Flow diversion (FD) is a novel endovascular technique based on the profound alteration of cerebrovascular hemodynamics, which emerged as a promising minimally invasive therapy for intracranial aneurysms. However, delayed post-procedural stroke remains an unexplained concern. A consistent follow-up-regimen has not yet been defined, but is required urgently to clarify the underlying cause of delayed ischemia. In the last two years, 223 patients were treated with six different FD devices in our center. We identified subacute, FD-induced segmental vasospasm (SV) in 36 patients as a yet unknown, delayed-type reaction potentially compromising brain perfusion to a critical level. Furthermore, 86% of all patients revealed significant SV approximately four weeks after treatment. In addition, 56% had SV with 25% stenosis, and 80% had additional neointimal hyperplasia. Only 13% exhibited SV-related high-grade stenosis. One of those suffered stroke due to prolonged SV, requiring neurocritical care and repeated intra-arterial (i.a.) biochemical angioplasty for seven days to prevent territorial infarction. Five patients suffered newly manifested, transient hemicrania accompanying a compensatorily increased ipsilateral leptomeningeal perfusion. One treated vessel obliterated permanently. Hence, FD-induced SV is a frequent vascular reaction after FD treatment, potentially causing symptomatic ischemia or even stroke, approximately one month post procedure. A specifically early follow-up-strategy must be applied to identify patients at risk for ischemia, requiring intensified monitoring and potentially anti-vasospastic treatment.

No description available.

Abdominal aortic aneurysm (AAA) is a major cardiovascular disease and involves enhancement of renin-angiotensin system and recruitment/activation of inflammatory factors such as matrix metalloproteases (MMP's). Caveolae has been shown to play a role in a number of different cardiovascular diseases through different mechanisms including regulation of oxidative stress, inflammation and degradation of extracellular matrix components through MMP's. In addition, endothelial cell caveolae are known to localize the Ang-II (AT1) receptor and regulate renin-angiotensin signaling. Based on these findings, we evaluated the role of caveolae in AAA formation in the murine model. Here, eight week old mice were co-infused with Ang-II and BAPN, a lysyl oxidase inhibitor, to induce AAA. We found that mice lacking the main structural protein of caveolae, caveolin-1, did not develop AAA compared to WT animals in spite of hypertensive blood pressures measured by telemetry in both groups. This finding suggests that intact Ang-II signaling remains in place in caveolin-1 knockout mice. To begin to address the underlying mechanism by which caveolae contributes to AAA, we measured the level of oxidative stress and MMP's in aneurysms. We found an increased expression of MMP-2 and MMP-9 in vessels of WT mice displaying aneurysms. This increase in expression was not observed in Cav-1 knockout mice. Furthermore, KO mice showed less oxidative stress then their WT counterparts as assessed by anti-nitrotyrosine staining. Next we examined the characteristics of early AAA formation in wild-type mice. We found caveolae associated proteins, endothelial nitric oxide synthase (eNOS) and NADPH oxidase 2 (Nox2), were upregulated in early AAA formation, particularly in the endothelium. Also, Vascular Cell Adhesion Molecule (VCAM) was upregulated in the endothelium. However, macrophage infiltration and MMP-2 activation was not observed in early AAA development. In order to elucidate the role of endothelial caveolae in the formation of AAA, we induced AAA, as previously described, in endothelial specific cav-1 knockout mice. Preliminarily findings show endothelial specific knockout mice do not form AAA as compared to their WT littermates. In conclusion, caveolae appears to play a critical role in the formation of AAA in mice via oxidative stress, and recruitment and/or activation of MMPs, specifically MMP-2 and MMP-9. Early markers of AAA formation include VCAM, NOX2, eNOS, and protein nitration. Also, preliminary results indicate that endothelial specific knockout mice do not develop AAA. / Cell Biology

