Biomechanics of Living Aortic Tissue to Predict Aneurysm Progression

Jorn Patrick Meekel

    Research output: PhD ThesisPhD-Thesis - Research and graduation internal

    6 Downloads (Pure)

    Abstract

    The exact pathways leading to AAA remain unclear, despite extensive research. So far, AAA treatment is mainly surgical, either in the elective setting to prevent rupture or in the acute setting of symptomatic and ruptured AAA. The risk of progressive aortic dilation and rupture can be modified by smoking cessation, thrombocyte aggregation inhibitors, statins and antihypertensives in case of hypertension are advised, albeit to varying extent. In this light, there is a need for a better understanding of the pathophysiology of AAA. Therefore, the aim was to lay the foundation for comprehensive research in AAA pathophysiology, starting from a different perspective using live human aortic tissue to understand AAA better and potentially find new therapeutic targets. In Chapter 2, a systematic review was performed, in which the aim was to identify potential prognostic markers (circulating biomarkers, biomechanical properties and genetic mutations) for AAA growth and rupture. Factors with an increased AAA expansion risk included AAA diameter, seropositivity for chlamydophila pneumonia, S-elastin peptides, inverse fluorodeoxyglucose uptake, and intraluminal thrombus size. Factors with an increased AAA rupture risk included peak wall stress and AAA diameter. Unfortunately, cautious clinical interpretation of the conclusions was advised, due to the nature of the original studies and high heterogeneity between the studies, which might also reflect the complex a multifactorial nature of AAA pathophysiology. In Chapter 3, a novel protocol was provided in which live aortic tissue sections were preserved for over 60 days. The ex vivo tissues contained live patient-specific leukocytes and macrophages, and alterations in RNA expression of different genes in these tissues was observed as result of ex vivo tissue stimulation using TGF-β. The current sectioning and preservation protocol was implemented for further stimulation studies, as presented in the following chapters. In Chapter 4, live aortic tissue sections from AAA patients and non-dilated aortas were compared using nanoindentation. This technique tests the hardness of materials on a microscopic scale. A decrease in microscopic stiffness in the medial layer (in outside to inside direction) was observed in live tissues of AAA patient compared to non-dilated live aortic tissue sections. Furthermore, decreased SMC levels, collagen and fibroblasts were found in the tissue sections of AAA patients. This decrease in cellular and extracellular structures was correlated to the reduction in microscopic stiffness in the medial layer. Chapter 5 illustrated how seeded endothelial cells and SMC form confluent multilayers mimick an the wall using a new protocol. Next, a progressive parallel cytoskeletal organization was observed over time. Also, nanoindentation was again used, and micromechanical properties and visco-elastic properties comparable to biological vascular structures were observed. In Chapter 6, SMC were seeded and electric cell-substrate impedance sensing was performed after stimulation with calcium-ion-binding ionomycin. This study shows a subgroup of AAA patients who present impaired SMC contractility in sporadic AAA, which further underlines the multifactorial nature of AAA. Furthermore, a decreased maximum contractility was observed in patients who underwent open redo repair after endovascular aneurysm repair and patients that were currently smoking. Next, perivascular adipose tissue (PVAT) was studied, following the increased interest in PVAT. In Chapter 7, a higher intra-individual PVAT density was observed around the aneurysm in AAA patients. These findings were further supported by a correlation between increased intra-individual PVAT density and increased aortic diameter after adjustment for confounders. Chapter 8 demonstrated increased expression of pro-inflammatory and aortic wall disruptive genes (PTPRC, CXCL8, LCK, CCL5 and MMP9), while a lower anti-inflammatory gene expression (PPARG) was observed. Co-culturing of non-dilated aortic tissue with PVAT of AAA patients led to increased expression of MMP9 and SMTN, which are known to be involved in aneurysmal formation and progression.
    Original languageEnglish
    QualificationPhD
    Awarding Institution
    • Vrije Universiteit Amsterdam
    Supervisors/Advisors
    • Blankensteijn, J.D., Supervisor, External person
    • Balm, R., Supervisor, External person
    • Yeung, Kak Khee, Co-supervisor, External person
    Award date25 Jan 2022
    Place of PublicationAmsterdam
    Print ISBNs9789463328210
    Electronic ISBNs9789463328210
    Publication statusPublished - 25 Jan 2022

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