Hemodynamic study in a real intracranial aneurysm: an in vitro and in silico approach

Mestrado de dupla diplomação com o Centro Federal de Educação Tecnológica Celso Suckow da Fonseca - Cefet/RJIntracranial aneurysm (IA) is a cerebrovascular disease with high rates of mortality and morbidity when it ruptures. It is known that changes in the intra-aneurysmal hemodynamic load play a significant factor in the development and rupture of IA. However, these factors are not fully understood. In this sense, the main objective of this work is to study the hemodynamic behavior during the blood analogues flow inside an AI and to determine its influence on the evolution of this pathology. To this end, experimental and numerical studies were carried out, using a real AI model obtained using computerized angiography. In the experimental approach, it was necessary, in the initial phase, to develop and manufacture biomodels from medical images of real aneurysms. Two techniques were used to manufacture the biomodels: rapid prototyping and gravity casting. The materials used to obtain the biomodels were of low cost. After manufacture, the biomodels were compared to each other for their transparency and final structure and proved to be suitable for testing flow visualizations. Numerical studies were performed with the aid of the Ansys Fluent software, using computational fluid dynamics (CFD), using the finite volume method. Subsequently, flow tests were performed experimentally and numerically using flow rates calculated from the velocity curve of a patient's doppler test. The experimental and numerical tests, in steady-state, made it possible to visualize the three-dimensional behavior of the flow inside the aneurysm, identifying the vortex zones created throughout the cardiac cycle. Correlating the results obtained in the two analyzes, it was possible to identify that the areas of vortexes are characterized by low speed and with increasing the fluid flow, the vortexes are positioned closer to the wall. These characteristics are associated with the rupture of an intracranial aneurysm. There was also a good qualitative correlation between numerical and experimental results.O aneurisma intracraniano (AI) é uma patologia cerebrovascular com altas taxas de mortalidade e morbidade quando se rompe. Sabe-se que alterações na carga hemodinâmica intra-aneurismática exerce um fator significativo no desenvolvimento e ruptura de AI, porém, esses fatores não estão totalmente compreendidos. Nesse sentido, o objetivo principal deste trabalho é o de estudar o comportamento hemodinâmico durante o escoamento de fluidos análogos do sangue no interior de um AI e determinar a sua influência na evolução da patologia. Para tal, foram realizados estudos experimentais e numéricos, utilizando um modelo de AI real obtido por meio de uma angiografia computadorizada. Na abordagem experimental foi necessário, na fase inicial, desenvolver e fabricar biomodelos a partir de imagens médicas de um aneurisma real. No fabrico dos biomodelos foram utilizadas duas técnicas: a prototipagem rápida e o vazamento por gravidade. Os materiais utilizados para a obtenção dos biomodelos foram de baixo custo. Após a fabricação, os biomodelos foram comparados entre si quanto à sua transparência e estrutura final e verificou-se serem adequados para testes de visualizações do fluxo. Os estudos numéricos foram realizados com recurso ao software Ansys Fluent, utilizando a dinâmica dos fluidos computacional (CFD), através do método dos volumes finitos. Posteriormente, foram realizados testes de escoamento experimentais e numéricos, utilizando caudais determinados a partir da curva de velocidades do ensaio doppler de um paciente. Os testes experimentais e numéricos, em regime permanente, possibilitaram a visualização do comportamento tridimensional do fluxo no interior do aneurisma, identificando as zonas de vórtices criadas ao longo do ciclo cardíaco. Correlacionando os resultados obtidos nas duas análises, foi possível identificar que as áreas de vórtices são caracterizadas por uma baixa velocidade e com o aumento do caudal os vórtices posicionam-se mais próximos da parede. Essas características apresentadas estão associadas com a ruptura de aneurisma intracraniano. Verificou-se, também, uma boa correlação qualitativa entre os resultados numéricos e experimentais

Exploring the Efficacy of miR-33 Antagonism in Promoting Regression of Intracranial Atherosclerosis in an Nonhuman Primate Model

