phase et la prise en compte de la cohérence temporelle des vitesses au sein du voxel. La méthode a été caractérisée et comparée à deux méthodes de référence / Intracranial aneurysms are the most common lethal predisposition amongst young adults. Its understanding remains limited to date while the development of new innovative endovascular treatments are increasingly available and allow for the treatment of more and more complex aneurysms with a non negligeable rate of complications. Most of the previous studies on intracranial aneurysms are based on low informative clinical series and the use of limited numerical simulation methods. They almost exclusively target the intrasaccular mechanical phenomena irrespective of the changes in the parent vessel induced by the aneurysm. In vitro, the use of silicone aneurysms embedded in a cardiovascular simulator showed an impact of the aneurysm on the the parent vessel flow conditions characterized by a decrease of its resistance. In vivo, flow MRI allowed to quantify this effect by analyzing the volumetric flow rate curves. Downstream to the aneurysm, the blood flow was dampened and presents a systolic diastolic demodulation with a collapse of resistive and pulsatility indexes. This effect was strongly correlated to the aneurysm volume. The flow diverter stents allowed for a measurable « hemodynamic reconstruction » of the parent vessel by restoring a normo modulated flow, and normal resistive and pulsatility indexes. An original method for the segmentation of internal carotid artery in 2D phase contrast MRI was proposed. It is based on the application of the Fourier Transform on the phase images and by taking into account the temporal coherence of velocities within the voxel. The method was characterized and compared to two reference methods

Objective: Dissecting aneurysms (DAs) of the vertebrobasilar territory manifesting with subarachnoid hemorrhage (SAH) are associated with significant morbi-mortality, especially in the case of re-hemorrhage. Sufficient reconstruction of the affected vessel is paramount, in particular, if a dominant vertebral artery (VA) is impacted. Reconstructive options include stent-assisted coiling and flow diversion (FD). The latter is technically less challenging and does not require catheterization of the fragile aneurysm. Our study aims to report a multicentric experience with FD for reconstruction of DA in acute SAH. Materials and Methods: This retrospective study investigated 31 patients (age: 30–78 years, mean 55.5 years) who had suffered from SAH due to a DA of the dominant VA. The patients were treated between 2010 and 2020 in one of the following German neurovascular centers: University Hospital Leipzig, Katharinenhospital Stuttgart, BG Hospital Bergmannstrost Halle/Saale, and Heinrich-Braun-Klinikum Zwickau. Clinical history, imaging, implanted devices, and outcomes were reviewed for the study. Results: Reconstruction with flow-diverting stents was performed in all cases. The p64 was implanted in 14 patients; one of them required an additional balloon expandable stent to reconstruct severe stenosis in the target segment. One case demanded additional liquid embolization after procedural rupture, and in one case, p64 was combined with a PED. Further 13 patients were treated exclusively with the PED. The p48MW-HPC was used in two patients, one in combination with two additional Silk Vista Baby (SVB). Moreover, one patient was treated with a single SVB, one with a SILK+. Six patients died [Glasgow Outcome Scale (GOS) 1]. Causes of death were periprocedural re-hemorrhage, thrombotic occlusion of the main pulmonary artery, and delayed parenchymal hemorrhage. The remaining three patients died in the acute–subacute phase related to the severity of the initial hemorrhage and associated comorbidities. One patient became apallic (GOS 2), whereas two patients had severe disability (GOS 3) and four had moderate disability (GOS 4). Eighteen patients showed a complete recovery (GOS 5). Conclusion: Reconstruction of VA-DA in acute SAH with flow-diverting stents is a promising approach. However, the severity of the condition is reflected by high overall morbi-mortality, even despite technically successful endovascular treatment.

Background and Purpose: Flow diversion is increasingly used as an endovascular treatment for intracranial aneurysms. In this retrospective multicenter study, we analyzed the safety and efficacy of the treatment of intracranial, unruptured, or previously treated but recanalized aneurysms using Flow Re-Direction Endoluminal Device (FRED) Jr with emphasis on midterm results. Materials and Methods: Clinical and radiological records of 150 patients harboring 159 aneurysms treated with FRED Jr at six centers between October 2014 and February 2020 were reviewed and consecutively included. Clinical outcome was measured by using the modified Rankin Scale (mRS). Anatomical results were assessed according to the O’Kelly-Marotta (OKM) scale and the Cekirge-Saatci Classification (CSC) scale. Results: The overall complication rate was 24/159 (16%). Thrombotic-ischemic events occurred in 18/159 treatments (11%). These resulted in long-term neurological sequelae in two patients (1%) with worsening from pre-treatment mRS 0–2 and mRS 4 after treatment. Complete or near-complete occlusion of the treated aneurysm according to the OKM scale was reached in 54% (85/158) at 6-month, in 68% (90/133) at 1-year, and in 83% (77/93) at 2-year follow-up, respectively. The rates of narrowing or occlusion of a vessel branch originating from the treated aneurysm according to the CSC scale were 11% (12/108) at 6-month, 20% (17/87) at 1-year, and 23% (13/57) at 2-year follow-up, respectively, with all cases being asymptomatic. Conclusions: In this retrospective multicenter study, FRED Jr was safe and effective in the midterm occlusion of cerebral aneurysms. Most importantly, it was associated with a high rate of good clinical outcome.

