Uropathic Observations in Mice Expressing a Constitutively Active Point Mutation in the 5-HT_(3A) Receptor Subunit

Mutant mice with a hypersensitive serotonin (5-HT)_(3A) receptor were generated through targeted exon replacement. A valine to serine mutation (V13′S) in the channel-lining M2 domain of the 5-HT_(3A) receptor subunit rendered the 5-HT₃ receptor ∼70-fold more sensitive to serotonin and produced constitutive activity when combined with the 5-HT_(3B) subunit. Mice homozygous for the mutant allele (5-HT_(3A)^(vs/vs)) had decreased levels of 5-HT_(3A) mRNA. Measurements on sympathetic ganglion cells in these mice showed that whole-cell serotonin responses were reduced, and that the remaining 5-HT₃ receptors were hypersensitive. Male 5-HT_(3A)^(vs/vs) mice died at 2-3 months of age, and heterozygous (5-HT_(3A)^(vs/+)) males and homozygous mutant females died at 4-6 months of age from an obstructive uropathy. Both male and female 5-HT_(3A) mutant mice had urinary bladder mucosal and smooth muscle hyperplasia and hypertrophy, whereas male mutant mice had additional prostatic smooth muscle and urethral hyperplasia. 5-HT_(3A) mutant mice had marked voiding dysfunction characterized by a loss of micturition contractions with overflow incontinence. Detrusor strips from 5-HT_(3A)^(vs/vs) mice failed to contract to neurogenic stimulation, despite overall normal responses to a cholinergic agonist, suggestive of altered neuronal signaling in mutant mouse bladders. Consistent with this hypothesis, decreased nerve fiber immunoreactivity was observed in the urinary bladders of 5-HT_(3A)^(vs/vs) compared with 5-HT_(3A) wild-type (5-HT_(3A)^(+/+)) mice. These data suggest that persistent activation of the hypersensitive and constitutively active 5-HT_(3A) receptor in vivo may lead to excitotoxic neuronal cell death and functional changes in the urinary bladder, resulting in bladder hyperdistension, urinary retention, and overflow incontinence

Analysis and computer program for rupture-risk prediction of abdominal aortic aneurysms

BACKGROUND: Ruptured abdominal aortic aneurysms (AAAs) are the 13(th )leading cause of death in the United States. While AAA rupture may occur without significant warning, its risk assessment is generally based on critical values of the maximum AAA diameter (>5 cm) and AAA-growth rate (>0.5 cm/year). These criteria may be insufficient for reliable AAA-rupture risk assessment especially when predicting possible rupture of smaller AAAs. METHODS: Based on clinical evidence, eight biomechanical factors with associated weighting coefficients were determined and summed up in terms of a dimensionless, time-dependent severity parameter, SP(t). The most important factor is the maximum wall stress for which a semi-empirical correlation has been developed. RESULTS: The patient-specific SP(t) indicates the risk level of AAA rupture and provides a threshold value when surgical intervention becomes necessary. The severity parameter was validated with four clinical cases and its application is demonstrated for two AAA cases. CONCLUSION: As part of computational AAA-risk assessment and medical management, a patient-specific severity parameter 0 < SP(t) < 1.0 has been developed. The time-dependent, normalized SP(t) depends on eight biomechanical factors, to be obtained via a patient's pressure and AAA-geometry measurements. The resulting program is an easy-to-use tool which allows medical practitioners to make scientific diagnoses, which may save lives and should lead to an improved quality of life

Mechanical behaviour and rupture of normal and pathological human ascending aortic wall

The mechanical properties of aortic wall, both healthy and pathological, are needed in order to develop and improve diagnostic and interventional criteria, and for the development of mechanical models to assess arterial integrity. This study focuses on the mechanical behaviour and rupture conditions of the human ascending aorta and its relationship with age and pathologies. Fresh ascending aortic specimens harvested from 23 healthy donors, 12 patients with bicuspid aortic valve (BAV) and 14 with aneurysm were tensile-tested in vitro under physiological conditions. Tensile strength, stretch at failure and elbow stress were measured. The obtained results showed that age causes a major reduction in the mechanical parameters of healthy ascending aortic tissue, and that no significant differences are found between the mechanical strength of aneurysmal or BAV aortic specimens and the corresponding age-matched control group. The physiological level of the stress in the circumferential direction was also computed to assess the physiological operation range of healthy and diseased ascending aortas. The mean physiological wall stress acting on pathologic aortas was found to be far from rupture, with factors of safety (defined as the ratio of tensile strength to the mean wall stress) larger than six. In contrast, the physiological operation of pathologic vessels lays in the stiff part of the response curve, losing part of its function of damping the pressure waves from the heart

