Excessive adventitial stress drives inflammation-mediated fibrosis in hypertensive aortic remodelling in mice

Hypertension induces significant aortic remodeling, often adaptive but sometimes not. To identify immuno-mechanical mechanisms responsible for differential remodeling, we studied thoracic aortas from 129S6/SvEvTac and C57BL/6J mice before and after continuous 14-day angiotensin II infusion, which elevated blood pressure similarly in both strains. Histological and biomechanical assessments of excised vessels were similar at baseline, suggesting a common homeostatic set-point for mean wall stress. Histology further revealed near mechano-adaptive remodeling of the hypertensive 129S6/SvEvTac aortas, but grossly maladaptive remodeling of C57BL/6J aortas. Bulk RNA sequencing suggested that increased smooth muscle contractile processes promoted mechano-adaptation of 129S6/SvEvTac aortas while immune processes prevented adaptation of C57BL/6J aortas. Functional studies confirmed an increased vasoconstrictive capacity of the former while immunohistochemistry demonstrated marked increases in inflammatory cells in the latter. We then used multiple computational biomechanical models to test the hypothesis that excessive adventitial wall stress correlates with inflammatory cell infiltration. These models consistently predicted that increased vasoconstriction against an increased pressure coupled with modest deposition of new matrix thickens the wall appropriately, restoring wall stress toward homeostatic consistent with adaptive remodeling. In contrast, insufficient vasoconstriction permits high wall stresses and exuberant inflammation-driven matrix deposition, especially in the adventitia, reflecting compromised homeostasis and gross maladaptation

Pathogenesis of systemic air embolism during bronchoscopic Nd : YAG laser operations

Background. The occurrence of systemic air embolism during bronchoscopic neodymium yttrium-aluminum garnet laser operations has been suspected. Here we describe its mechanism

Quantification of regional differences in aortic stiffness in the aging human

There has been a growing awareness over the past decade that stiffening of the aorta, and its attendant effects on hemodynamics, is both an indicator and initiator of diverse cardiovascular, neurovascular, and renovascular diseases. Although different clinical metrics of arterial stiffness have been proposed and found useful in particular situations, there remains a need to understand better the complex interactions between evolving aortic stiffness and the hemodynamics. Computational fluid–solid-interaction (FSI) models are amongst the most promising means to understand such interactions for one can parametrically examine effects of regional variations in material properties and arterial geometry on local and systemic blood pressure and flow. Such models will not only increase our understanding, they will also serve as important steps towards the development of fluid–solid-growth (FSG) models that can further examine interactions between the evolving wall mechanics and hemodynamics that lead to arterial adaptations or disease progression over long periods. In this paper, we present a consistent quantification and comparison of regional nonlinear biaxial mechanical properties of the human aorta based on 19 data sets available in the literature and we calculate associated values of linearized stiffness over the cardiac cycle that are useful for initial large-scale FSI and FSG simulations. It is shown, however, that there is considerable variability amongst the available data and consequently that there is a pressing need for more standardized biaxial testing of the human aorta to collect data as a function of both location and age, particularly for young healthy individuals who serve as essential controls

Effect of left ventricular volume on results of coronary artery bypass grafting

After coronary artery bypass grafting, our patients with ischemic cardiomyopathy and significant left ventricular (LV) dilation demonstrated an improvement in angina symptoms, acceptable operative and medium-term survival, a trend toward improvement in LV ejection fraction, and a significant reduction in LV chamber size. Our results suggest that patients with ischemic cardiomyopathy and LV dilation should not be excluded from surgical revascularization based on ventricular size alone

CD4(+)CD25(+) regulatory T cells suppress allograft rejection mediated by memory CD8(+) T cells via a CD30-dependent mechanism

CD4(+)CD25(+) regulatory T (Treg) cells suppress naive T cell responses, prevent autoimmunity, and delay allograft rejection. It is not known, however, whether Treg cells suppress allograft rejection mediated by memory T cells, as the latter mount faster and stronger immune responses than their naive counterparts. Here we show that antigen-induced, but not naive, Treg cells suppress allograft rejection mediated by memory CD8(+) T cells. Suppression was allospecific, as Treg cells induced by third-party antigens did not delay allograft rejection. In vivo and in vitro analyses revealed that the apoptosis of allospecific memory CD8(+) T cells is significantly increased in the presence of antigen-induced Treg cells, while their proliferation remains unaffected. Importantly, neither suppression of allograft rejection nor enhanced apoptosis of memory CD8(+) T cells was observed when Treg cells lacked CD30 or when CD30 ligand–CD30 interaction was blocked with anti–CD30 ligand Ab. This study therefore provides direct evidence that pathogenic memory T cells are amenable to suppression in an antigen-specific manner and identifies CD30 as a molecule that is critical for the regulation of memory T cell responses