Background: In the last decade, flow diversion (FD) has been established as hemodynamic treatment for cerebral aneurysms arising from proximal and distal cerebral arteries. However, two significant limitations remain—the need for 0.027” microcatheters required for delivery of most flow diverting stents (FDS), and long-term dual anti-platelet therapy (DAPT) in order to prevent FDS-associated thromboembolism, at the cost of increasing the risk for hemorrhage. This study reports the experience of three neurovascular centers with the p64MW-HPC, a FDS with anti-thrombotic coating that is implantable via a 0.021” microcatheter. Materials and methods: Three neurovascular centers contributed to this retrospective analysis of patients that had been treated with the p64MW-HPC between March 2020 and March 2021. Clinical data, aneurysm characteristics, and follow-up results, including procedural and post-procedural complications, were recorded. The hemodynamic effect was assessed using the O’Kelly–Marotta Scale (OKM). Results: Thirty-two patients (22 female, mean age 57.1 years) with 33 aneurysms (27 anterior circulation and six posterior circulation) were successfully treated with the p64MW-HPC. In 30/32 patients (93.75%), aneurysmal perfusion was significantly reduced immediately post implantation. Follow-up imaging was available for 23 aneurysms. Delayed aneurysm perfusion (OKM A3: 8.7%), reduction in aneurysm size (OKM B1-3: 26.1%), or sufficient separation from the parent vessel (OKM C1-3 and D1: 65.2%) was demonstrated at the last available follow-up after a mean of 5.9 months. In two cases, device thrombosis after early discontinuation of DAPT occurred. One delayed rupture caused a caroticocavernous fistula. The complications were treated sufficiently and all patients recovered without permanent significant morbidity. Conclusion: Treatment with the p64MW-HPC is safe and feasible and achieves good early aneurysm occlusion rates in the proximal intracranial circulation, which are comparable to those of well-established FDS. Sudden interruption of DAPT in the early post-interventional phase can cause in-stent thrombosis despite the HPC surface modification. Deliverability via the 0.021” microcatheter facilitates treatment in challenging vascular anatomies.

Background and Purpose: Low-profile flow diverter stents (FDS) quite recently amended peripheral segments as targets for hemodynamic aneurysm treatment; however, reports on outcomes, especially later than 3 months, are scarce. This study therefore reports our experience with the novel silk vista baby (SVB) FDS and respective outcomes after 8 and 11 months with special respect to specific adverse events. Materials and Methods: Forty-four patients (mean age, 53 years) harboring 47 aneurysms treated with the SVB between June 2018 and December 2019 were included in our study. Clinical, procedural, and angiographic data were collected. Follow-ups were performed on average after 3, 8, and 11 months, respectively. Treatment effect was assessed using the O’Kelly Marotta (OKM) grading system. Results: Overall, angiographic follow-ups were available for 41 patients/45 aneurysms. Occlusion or significant reduction in aneurysmal perfusion (OKM: D1, B1–B3 and A2–A3) was observed in 98% of all aneurysms after 8 months. Only 2% of the treated aneurysms remained morphologically unaltered and without an apparent change in perfusion (OKM A1). Adverse events in the early post-interventional course occurred in seven patients; out of them, mRS-relevant morbidity at 90 days related to FDS treatment was observable in two patients. One death occurred in the context of severe SAH related to an acutely ruptured dissecting aneurysm of the vertebral artery. Conclusion: The SVB achieves sufficient occlusion rates of intracranial aneurysms originating from peripheral segments, which are comparable to prior established conventional FDS with acceptably low complication rates. However, alteration of a hemodynamic equilibrium in distal localizations requires special attention to prevent ischemic events.

La sélection de variables est une tâche primordiale en fouille de données et apprentissage automatique. Il s’agit d’une problématique très bien connue par les deux communautés dans les contextes, supervisé et non-supervisé. Le contexte semi-supervisé est relativement récent et les travaux sont embryonnaires. Récemment, l’apprentissage automatique a bien été développé à partir des données partiellement labélisées. La sélection de variables est donc devenue plus importante dans le contexte semi-supervisé et plus adaptée aux applications réelles, où l’étiquetage des données est devenu plus couteux et difficile à obtenir. Dans cette thèse, nous présentons une étude centrée sur l’état de l’art du domaine de la sélection de variable en s’appuyant sur les méthodes qui opèrent en mode semi-supervisé par rapport à celles des deux contextes, supervisé et non-supervisé. Il s’agit de montrer le bon compromis entre la structure géométrique de la partie non labélisée des données et l’information supervisée de leur partie labélisée. Nous nous sommes particulièrement intéressés au «small labeled-sample problem» où l’écart est très important entre les deux parties qui constituent les données. / Feature selection is an important task in data mining and machine learning processes. This task is well known in both supervised and unsupervised contexts. The semi-supervised feature selection is still under development and far from being mature. In general, machine learning has been well developed in order to deal with partially-labeled data. Thus, feature selection has obtained special importance in the semi-supervised context. It became more adapted with the real world applications where labeling process is costly to obtain. In this thesis, we present a literature review on semi-supervised feature selection, with regard to supervised and unsupervised contexts. The goal is to show the importance of compromising between the structure from unlabeled part of data, and the background information from their labeled part. In particular, we are interested in the so-called «small labeled-sample problem» where the difference between both data parts is very important.