Atherosclerosis, characterized by lipid accumulation and arterial inflammation, is a major contributor to global morbidity and mortality. Despite significant progress in understanding atherosclerosis in extracranial arteries, the study of intracranial atherosclerosis (ICAS) has been relatively neglected, despite its crucial role in stroke and vascular cognitive impairment. Challenges related to ICAS, including its location within the cranium and limited availability of suitable animal models, have hindered research progress in this area. Although nonhuman primates (NHPs) are commonly used for studying extracranial atherosclerosis, a comprehensive understanding of ICAS pathophysiology in these animals is lacking. By subjecting NHPs to a high-fat/cholesterol diet, we successfully induced measurable ICAS, providing a unique opportunity to investigate underlying mechanisms and potential therapeutic strategies for ICAS regression. This study presents a robust NHP model of ICAS development and explores the potential of miR-33 antagonism for promoting atherosclerosis regression. Mouse studies have shown that inhibiting miR-33a can stabilize or regress atherosclerosis in extracranial arteries, but their translatability is limited. To address this, we employed an NHP model that closely mimics human miR-33a and miR-33b expression and atherosclerosis development. Our investigation aims to assess the effectiveness of miR-33 antagonism in promoting ICAS regression in 61 NHPs, using histological characterization and digital pathology techniques to evaluate ICAS morphology and composition. Surprisingly, our results showed no histological evidence supporting the efficacy of miR-33 antagonism in improving ICAS regression measures. This study significantly contributes to our understanding of ICAS and its potential treatment strategies by establishing a reliable animal model for ICAS development. However, further investigation is required to determine the role of miR-33 antagonism in atherosclerosis regression. These findings have important implications for future research and the development of therapeutic strategies to improve brain health and function while reducing the burden of ICAS on stroke and vascular cognitive impairment

Cerebral Circulation

Diagnostics and diseases related to the cerebrovascular system are constantly evolving and updating. 3D augmented reality or quantification of cerebral perfusion are becoming important diagnostic tools in daily practice and the role of the cerebral venous system is being constantly revised considering new theories such as that of “the glymphatic system.” This book provides updates on models, diagnosis, and treatment of diseases of the cerebrovascular system

Front Lines of Thoracic Surgery

Front Lines of Thoracic Surgery collects up-to-date contributions on some of the most debated topics in today's clinical practice of cardiac, aortic, and general thoracic surgery,and anesthesia as viewed by authors personally involved in their evolution. The strong and genuine enthusiasm of the authors was clearly perceptible in all their contributions and I'm sure that will further stimulate the reader to understand their messages. Moreover, the strict adhesion of the authors' original observations and findings to the evidence base proves that facts are the best guarantee of scientific value. This is not a standard textbook where the whole discipline is organically presented, but authors' contributions are simply listed in their pertaining subclasses of Thoracic Surgery. I'm sure that this original and very promising editorial format which has and free availability at its core further increases this book's value and it will be of interest to healthcare professionals and scientists dedicated to this field

Advances in the Treatment of Ischemic Stroke

In recent years research on ischemic stroke has developed powerful therapeutic tools. The novel frontiers of stem cells therapy and of hypothermia have been explored, and novel brain repair mechanisms have been discovered. Limits to intravenous thrombolysis have been advanced and powerful endovascular tools have been put at the clinicians' disposal. Surgical decompression in malignant stroke has significantly improved the prognosis of this often fatal condition. This book includes contributions from scientists active in this innovative research. Stroke physicians, students, nurses and technicians will hopefully use it as a tool of continuing medical education to update their knowledge in this rapidly changing field

