John S. Wilson

Importance of initial aortic properties on the evolving regional anisotropy, stiffness and wall thickness of human abdominal aortic aneurysms

Complementary advances in medical imaging, vascular biology and biomechanics promise to enable computational modelling of abdominal aortic aneurysms to play increasingly important roles in clinical decision processes. Using a finite-element-based growth and remodelling model of evolving aneurysm geometry and material properties, we show that regional variations in material anisotropy, stiffness and wall thickness should be expected to arise naturally and thus should be included in analyses of aneurysmal enlargement or wall stress. In addition, by initiating the model from best-fit material parameters estimated for non-aneurysmal aortas from different subjects, we show that the initial state of the aorta may influence strongly the subsequent rate of enlargement, wall thickness, mechanical behaviour and thus stress in the lesion. We submit, therefore, that clinically reliable modelling of the enlargement and overall rupture-potential of aneurysms may require both a better understanding of the mechanobiological processes that govern the evolution of these lesions and new methods of determining the patient-specific state of the pre-aneurysmal aorta (or correlation to currently unaffected portions thereof) through knowledge of demographics, comorbidities, lifestyle, genetics and future non-invasive or minimally invasive tests.

Biochemomechanics of Intraluminal Thrombus in Abdominal Aortic Aneurysms

Most computational models of abdominal aortic aneurysms address either the hemodynamics within the lesion or the mechanics of the wall. More recently, however, some models have appropriately begun to account for the evolving mechanics of the wall in response to the changing hemodynamic loads. Collectively, this large body of work has provided tremendous insight into this life-threatening condition and has provided important guidance for current research. Nevertheless, there has yet to be a comprehensive model that addresses the mechanobiology, biochemistry, and biomechanics of thrombus-laden abdominal aortic aneurysms. That is, there is a pressing need to include effects of the hemodynamics on both the development of the nearly ubiquitous intraluminal thrombus and the evolving mechanics of the wall, which depends in part on biochemical effects of the adjacent thrombus. Indeed, there is increasing evidence that intraluminal thrombus in abdominal aortic aneurysms is biologically active and should not be treated as homogeneous inert material. In this review paper, we bring together diverse findings from the literature to encourage next generation models that account for the biochemomechanics of growth and remodeling in patient-specific, thrombus-laden abdominal aortic aneurysms.

Parametric study of effects of collagen turnover on the natural history of abdominal aortic aneurysms

Abdominal aortic aneurysms (AAAs) are characterized by significant changes in the architecture of the aortic wall, notably, loss of functional elastin and smooth muscle. Because collagen is the principal remaining load-bearing constituent of the aneurysmal wall, its turnover must play a fundamental role in the natural history of the lesion. Nevertheless, detailed investigations of the effects of different aspects of collagen turnover on AAA development are lacking. A finite-element membrane model of the growth and remodelling of idealized AAAs was thus used to investigate parametrically four of the primary aspects of collagen turnover: rates of production, half-life, deposition stretch (prestretch) and material stiffness. The predicted rates of aneurysmal expansion and spatio-temporal changes in wall thickness, biaxial stresses and maximum collagen fibre stretch at the apex of the lesion depended strongly on all four factors, as did the predicted clinical endpoints (i.e. arrest, progressive expansion or rupture). Collagen turnover also affected the axial expansion, largely due to mechanical changes within the shoulder region of the lesion. We submit, therefore, that assessment of rupture risk could be improved by future experiments that delineate and quantify different aspects of patient-specific collagen turnover and that such understanding could lead to new targeted therapeutics.

Mechanobiological stability: a new paradigm to understand the enlargement of aneurysms?

Static and dynamic mechanical instabilities were previously suggested, and then rejected, as mediators of aneurysmal development, which leaves open the question of the underlying mechanism. In this paper, we suggest as a new paradigm the interpretation of aneurysms as mechanobiological instabilities. For illustrative purposes, we compare analytical calculations with computational simulations of the growth and remodelling of idealized fusiform abdominal aortic aneurysms and experimental and clinical findings. We show that the concept of mechanobiological stability is consistent with the impact of risk factors such as age, smoking or diabetes on the initiation and enlargement of these lesions as well as adaptive processes in the healthy abdominal aorta such as dilatation during ageing or in hypertension. In general, high stiffness, an increased capacity for stress-mediated matrix production, and slow matrix turnover all improve the mechanobiological stability of blood vessels. This theoretical understanding may help guide prognosis and the development of future therapies for aneurysms as it enables systematic ways to attenuate enlargement.

A Computational Model of Biochemomechanical Effects of Intraluminal Thrombus on the Enlargement of Abdominal Aortic Aneurysms

Abdominal aortic aneurysms (AAAs) typically develop an intraluminal thrombus (ILT), yet most computational models of AAAs have focused on either the mechanics of the wall or the hemodynamics within the lesion, both in the absence of ILT. In the few cases wherein ILT has been modeled directly, as, for example, in static models that focus on the state of stress in the aortic wall and the associated rupture risk, thrombus has been modeled as an inert, homogeneous, load-bearing material. Given the biochemomechanical complexity of an ILT, there is a pressing need to consider its diverse effects on the evolving aneurysmal wall. Herein, we present the first growth and remodeling model that addresses together the biomechanics, mechanobiology, and biochemistry of thrombus-laden AAAs. Whereas it has been shown that aneurysmal enlargement in the absence of ILT depends primarily on the stiffness and turnover of fibrillar collagen, we show that the presence of a thrombus within lesions having otherwise the same initial wall composition and properties can lead to either arrest or rupture depending on the biochemical effects (e.g., release of proteases) and biomechanical properties (e.g., stiffness of fibrin) of the ILT. These computational results suggest that ILT should be accounted for when predicting the potential enlargement or rupture risk of AAAs and highlight specific needs for further experimental and computational research.