Sirtuin-1 (SirT1) is a nicotinamide adenine dinucleotide (NAD+)-dependent lysine deacetylase expressed ubiquitously in the body. In the vasculature, SirT1 is present in endothelial and vascular smooth muscle cells (VSMCs), where it has been shown to promote anti-inflammatory and anti-oxidant effects. As a result, SirT1 is known to play a protective role in the vasculature wall from pathologies such as atherosclerosis, arterial stiffness, and aortic aneurysm. Hence, SirT1 is considered an attractive therapeutic target for vascular diseases and potentially, aging-related and metabolic diseases. However, currently available SirT1 activators have failed to reach the clinic. Thus, novel approaches to activate SirT1 are needed. In this study, we first sought to optimize a novel fluorescence-based SirT1 activity assay, with which to reliably assess intracellular SirT1 activity and the efficacy of SirT1 activators and inhibitors. We next sought to use the SirT1 activity assay to screen novel compounds identified by an in silico docking analysis and hypothesized to activate SirT1. Lastly, we generated adeno-associated viruses (AAV) overexpressing wildtype (WT) or a redox-resistant (3M) SirT1 to analyze the effects of overexpressing SirT1 in VSMCs, in normal and oxidative stress conditions. For the activity assay, our results showed that an optimal standard curve range was between 0 ng and 12 ng of substrate (acetylated-p53 peptide). After testing different commercially available human recombinant SirT1s, the Anaspec SirT1 of the highest concentration showed a decrease in measured fluorescence for acetylated-p53 peptide with higher SirT1 (ng), indicating the enzyme and the assay were functional. However, when novel small molecules (A4, B4, and G3) hypothesized to activate SirT1 were added to reactions, the total p53 peptide fluorescence values increased compared to the control, suggesting some interference of the molecules with the assay detection. After AAV infection in VSMCs, SirT1 expression, measured by HA-tag, increased for AAV WT (n=3, p=0.04) and similarly for AAV 3M SirT1, indicating that the AAVs efficiently infect VSMCs. SirT1 activity, measured by Western Blot as decreased acetylated-histone (H3), also appeared to increase for both AAV WT and AAV 3M. A similar trend was shown for VSMCs under oxidant stress conditions (n=2). In conclusion, we successfully established a standard curve range for a novel SirT1 activity assay. Further trials are needed to ensure activity assay reproducibility before testing the efficacy of SirT1 activators and inhibitors. Infection of AAV WT and 3M SirT1 led to an increase in the expression and activity of SirT1 in VSMCs. The expression of SirT1 by AAV may be a promising therapeutic option for in vivo prevention and treatment of vascular diseases. / 2026-03-01T00:00:00Z

Obstructive sleep apnea (OSA) is common in older U.S. adults and the prevalence is anticipated to rise in this age group along with obesity, a prominent risk factor for OSA. Recently, OSA was determined to be highly prevalent among patients with abdominal aortic aneurysm (AAA) disease. Objectives: Examine associations between OSA risk and physical activity (PA), metabolic syndrome (MetSyn), and exercise responses to cardiopulmonary exercise testing (CPET) in elderly patients with AAA disease. Methods: Elderly patients (n=326 for Studies 1 and 2; n=114 for Study 3) newly diagnosed with small AAAs (aortic diameter "2.5 and < 5.5 cm) were recruited. Data collection for all participants included: extraction of medical history and drug information from medical records; completion of a physical examination to assess resting vital signs and anthropometrics; fasting blood draw for several biochemical analyses; completion of a cardiopulmonary exercise test (CPET); and completion of interviews and questionnaires for health history, PA, and OSA risk. Results: 57% of subjects were High-risk for OSA and 17% were classified in the highest-risk Berlin Risk Score (BRS) 3 group; these subjects reported fewer blocks walked/day, flights of stairs climbed/day, and expended fewer Calories when engaged in these activities compared to Low-risk counterparts, independent of obesity. Among those at High-risk for OSA, 45% had MetSyn. Subjects with the highest BRS also had the highest prevalence of MetSyn and values for the MetSyn component biomarkers. Exercise capacity and physiological responses at rest, during exercise, and recovery were similar between groups at High- and Low-risk for OSA. Conclusions: Reduced levels of PA among elderly AAA patients at High-risk for OSA could have unfavorable implications for cardiovascular disease (CVD) risk and all-cause and CVD mortality.  Subjects demonstrating the most clinical symptoms of OSA showed a significantly higher prevalence for MetSyn and several of the biomarkers that determine MetSyn. In clinical practice, the BRS may be useful for identifying those AAA patients at increased risk for both OSA and MetSyn. / Ph. D.

