TGFβ (transforming growth factor-β) blockade induces a human-like disease in a nondissecting mouse model of abdominal aortic aneurysm

Objective-Current experimental models of abdominal aortic aneurysm (AAA) do not accurately reproduce the major features of human AAA. We hypothesized that blockade of TGF beta (transforming growth factor-beta) activity-a guardian of vascular integrity and immune homeostasis-would impair vascular healing in models of nondissecting AAA and would lead to sustained aneurysmal growth until rupture. Approach and Results-Here, we test this hypothesis in the elastase-induced AAA model in mice. We analyze AAA development and progression using ultrasound in vivo, synchrotron-based ultrahigh resolution imaging ex vivo, and a combination of biological, histological, and flow cytometry-based cellular and molecular approaches in vitro. Systemic blockade of TGF beta using a monoclonal antibody induces a transition from a self-contained aortic dilatation to a model of sustained aneurysmal growth, associated with the formation of an intraluminal thrombus. AAA growth is associated with wall disruption but no medial dissection and culminates in fatal transmural aortic wall rupture. TGF beta blockade enhances leukocyte infiltration both in the aortic wall and the intraluminal thrombus and aggravates extracellular matrix degradation. Early blockade of IL-1 beta or monocyte-dependent responses substantially limits AAA severity. However, blockade of IL-1 beta after disease initiation has no effect on AAA progression to rupture. Conclusions-Endogenous TGF beta activity is required for the healing of AAA. TGF beta blockade may be harnessed to generate new models of AAA with better relevance to the human disease. We expect that the new models will improve our understanding of the pathophysiology of AAA and will be useful in the identification of new therapeutic targets

Proteomics in cardiovascular disease: recent progress and clinical implication and implementation

Introduction: Although multiple efforts have been initiated to shed light into the molecular mechanisms underlying cardiovascular disease, it still remains one of the major causes of death worldwide. Proteomic approaches are unequivocally powerful tools that may provide deeper understanding into the molecular mechanisms associated with cardiovascular disease and improve its management. Areas covered: Cardiovascular proteomics is an emerging field and significant progress has been made during the past few years with the aim of defining novel candidate biomarkers and obtaining insight into molecular pathophysiology. To summarize the recent progress in the field, a literature search was conducted in PubMed and Web of Science. As a result, 704 studies from PubMed and 320 studies from Web of Science were retrieved. Findings from original research articles using proteomics technologies for the discovery of biomarkers for cardiovascular disease in human are summarized in this review. Expert commentary: Proteins associated with cardiovascular disease represent pathways in inflammation, wound healing and coagulation, proteolysis and extracellular matrix organization, handling of cholesterol and LDL. Future research in the field should target to increase proteome coverage as well as integrate proteomics with other omics data to facilitate both drug development as well as clinical implementation of findings