Complex Internal Carotid Artery Aneurysms

Complex intracranial aneurysms represent vascular lesions with attributes complicating their treatment. Giant intracranial aneurysms (GIA; ≥25 mm) are a rare subgroup of complex aneurysms with a particularly poor natural history. Due to their large size, giant aneurysms often present with cranial nerve dysfunctions. In this retrospective study, we aimed to provide a comprehensive description of the anatomical features of giant aneurysms in the internal carotid artery (ICA). Complex aneurysms are often difficult to approach directly, necessitating indirect treatment strategies. We therefore analysed a case series of bypass surgery and flow diversion in relation to the execution and outcomes in different segments of the ICA. All patients were admitted to the Helsinki University Hospital and for the analyses they were retrospectively recalled from the aneurysm database. For the series of giant aneurysms, we identified 125 patients with 129 GIAs (50 aneurysms in the ICA), from 1987 to 2007. For the series of bypass surgeries, included were 39 patients with 41 complex ICA aneurysms that were treated between 1998 and 2016. For the series of flow diversions, 62 patients with 76 ICA aneurysms were included from 2014 to 2019. In the treatment-oriented series, we analysed the internal carotid artery in segments, as this dictates the selection of treatment strategy. All the imaging studies and medical records were reviewed for relevant features in relation to aneurysms, complications and patient outcomes. The ICA was the most frequent location for GIAs in the cerebral arteries (39%) and most of these aneurysms were located specifically in the cavernous ICA segment (42%). Half of all GIAs presented mainly with symptoms of mass effect (50%). The cavernous GIAs were only rarely ruptured (10%) in contrary to the supraclinoid GIAs (36%). In general, wall calcification and intraluminal thrombosis were more seldom diagnosed in ruptured than in unruptured GIAs. In treatment of the complex ICA aneurysms with bypass procedures, the strategic goal of aneurysm treatment was achieved in 95% of cases (occlusion, 83%; flow modification, 12%). With flow diversion of the ICA aneurysms, 61% of aneurysms were occluded at 6-month follow-up and 69% at the latest follow-up. In both groups of treatment, the cavernous aneurysms became occluded slightly more often than the aneurysms in the supraclinoid region. Posttreatment large-scale strokes were rare (3-6%), but minor complications were seen more often. The pretreatment cranial nerve dysfunctions improved only moderately at best (cranial nerve-specific improvement rate of up to 60%). Respectively in groups of bypass and flow diversion, 74% and 85% of patients with unruptured aneurysms had favourable outcome at the latest follow-up. In both groups, only 25% of patients having unruptured aneurysms and presenting with poor functional status improved significantly to having a favourable outcome. The ICA is the most common location for GIAs and patients often present with symptoms of mass effect. Indirect treatment of complex ICA aneurysms with bypass procedures or flow diversion is feasible. Major treatment-related complications are rare, but minor complications occur at a non-negligible rate. Cranial nerve dysfunctions improve only in a proportion of patients. Lately, flow diverters have taken over the treatment of many complex ICA aneurysms, but the best treatment strategy should be assessed on a case-by-case basis, taking into consideration the burden of complex features of these aneurysms.Komplekseilla kallonsisäisillä aivovaltimopullistumilla eli aneurysmilla on ominaisuuksia, jotka tekevät aneurysmien hoidosta erityisen vaikeaa. Yhden alaryhmän muodostavat jättianeurysmat (≥25 mm), joilla on hoitamattomana erityisen korkea riski aiheuttaa aneurysmille tyypillinen hengenvaarallinen lukinkalvonalainen aivoverenvuoto. Kokonsa takia jättianeurysmat voivat tulla diagnosoiduksi myös esimerkiksi viereisten hermorakenteiden toimintahäiriöitä aiheuttaessaan. Kaikkiaan kompleksit aneurysmat, kuten jättianeurysmat, ovat harvinaisia ja siten niistä julkaistut aiemmat sarjat ovat olleet pääasiallisesti pieniä. Tässä retrospektiivisessä tutkimuksessa tavoitteemme oli seikkaperäisesti kuvailla sisemmän kaulavaltimon alueella sijainneiden jättianeurysmien anatomisia ominaisuuksia. Toisaalta kompleksien aneurysmien hoitamiseksi tarvitaan usein epäsuoria menetelmiä aneurysman sulkemiseksi verenkierrosta. Tämän takia analysoimme myös aivovaltimo-ohitusleikkausten sekä suonensisäisten virtausohjureiden (flow diverter) hoidolliset tulokset sisemmän kaulavaltimon aneurysmien osalta. Kaikki tutkimukseen sisällytetyt potilaat olivat olleet hoidossa HUS Helsingin yliopistollisessa sairaalassa, ja potilastiedot haettiin sarjoittain aneurysmarekisteristä vuosien 1989 ja 2019 väliseltä ajalta. Kaikki kuvantamistutkimukset sekä potilastiedot analysoitiin aneurysmiin, hoitotuloksiin ja hoidon komplikaatioihin liittyvien olennaisten tietojen osalta. Tutkimuksessamme totesimme, että sisempi kaulavaltimo on yleisin sijainti aivovaltimoiden jättianeurysmille ja tässä sijainnissa potilailla on usein aneurysman aiheuttamia aivohermo-oireita näkökyvyn häiriön muodossa. Epäsuora kompleksien aneurysmien hoito aivovaltimo-ohitteilla tai virtausohjureilla on toteuttamiskelpoista ja suurin osa aneurysmista sulkeutui seurannan aikana, mutta parhaimmillaan vain noin puolessa tapauksista aivohermo-oireet lievittyivät. Vakavat hoitoon liittyvät komplikaatiot olivat harvinaisia, mutta vähäisempiä tai ohittuvia oireita aiheuttaneita komplikaatioita todettiin useammin. Aivovaltimo-ohitusleikkaukset ovat erityisen vaativa hoitomuoto ja viime vuosina onkin suonensisäisillä virtausohjureilla hoidettu yhä enemmän komplekseja aneurysmia. Paras hoitomenetelmä tulisi valita tapauskohtaisesti ja punniten erilaisten aneurysman kompleksien ominaisuuksien aiheuttamaa kokonaishaastetta