Yes / Abdominal aortic aneurysm (AAA) is a silent, progressive disease with high mortality and increasing prevalence with aging. Smooth muscle cell (SMC) dysfunction contributes to gradual dilatation and eventual rupture of the aorta. Here we studied phenotypic characteristics in SMC cultured from end-stage human AAA (5cm) and cells cultured from a porcine carotid artery (PCA) model of early and end-stage aneurysm. Human AAA-SMC presented a secretory phenotype and expressed elevated levels of differentiation marker miR-145 (2.2-fold, P<.001) and senescence marker SIRT-1 (1.3-fold, P<.05), features not recapitulated in aneurysmal PCA-SMC. Human and end-stage porcine aneurysmal cells were frequently multi-nucleated (3.9-fold, P<.001 and 1.8-fold, P<.01 respectively, versus control cells) and displayed aberrant nuclear morphology. Human AAA-SMC exhibited higher levels of the DNA damage marker H2AX (3.9-fold, P<.01 vs. control SMC). These features did not correlate with patients’ chronological age; and are therefore potential markers for pathological premature vascular aging. Early-stage PCA-SMC (control and aneurysmal) were indistinguishable from one another across all parameters. The principal limitation of human studies is tissue availability only at end-stage disease. Refinement of a porcine bioreactor model would facilitate study of temporal modulation of SMC behaviour during aneurysm development and potentially identify therapeutic targets to limit AAA progression. / Supported in part by a grant from the Leeds Teaching Hospitals Charitable Foundation (9R11/8002)

Yes / (1) Abdominal aortic aneurysm (AAA) is a silent, progressive disease with significant mortality from rupture. Whilst screening programmes are now able to detect this pathology early in its development, no therapeutic intervention has yet been identified to halt or retard aortic expansion. The inability to obtain aortic tissue from humans at early stages has created a necessity for laboratory models, yet it is essential to create a timeline of events from EARLY to END stage AAA progression. (2) We used a previously validated ex vivo porcine bioreactor model pre-treated with protease enzyme to create "aneurysm" tissue. Mechanical properties, histological changes in the intact vessel wall, and phenotype/function of vascular smooth muscle cells (SMC) cultured from the same vessels were investigated. (3) The principal finding was significant hyperproliferation of SMC from EARLY stage vessels, but without obvious histological or SMC aberrancies. END stage tissue exhibited histological loss of α-smooth muscle actin and elastin; mechanical impairment; and, in SMC, multiple indications of senescence. (4) Aortic SMC may offer a therapeutic target for intervention, although detailed studies incorporating intervening time points between EARLY and END stage are required. Such investigations may reveal mechanisms of SMC dysfunction in AAA development and hence a therapeutic window during which SMC differentiation could be preserved or reinstated. / This research was funded in part by The Leeds Teaching Hospitals Charitable Foundation (R11/8002). E.R.C. was supported by a PhD studentship from the Engineering and Physical Sciences Research Council (EPSRC; EP/F500513/1). R.J.H. was the recipient of an Intercalated Batchelor of Science Degree in Science award from the Royal College of Surgeons of England. M.A.B.(FS/18/12/33270 and FS/12/54/29671), K.I.B. (FS/12/26/29395), and K.J.G. (FS/11/91/29090) were supported by BHF Clinical Research Training Fellowships.

Yes / Early vascular ageing (EVA) is a pathological phenomenon whereby the vascular system ages more quickly than chronological age. This underpins many cardiovascular diseases including the complications of type 2 diabetes, aneurysm formation and hypertension. Smooth muscle cells (SMC) are the principal cell type in the vascular wall and maintain vascular tone. EVA-related phenotypic switching of these cells contributes towards disease progression. EVA is distinct from chronological ageing, and research is ongoing to identify a definitive molecular signature of EVA. This will facilitate the discovery of new clinical tests for early detection of EVA and identify therapeutic targets to halt (or prevent) EVA in SMC, thus reducing macrovascular morbidity and mortality.