Stress-strain analysis of aortic aneurysms

Tato práce se zabývá problematikou aneurysmat břišní aorty a možností využít konečnoprvkovou deformačně-napěťovou analýzu těchto aneurysmat ke stanovení rizika ruptury. První část práce je věnována úvodu do problematiky, popisu kardiovaskulární soustavy člověka s důrazem na abdominální aortu, anatomii, fyziologii a patologii stěny tepny s důrazem na procesy vedoucí ke vzniku aneurysmatu. Dále se práce věnuje rizikovým faktorům přispívajících ke vzniku aneurysmat spolu s analýzou současných klinických postupů ke stanovení rizika ruptury spolu se srovnáním navrhovaného kritéria maximálního napětí. Dominantní část této disertace je věnována identifikaci faktorů ovlivňujících napjatost a deformaci stěny aneurysmatu spolu s návrhem nových postupů, prezentací vlastních poznatků vedoucích ke zpřesnění určení rizika ruptury pomocí deformačně- napěťové analýzy a metody konečných prvků. Nejprve je analyzován vliv geometrie, vedoucí k závěru, že je nezbytné používání individuálních geometrií pacienta. Dále je pozornost zaměřena na odbočující tepny, které ve stěně působí jako koncentrátor napětí a mohou tedy ovlivňovat napjatost v ní. Jako další podstatný faktor byl identifikován vliv nezatížené geometrie a bylo napsáno makro pro její nalezení, které bylo opět zahrnuto jako standardní součást do výpočtového modelu. Mechanické vlastnosti jak stěny aneurysmatu, tak intraluminálního trombu jsou experimentálně testovány pomocí dvouosých zkoušek. Také je zde analyzován vliv modelu materiálu, kde je ukázáno, že srovnávání maximálních napětí u jednotlivých modelů materiálu není vhodné díky zcela rozdílným gradientům napětí ve stěně aneurysmatu. Dále je zdůrazněna potřeba znalosti distribuce kolagenních vláken ve stěně a navržen program k jejímu získání. Intraluminální trombus je analyzován ve dvou souvislostech. Jednak je ukázán vliv jeho ruptury na napětí ve stěně a jednak je analyzován vliv jeho poroelastické struktury na totéž. Posledním identifikovaným podstatným faktorem je zbytková napjatost ve stěně. Její významnost je demonstrována na několika aneurysmatech a i tato je zahrnuta jako integrální součást do našeho výpočtového modelu.Na závěr jsou pak navrženy další možné směry výzkumu.This thesis deals with abdominal aortic aneurysms and the possibility of using finite element method in assessment of their rupture risk. First part of the thesis is dedicated to an introduction into the problem, description of human cardiovascular system where the abdominal aorta, its anatomy, physiology and pathology is emphasized. There Processes leading to formationing of abdominal aortic aneurysms are also discussed. Risk factors contributing to creation of aneurysms are discussed next. Finally, an analysis of current clinical criteria which determine rupture risk of an abdominal aortic aneurysm is presented and compared with the new maximum stress criterion being currently in development. Main part of the thesis deals with the identification of relevant factors which affect stress and deformation of aneurysmal wall. This is connected with proposals of new approaches leading to predicting the rupture risk more accurately by using finite element stress-strain analysis. The impact of geometry is analyzed first with the conclusion that patient-specific geometry is a crucial input in the computational model. Therefore its routine reconstruction has been managed. Attention is then paid to the branching arteries which were neglected so far although they cause a stress concentration in arterial wall. The necessity of knowing the unloaded geometry of aneurysm is then emphasized. Therefore a macro has been written in order to be able to find the unloaded geometry for any patient-specific geometry of aneurysm. Mechanical properties of both aneurysmal wall and intraluminal thrombus were also experimentally tested and their results were fitted by an isotropic material model. The effect of the material model itself has been also investigated by comparing whole stress fields of several aneurysms. It has been shown that different models predict completely different stresses due to different stress gradients in the aneurysmal wall. The necessity of known collagen fiber distribution in arterial wall is also emphasized. A special program is then presented enabling us to obtain this information. Effect of intraluminal thrombus on the computed wall stress is analyzed in two perspectives. First the effect of its failure on wall stress is shown and also the impact of its poroelastic structure is analyzed. Finally the residual stresses were identified as an important factor influencing the computed wall stress in aneurysmal wall and they were included into patient-specific finite element analysis of aneurysms. Further possible regions of investigation are mentioned as the last part of the thesis.

Diagnosis, Rupture Risk Evaluation and Therapeutic Intervention of Abdominal Aortic Aneurysms Using Targeted Nanoparticles

Abdominal aortic aneurysm (AAA) disease causes dilation of the aorta that can lead to aortic rupture and death if not treated early. It is the 14th leading cause of death in the U.S. and is cited as the 10th leading cause of death in men over age 55, affecting thousands of patients and their families. To date, AAA patients have minimal access to safe and efficient imaging modalities for diagnosis as well as pharmacotherapies. AAA is usually detected and monitored with ultrasonography or contrast-enhanced computed tomography (C.T.), which doesn’t provide biomechanical information of the AAAs that are essential for predicting rupture risks. Furthermore, unfortunately, there is no currently known pharmaceutical treatment to cure the AAAs. Key pathological processes occurring within AAAs include inflammation, vascular smooth muscle cell apoptosis, and extracellular matrix (ECM) degradation. The deterioration of the elastic lamina in the aneurysmal wall is a consistent feature of AAAs and the fact that the adult elastic lamina does not remodel in aneurysm progression, making it an ideal target for delivering contrast agents and treatments. In this research, we have delivered gold nanoparticles (AuNPs), a commonly used C.T. contrast agent, and pentagalloyl glucose (PGG) loaded nanoparticles to the AAAs in an angiotensin II (AngII) infusion induced mouse model by conjugating the nanoparticles with antibodies that target degraded elastin. Here, owing to their degraded elastin targeting ability, we have observed a positive correlation between the quantities of the locally accumulated AuNPs in the aneurysmal tissue in C.T. scans and the elastin damage levels of the AAAs. Furthermore, the AuNPs accumulations were found negatively correlated to the mechanical properties of the AAAs, which makes AuNPs a potential non-invasive surrogate marker of AAA rupture risk. Moreover, we have shown that targeted delivery of PGG could reverse the aortic dilation, ameliorate the inflammation, restore the elastin as well as the AAA mechanical properties of the aneurysmal tissue. Therefore, PGG loaded nanoparticles can be an effective treatment option for early to middle stage aneurysms to prevent disease progression