Inhibition of plasmin-mediated TAFI activation may affect development but not progression of abdominal aortic aneurysms

Objective: Thrombin-activatable fibrinolysis inhibitor (TAFI) reduces the breakdown of fibrin clots through its action as an indirect inhibitor of plasmin. Studies in TAFI-deficient mice have implicated a potential role for TAFI in Abdominal Aortic Aneurysm (AAA) disease. The role of TAFI inhibition on AAA formation in adult ApoE-/- mice is unknown. The aim of this paper was to investigate the effects of TAFI inhibition on AAA development and progression. Methods: Using the Angiotensin II model of AAA, male ApoE-/- mice were infused with Angiotensin II 750ng/kg/min with or without a monoclonal antibody inhibitor of plasmin-mediated activation of TAFI, MA-TCK26D6, or a competitive small molecule inhibitor of TAFI, UK-396082. Results: Inhibition of TAFI in the Angiotensin II model resulted in a decrease in the mortality associated with AAA rupture (from 40.0% to 16.6% with MA-TCK26D6 (log-rank Mantel Cox test p = 0.16), and 8.3% with UK-396082 (log-rank Mantel Cox test p = 0.05)). Inhibition of plasmin-mediated TAFI activation reduced the incidence of AAA from 52.4% to 30.0%. However, late treatment with MA-TCK26D6 once AAA were already established had no effect on the progression of AAA in this model. Conclusions: The formation of intra-mural thrombus is responsible for the dissection and early rupture in the angiotensin II model of AAA, and this process can be prevented through inhibition of TAFI. Late treatment with a TAFI inhibitor does not prevent AAA progression. These data may indicate a role for inhibition of plasmin-mediated TAFI activation in the early stages of AAA development, but not in its progression

Non-linear viscoelastic behavior of abdominal aortic aneurysm thrombus

The objective of this work was to determine the linear and non-linear viscoelastic behavior of abdominal aortic aneurysm thrombus and to study the changes in mechanical properties throughout the thickness of the thrombus. Samples are gathered from thrombi of seven patients. Linear viscoelastic data from oscillatory shear experiments show that the change of properties throughout the thrombus is different for each thrombus. Furthermore the variations found within one thrombus are of the same order of magnitude as the variation between patients. To study the non-linear regime, stress relaxation experiments are performed. To describe the phenomena observed experimentally, a non-linear multimode model is presented. The parameters for this model are obtained by fitting this model successfully to the experiments. The model cannot only describe the average stress response for all thrombus samples but also the highest and lowest stress responses. To determine the influence on the wall stress of the behavior observed the model proposed needs to implemented in the finite element wall stress analysis

Fluid-structure interaction in abdominal aortic aneurysms: effects of asymmetry and wall thickness

BACKGROUND: Abdominal aortic aneurysm (AAA) is a prevalent disease which is of significant concern because of the morbidity associated with the continuing expansion of the abdominal aorta and its ultimate rupture. The transient interaction between blood flow and the wall contributes to wall stress which, if it exceeds the failure strength of the dilated arterial wall, will lead to aneurysm rupture. Utilizing a computational approach, the biomechanical environment of virtual AAAs can be evaluated to study the affects of asymmetry and wall thickness on this stress, two parameters that contribute to increased risk of aneurysm rupture. METHODS: Ten virtual aneurysm models were created with five different asymmetry parameters ranging from β = 0.2 to 1.0 and either a uniform or variable wall thickness to study the flow and wall dynamics by means of fully coupled fluid-structure interaction (FSI) analyses. The AAA wall was designed to have a (i) uniform 1.5 mm thickness or (ii) variable thickness ranging from 0.5 – 1.5 mm extruded normally from the boundary surface of the lumen. These models were meshed with linear hexahedral elements, imported into a commercial finite element code and analyzed under transient flow conditions. The method proposed was then compared with traditional computational solid stress techniques on the basis of peak wall stress predictions and cost of computational effort. RESULTS: The results provide quantitative predictions of flow patterns and wall mechanics as well as the effects of aneurysm asymmetry and wall thickness heterogeneity on the estimation of peak wall stress. These parameters affect the magnitude and distribution of Von Mises stresses; varying wall thickness increases the maximum Von Mises stress by 4 times its uniform thickness counterpart. A pre-peak systole retrograde flow was observed in the AAA sac for all models, which is due to the elastic energy stored in the compliant arterial wall and the expansion force of the artery during systole. CONCLUSION: Both wall thickness and geometry asymmetry affect the stress exhibited by a virtual AAA. Our results suggest that an asymmetric AAA with regional variations in wall thickness would be exposed to higher mechanical stresses and an increased risk of rupture than a more fusiform AAA with uniform wall thickness. Therefore, it is important to accurately reproduce vessel geometry and wall thickness in computational predictions of AAA biomechanics