Abdominal aortic aneurysm (AAA) is characterized by a bulge in the abdominal aorta. AAA development is mostly asymptomatic, but such a bulge may suddenly rupture, which is associated with a high mortality rate. Unfortunately, there is no medication that can prevent AAA from expanding or rupturing. Therefore, patients with detected AAA are monitored until treatment indication, such as maximum AAA diameter of 55 mm or expansion rate of 1 cm/year. Models of AAA development may help to understand the disease progression and to inform decision-making on a patient-specific basis. AAA growth and remodeling (G&amp;R) models are rather complex, and before the challenge is undertaken, sound clinical validation is required. In Paper A, an existing thick-walled model of growth and remodeling of one layer of an AAA slice has been extended to a two-layered model, which better reflects the layered structure of the vessel wall. A parameter study was performed to investigate the influence of mechanical properties and G&amp;R parameters of such a model on the aneurysm growth. In Paper B, the model from Paper A was extended to an organ level model of AAA growth. Furthermore, the model was incorporated into a Fluid-Solid-Growth (FSG) framework. A patient-specific geometry of the abdominal aorta is used to illustrate the model capabilities. In Paper C, the evolution of the patient-specific biomechanical characteristics of the AAA was investigated. Four patients with five to eight Computed Tomography-Angiography (CT-A) scans at different time points were analyzed. Several non-trivial statistical correlations were found between the analyzed parameters. In Paper D, the effect of different growth kinematics on AAA growth was investigated. The transverse isotropic in-thickness growth was the most suitable AAA growth assumption, while fully isotropic growth and transverse isotropic in-plane growth produced unrealistic results. In addition, modeling of the tissue volume change improved the wall thickness prediction, but still overestimated thinning of the wall during aneurysm expansion. / Bukaortaaneurysm (AAA) kännetecknas av en utbuktning hos aortaväggen i buken. Tillväxt av en AAA är oftast asymtomatisk, men en sådan utbuktning kan plö̈tsligt brista, vilket har hög dödlighet. Tyvärr finns det inga mediciner som kan förhindra AAA från att expandera eller brista. Patienter med upptä̈ckt AAA hålls därför under uppsikt tills operationskrav är uppnådda, såsom maximal AAA-diameter på 55 mm eller expansionstakt på 1 cm/år. Modeller för AAA-tillväxt kan bidra till att öka förståelsen för sjukdomsförloppet och till att förbättra beslutsunderlaget på en patientspecifik basis. AAA modeller för tillväxt och strukturförändring (G&amp;R) är ganska komplicerade och innan man tar sig an denna utmaning krävs de god klinisk validering. I Artikel A har en befintlig tjockväggig modell för tillväxt av ett skikt av en AAA-skiva utö̈kats till en två-skiktsmodell. Denna modell återspeglar bättre den skiktade strukturen hos kärlväggen. Genom en parameterstudie undersö̈ktes påverkan av mekaniska egenskaper och G&amp;R-parametrar hos en sådan modell för AAA-tillväxt. I Artikel B utvidgades modellen från Artikel A till en organnivå-modell för AAA-tillväxt. Vidare inkorporerades modellen i ett “Fluid–Solid–Growth” (FSG) ramverk. En patientspecifik geometri hos bukaortan användes för att illustrera möjligheterna med modellen. I Artikel C undersöktes utvecklingen av patientspecifika biomekaniska egenskaper hos AAA. Fyra patienter som skannats fem till åtta gånger med “Computed Tomography-Angiography” (CT-A) vid olika tillfällen analyserades. Flera icke triviala statistiska samband konstaterades mellan de analyserade parametrarna. I Artikel D undersöktes effekten av olika tillväxt-kinematik för AAA tillväxt. En modell med transversellt-isotrop-i-tjockleken-tillväxt var den bäst lämpade för AAA tillväxt, medans antagandet om fullt-isotrop-tillväxt och transversellt-isotrop-i-planet-tillväxt producerade orimliga resultat. Dessutom gav modellering av vävnadsvolymsförändring ett förbättrat väggtjockleks resultat men en fortsatt överskattning av väggförtunningen under AAA-expansionen. / <p>QC 20161201</p>

Diss. Linköping : Linköpings universitet, 2005.