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Project

Personalized diagnosis and treatment of aortic aneurysms through in-depth microstructural tissue analysis

Cardiovascular diseases are the leading cause of death worldwide. In Belgium, at least 60 000 people suffer from an aortic aneurysm, a permanent dilatation of the aorta caused by weakening in the aortic wall. The most feared complication is aortic dissection or rupture, associated with mortality rates up to 95%. Despite these alarming numbers, the diagnosis and treatment of aortic aneurysms have hardly evolved over the last 20 years.

To improve the therapeutic strategies related to this disease, many research steps must be undertaken. This thesis focuses on the improvement of the clinical practice involving ascending thoracic aortic aneurysms, by determining new predictive parameters for rupture risk and by investigating the applicability of a recently developed surgery for Marfan patients. Marfan syndrome is a genetic connective tissue disorder leading to thoracic aortic aneurysms among other symptoms. In addition, we aim to develop a controlled in vitro environment to facilitate and improve further research on vascular adaptation to altered mechanical environments.

Thoracic aortic aneurysms are a multifactorial disease with the onset and progression still not fully understood. Fundamental information on the microstructural and mechanical patterns along the length of the thoracic aorta is still missing. To this end, we analyzed four human thoracic aortas at 28 specific locations. The analysis revealed various longitudinal differences in the aortic microstructure (decrease of the tunica media thickness and elastin and smooth muscle cell content; increase of the tunica intima thickness and collagen content) and passive mechanical response (increase in stiffness). The lack of thickening of the subendothelial layer during arterial ageing may explain the higher prevalence of ascending thoracic aortic aneurysms, while the reduced presence of elastin may explain the increased growth rate of descending thoracic aortic aneurysms.

The surgical decision for treating thoracic aortic aneurysms is currently based on a geometry criterion using the maximum aneurysm diameter as a predictor for complication risk. Although shown to be inefficient and unreliable, this criterion has been the standard for many years. We aimed to pave the way for a personalized, biomechanics-based complication risk assessment strategy for ascending thoracic aortic aneurysms. For 30 patients, biomechanical and structural properties of resected aneurysmatic tissue as well as the aortic morphology and patient characteristics were determined. Geometry-related factors, gender, age, height, blood pressure and body mass index appeared to significantly influence the biomechanics, i.e. the tissue strength, of the aneurysmatic tissue. Additional research combining these five parameters may lead to a novel, improved criterion for determining the rupture risk in patients presenting with an ascending thoracic aortic aneurysm.

Research regarding the onset, development and treatment of aneurysms is mainly performed on in vivo small animal models that do not recapitulate the pathology completely and on in vitro cell cultures where the environmental interactions are lacking. Within our research group, we recently developed a mechanically induced thoracic aortic aneurysm model and concluded a set of 13 sheep experiments. A pulmonary autograft, unreinforced or reinforced with a macroporous mesh, was thereby placed in aortic position and subjected to non-homeostatic pressure and flow conditions. MRI imaging over 6 months showed asymmetric aneurysm formation. Mechanical analysis of the samples revealed two types of vascular remodeling: some samples stiffened at low strain, showing more aorta-like behavior, while other samples stiffened at higher strain, behaving like native pulmonary artery. All samples showed smooth muscle cell atrophy, more stretched elastin fibers and unchanged or increased collagen deposition. Adding a macroporous reinforcement resulted in a more prominent loss of smooth muscle cells in the pulmonary autograft. But in this context, thinning of the media did not necessarily resulted in loss of strength or an increased propensity for dissection. The mesh was incorporated in the vessel wall with a fibrotic sheet consisting of collagen fibers, fibroblasts and neovessels.

The animal model contained too many variables to be able to precisely define the underlying factors that enable or limit vascular adaptation. Therefore, we started developing an innovative approach to assess the mechanobiological responses of arteries to a changed mechanical environment. Arterial tissue is thereby placed in a bioreactor set-up mimicking the physiological environment, while the mechanical environment (blood pressure, heart rate, blood flow and prestretch) can be altered. The analysis of arterial tissue exposed to various loading conditions in vitro may generate valuable insights in vascular remodeling and the underlying processes.

The scientific basis to improve the current therapeutic strategies related to diseases of the ascending aorta has been laid within this thesis framework. Next, translating the biomedical science into clinical practice is a challenging, but achievable goal. We feel it is feasible because of the multidisciplinary approach of combining clinical, engineering and biological expertise to cover in vitro, in vivo and in silico research levels. The consecutive research steps are initiated or well prepared within our research group. An aortic aneurysm is a silent disease with aortic rupture or dissection as feared complications. The diagnosis of the aneurysm and the associated risk of rupture or dissection is highly challenging. Additionally, the standard treatment is very invasive and dangerous. There is ample need for improvement of both.

Concerning the diagnosis, we aim at defining a more reliable criterion backed up by microstructural information on the aneurysmal tissue. To this end, we will create a highly unique dataset in which the imaging data, geometry, mechanical properties, microstructural parameters and patient characteristics are stored. Correlations between clinically measurable parameters and microstructural parameters that indicate rupture risk will be checked.

Concerning the treatment, the use of a personalized exostent can be a less invasive and less hazardous solution. By means of sheep experiments, we will gain knowledge on how this exostent is incorporated in the aortic wall and how it influences the microstructural properties of the aortic wall. Histological staining, immunofluorescent labelling and high-performance liquid chromatography will be performed. Providing a microstructurally-based qualitative and quantitative evaluation of the performance of the exostent has the potential to increase the use of the exostent in clinical practice and expand its applications. 

Date:1 Oct 2016 →  3 Jun 2021
Keywords:Aortic aneurysm, Microstructural analysis, Sheep model, Ross procedure
Disciplines:Cardiac and vascular medicine, Surgery
Project type:PhD project