Cerebrovascular Dysfunction and Degeneration in Alzheimer’s Disease Pathophysiology

Alzheimer’s disease (AD) is a terminal illness and the most common form of dementia, which disproportionately affects the aged population. The pathophysiology of AD is characterized by neurodegeneration that slowly progresses, affecting regions of the brain that are involved in learning, memory, language, and executive function. In patients with the disease, early symptoms include non-disruptive forgetfulness that evolves into the inability to form new memories and ultimately the loss of autonomy at late stages. Histopathological hallmarks in the brain from patients with AD is the presence of amyloid-β (Aβ)-plaques and neurofibrillary tangles (NFT) deposited in the parenchyma. Since the discovery of these hallmarks, the majority of AD research has disproportionately focused on Aβ -plaques and NFT. Although the etiology of AD remains unknown, considerable advances have been made describing the cellular, molecular, and genetic contributions to the disease. Aging is the important risk factor for the development of AD, many other factors that increase the risk of developing AD later in life are vascular in nature. The function of the cardiovascular system is known to decline during healthy aging, and the same is true for the cerebrovasculature. Empirical evidence has demonstrated a decline cerebrovascular function in AD that exceeds the decline that occurs in healthy aging. Cerebrovascular dysfunction is the major contributor to the development of hypoperfusion and hypometabolism in patients diagnosed with AD. Cerebral amyloid angiopathy (CAA) is a neuropathological condition defined by the abnormal accumulation of Aβ on the walls of the cerebrovasculature. CAA occurs in as many as 90% of patients with AD and is implicated in the weakening of the walls of cerebral blood vessels. The occurrence of microhemorrhages, aneurysms, and microinfarctions are pathological manifestations associated with weakened walls of cerebral blood vessels in the brains of patients with confirmed AD. Noteworthy, cerebrovascular dysfunction, hypoperfusion, and hypometabolism occur before the onset of Aβ-plaque and NFT deposition in the brain of patients and animal models with AD. These findings provide a compelling basis that suggest a prominent role of dysfunctional cerebrovasculature in the etiology and for the progression of AD. Although the overwhelming evidence that implicates cerebrovascular dysfunction in AD, a thorough account of the changes that occur to the cerebrovasculature nor the mechanisms that drive these changes during the development and progression of AD has not been previously reported. The overarching goal(s) of this work are to; (1) provide a thorough description of the changes that occur to the cerebrovasculature during age and the progression of AD; (2) describe the mechanisms involved in cerebrovascular damage in AD; and (3) characterize the degeneration that results from cerebrovascular hypoperfusion. These overarching goals were achieved by completing five separate studies. Described in study 1, we investigated the effects of hypoxia on astrocytic mitochondria by assessing mitochondrial fission-fusion dynamics, reactive oxygen species production, synthesis of ATP, and mitophagy. Overall, we found a drastic mitochondrial network change that is triggered by metabolic crisis during hypoxia; these changes are followed by mitochondrial degradation and retraction of astrocytic extensions during reoxygenation. In study 2, we provide a novel model for the gradual development of cerebrovascular hypoperfusion in mice. Cerebrovascular hypoperfusion developed over 34-days by inserting an ameroid constrictor ring and microcoil bilaterally around the external carotid arteries. We investigated the neurodegenerative effects of hypoperfusion in mice by assessing both gray and white matter pathology. Histopathological analyses of the brain revealed neuronal and axonal degeneration as well as necrotic lesions. The most severely affected regions were located in the hippocampus and corpus callosum. Described in study 3, we performed a series of experiments to investigate the effects of Aβ on cerebrovascular endothelial cells. In this study, we focused on characterizing the changes to mitochondrial oxidative phosphorylation, superoxide production, mitochondrial calcium, ATP synthesis, and endothelial cell death. These results describe a mechanism for mitochondrial degeneration caused by the production of mitochondrial superoxide, which was driven by increased mitochondrial Ca2+ uptake. We found that persistent superoxide production injures mitochondria and disrupts electron transport in cerebrovascular endothelial cells. In study 4, we developed a method to evaluate the cerebrovasculature of the whole-brain and constructed analyses to assess the angioarchitecture. We used vascular corrosion casting method to replicate the cerebrovasculature in adult mice and used MicroCT to acquire volumetric imaging data of the cerebrovascular network at a resolution required to investigate the microvasculature. Our analyses of the cerebrovasculature evaluated the morphology, topology, and organization of the angioarchitecture. With these developments, we investigated the effects of age and progression of disease on the cerebrovasculature in wild type mice and the triple transgenic mouse model of AD. Study 5 provides data describing degenerative changes to the microvascular network that progress with age in the triple transgenic mouse model of AD. These changes to the microvasculature occurred early, before the onset of Aβ-plaque deposition and NFT development. Overall, this body of work provides evidence of an early cerebrovascular disruption in the etiology of AD that progresses with age. Aβ mediates early cerebrovascular damage through direct interaction with vascular endothelial cells. Microvascular degeneration can lead to hypoperfusion which damages both gray and white matter. Hypoperfusion-associated hypoxia may mediate parenchymal damage by disrupting mitochondrial fission-fusion dynamics and enhancing mitophagy. These data provide a basis for the development of novel therapeutic strategies that target the changes to the cerebrovasculature for the treatment of AD. These observations may substantiate a prophylactic strategy for the treatment of AD by preventing the initial factors that lead to compromised cerebrovasculature

