Keshmiri, A. | bioRxiv Science

bioRxiv2021

A Coupled Flow-Thermoregulation Lumped Model to Investigate Cardiac Function

AO_SCPLOWBSTRACTC_SCPLOWLumped (zero-dimensional) technique is a robust and widely used approach to mathematically model and explore bulk behaviour of different physical phenomena in a lower expense. In modelling of cardio/cerebrovascular fluid dynamics, this technique facilitates the assessment of relevant metrics such as flow, pressure, and temperature at different locations over a large network/domain. Furthermore, they can be employed as boundary conditions in multiscale modelling of physiological flows. In this methodology paper, a lumped model for the cardiovascular flow simulation along with a two-node thermoregulation model are employed. The lumped models are built upon previous studies and are amended appropriately to focus on cardiac function. The output of the coupled model can either be used for assessing the cardiac function in different physiological conditions or it can provide the input data for other investigations. Noteworthy to mention that, the present model has been specifically developed for investigation on the effects of atrial fibrillation on cardiac performance.

bioengineering↗

bioRxiv2019

A pivotal role for Nrf2 in endothelial detachment- implications for endothelial erosion of stenotic plaques

Endothelial erosion of atherosclerotic plaques and resulting thrombosis causes approximately 30% of acute coronary syndromes (ACS). As changes in the haemodynamic environment strongly influence endothelial function and contribute to plaque development, we reconstructed the coronary artery geometries of plaques with thrombi overlying intact fibrous caps from 17 ACS patients and performed computational fluid dynamic analysis. The results demonstrated that erosions frequently occur within areas of stenosis exposed to elevated flow. We recapitulated this flow environment in vitro, exposing human coronary artery endothelial cells to elevated flow and modelled smoking (a risk factor for erosion) by exposure to a combination of aqueous cigarette smoke extract and TNF. This treatment induced endothelial detachment, which increased with pharmacological activation of the antioxidant system controlled by transcription factor Nrf2 (encoded by NFE2L2). The expression of Oxidative Stress Growth INhibitor genes OSGIN1 and OSGIN2 increased under these conditions and also in the aortas of mice exposed to cigarette smoke. Sustained high level expression of OSGIN1+2 resulted in cell cycle arrest, induction of senescence, loss of focal adhesions and actin stress fibres, and dysregulation of autophagy. Overexpression of either Nrf2 or OSGIN1+2 induced cell detachment, which did not depend on apoptosis, and could be partially rescued by inhibition of HSP70 using VER-155008, or AMP kinase activation using metformin. These findings demonstrate that under elevated flow, smoking-induced hyperactivation of Nrf2 can trigger endothelial cell detachment, highlighting a novel mechanism that could contribute to ACS involving endothelial erosion overlying stenotic plaques.

cell biology↗