Evolving anisotropy and degree of elastolytic insult in abdominal aortic aneurysms: Potential clinical relevance?

Accurately estimating patient-specific rupture risk remains a primary challenge in timing interventions for abdominal aortic aneurysms (AAAs). By re-analyzing published biaxial mechanical testing data from surgically repaired human AAAs, material anisotropy emerged as a potentially important determinant of patient-specific lesion progression. That is, based on a new classification scheme, we discovered that anisotropic aneurysmal specimens correlated with increased patient age at surgery when compared with more isotropic specimens (79.7 vs. 70.9 years, p<0.002), despite no significant difference in maximum diameter. Furthermore, using an idealized axisymmetric, finite-element growth and remodeling model of AAA progression, we found that both the initial axial extent of elastin loss and ongoing damage to elastin in the shoulder region of the AAA directly affected the degree of anisotropy as the lesion evolved, with more extensive insults increasing the anisotropy. This effect appeared to be mediated by alterations in axial loading and subsequent differences in orientation of deposited collagen fibers. While the observed increased age before surgical intervention may suggest a potential benefit of anisotropic remodeling, future biaxial tests coupled with pre-surgical data on expansion rates and detailed theoretical analyses of the biostability of a lesion as a function of anisotropy will be required to verify its clinical relevance to patient-specific rupture risk.

In vivo quantification of regional circumferential Green strain in the thoracic and abdominal aorta by 2D spiral cine DENSE MRI

INTRODUCTION Regional tissue mechanics play a fundamental role in patient-specific cardiovascular function. Nevertheless, regional assessments of aortic kinematics remain lacking due to the challenge of imaging the thin aortic wall. Herein, we present a novel application of DENSE (Displacement Encoding with Stimulated Echoes) MRI to quantify the circumferential Green strain of the thoracic and abdominal aorta. METHODS 2D spiral cine DENSE and steady-state free procession (SSFP) cine images were acquired at 3T at the infrarenal aorta (IAA), descending thoracic aorta (DTA), or distal aortic arch (DAA) in a pilot study of 6 healthy volunteers. DENSE data was processed with multiple custom noise-reduction techniques to calculate circumferential Green strain across 16 equispaced sectors around the aorta. Each volunteer was scanned twice to evaluate interstudy repeatability. RESULTS Circumferential strain was heterogeneously distributed in all volunteers and locations. Spatial heterogeneity index by location was 0.37 (IAA), 0.28 (DTA), and 0.59 (DAA). Mean peak strain by DENSE for each cross-section was consistent with the homogenized linearized strain estimated from SSFP cine. The mean difference in peak strain across all sectors following repeat imaging was -0.1±2.2%, with a mean absolute difference of 1.7%. CONCLUSIONS Aortic cine DENSE MRI is a viable non-invasive technique for quantifying heterogeneous regional aortic wall strain and has significant potential to improve patient-specific clinical assessments of numerous aortopathies, as well as to provide the lacking spatiotemporal data required to refine computational models of aortic growth and remodeling.

Constitutive Formulations for Soft Tissue Growth and Remodeling

Abstract Soft tissues exhibit a remarkable ability to grow and remodel in health and disease, typically while exposed to complex biochemomechanical loads. There is, therefore, a pressing need to model such processes within the context of biomechanics. In this chapter, we briefly review mechanobiological motivations for the development of constitutive relations for the growth and remodeling of load-bearing soft tissues, and illustrate a few select constitutive approaches. We then highlight some specific examples, while directing the reader to key references for tissue specific studies. While much progress has been made, much remains to be accomplished, particularly the elucidation and modeling of the intracellular signaling pathways that ultimately give rise to tissue level manifestations that include changes in geometry, structure, and properties.

Demonstration of circumferential heterogeneity in displacement and strain in the abdominal aortic wall by spiral cine DENSE MRI: Displacement and Strain in Abd Ao

Knowledge of tissue properties of the abdominal aorta can improve understanding of vascular disease and guide interventional approaches. Existing MRI methods to quantify aortic wall displacement and strain are unable to discern circumferential heterogeneity.

Potential biomechanical roles of risk factors in the evolution of thrombus-laden abdominal aortic aneurysms

Abdominal aortic aneurysms (AAAs) typically harbour an intraluminal thrombus (ILT), yet most prior computational models neglect biochemomechanical effects of thrombus on lesion evolution. We recently proposed a growth and remodelling model of thrombus-laden AAAs that introduced a number of new constitutive relations and associated model parameters. Because values of several of these parameters have yet to be elucidated by clinical data and could vary significantly from patient to patient, the aim of this study was to investigate the possible extent to which these parameters influence AAA evolution. Given that some of these parameters model potential effects of factors that influence the risk of rupture, this study also provides insight into possible roles of common risk factors on the natural history of AAAs. Despite geometrical limitations of a cylindrical domain, findings support current thought that smoking, hypertension, and female sex likely increase the risk of rupture. Although thrombus thickness is not a reliable risk factor for rupture, the model suggests that the presence of ILT may have a destabilizing effect on AAA evolution, consistent with histological findings from human samples. Finally, simulations support two hypotheses that should be tested on patient-specific geometries in the future. First, ILT is a potential source of the staccato enlargement observed in many AAAs. Second, ILT can influence rupture risk, positively or negatively, via competing biomechanical (eg, stress shielding) and biochemical (ie, proteolytic) effects. Although further computational and experimental studies are needed, the present findings highlight the importance of considering ILT when predicting aneurysmal enlargement and rupture risk.