Patient-Specific Computational Modeling of Upper Extremity Arteriovenous Fistula Creation: Its Feasibility to Support Clinical Decision-Making

<div><h3>Introduction</h3><p>Inadequate flow enhancement on the one hand, and excessive flow enhancement on the other hand, remain frequent complications of arteriovenous fistula (AVF) creation, and hamper hemodialysis therapy in patients with end-stage renal disease. In an effort to reduce these, a patient-specific computational model, capable of predicting postoperative flow, has been developed. The purpose of this study was to determine the accuracy of the patient-specific model and to investigate its feasibility to support decision-making in AVF surgery.</p> <h3>Methods</h3><p>Patient-specific pulse wave propagation models were created for 25 patients awaiting AVF creation. Model input parameters were obtained from clinical measurements and literature. For every patient, a radiocephalic AVF, a brachiocephalic AVF, and a brachiobasilic AVF configuration were simulated and analyzed for their postoperative flow. The most distal configuration with a predicted flow between 400 and 1500 ml/min was considered the preferred location for AVF surgery. The suggestion of the model was compared to the choice of an experienced vascular surgeon. Furthermore, predicted flows were compared to measured postoperative flows.</p> <h3>Results</h3><p>Taken into account the confidence interval (25^th and 75^th percentile interval), overlap between predicted and measured postoperative flows was observed in 70% of the patients. Differentiation between upper and lower arm configuration was similar in 76% of the patients, whereas discrimination between two upper arm AVF configurations was more difficult. In 3 patients the surgeon created an upper arm AVF, while model based predictions allowed for lower arm AVF creation, thereby preserving proximal vessels. In one patient early thrombosis in a radiocephalic AVF was observed which might have been indicated by the low predicted postoperative flow.</p> <h3>Conclusions</h3><p>Postoperative flow can be predicted relatively accurately for multiple AVF configurations by using computational modeling. This model may therefore be considered a valuable additional tool in the preoperative work-up of patients awaiting AVF creation.</p> </div

Biomechanics and Pathobiology of Aortic Aneurysms

Biomechanical weakening of the aorta leads to aneurysm formation and/or dissection and total biomechanical failure results in rupture, which is often fatal. The most common aneurysm is the abdominal aortic aneurysm (AAA) whereas thoracic aortic aneurysms (TAA) involve the ascending or descending segments of the aorta. Biomechanical strength of the aorta is maintained in part via balance between the integrity of the aortic medial and adventitial extracellular matrix and the health of the mural cells. From a biomechanical perspective, aneurysms rupture or dissect when wall stresses locally exceed the wall strength. Pathobiologic mechanisms, pre-disposing disorders and variability of patient demographic characteristics can weaken the aortic wall while increased blood pressure and dilatation increase the stress acting on it, leading to further aneurysm expansion. Thoracic and abdominal aortic aneurysms arise from very different pathophysiologies that ultimately result in a final common outcome of matrix degeneration and biomechanical failure. Therefore, the patient-specific knowledge of both wall stress and wall strength distributions for a given aneurysm will greatly improve the ability to identify those aortic aneurysms that are at highest risk of rupture. Towards this end, the biomechanics of AAA has been studied extensively by many groups whereas TAA biomechanics has not been fully considered. This chapter articulates the state-of-the-art of aortic biomechanics, including the modeling of tensile strength and wall stress distributions and the biological mechanisms which influence them. The potential clinical utility of these biomechanical estimates in predicting AAA rupture is also discussed