On the genetics of intracranial aneurysm and on growth factor induced angiogenesis in the murine brain

Cerebrovascular diseases continue to challenge us by robbing lives and leaving many disabled still in their prime working age. Some cerebrovascular diseases are more acute in nature, and some erode the quality of life over a long period of time. A life-threatening form of acute cerebrovascular disease is brought on by the rupture of an intracranial aneurysm (IA). Most IAs are berry-shaped pouches at the forking site of cerebral arteries. Since according to autopsy results, 2-5% of the population harbours IA, it is a common disease. Most IA go unnoticed during one s lifetime, however, often the first symptom they give is their deadly rupture. Likely, both environmental factors and a compound genetic susceptibility, contribute to the risk of IA, making it a complex disease. The aim of studies I-III was to test whether in humans common genetic variants contribute to the susceptibility to IA (I,II), and to seek genetic evidence for their pathomechanism (III). In multinational genome-wide association studies (I,II) we identified 5 loci with strong statistical evidence of association with IA, and a further 14 loci with suggestive evidence. Further, we found that suggestive IA risk locus at 5q26 is strongly associated with high systolic blood pressure in over 210 000 individuals of European descent, highlighting the connection between hypertension and IA (III). To gain further insight into cerebral vasculopathies and to facilitate the development of novel therapies, in study (IV) we turned our attention to vascular growth factor induced angiogenesis in a model organism. We tested by viral gene transfer the known vascular growth factors in the murine central nervous system and characterised extensively the angiogenesis upon treatment. The aim of the study was to identify the best candidate vascular growth factor(s) for therapeutic brain angiogenesis. We identified placenta growth factor as the most safe and efficient candidate for therapeutic revascularisation of the central nervous system. We envision a placenta growth factor enhanced multiple bur hole indirect extracranial-intracranial bypass as a novel therapeutic approach in the brain, possibly aiding the treatment of diseases such as chronic cerebral hypoperfusion, complex IAs and stroke