TTC is associated with slowly resolving global myocardial oedema, the acute extent of which correlates with regional contractile disturbance and acute release of both catecholamines and NT-proBNP.
Background:
Aortic valve stenosis is an increasingly prevalent degenerative and inflammatory disease. Transcatheter aortic valve implantation (TAVI) has revolutionized its treatment, thereby avoiding its life-threatening/disabling consequences. Whether aortic valve stenosis is accelerated by inflammation and whether it is itself a cause of inflammation are unclear. We hypothesized that the large shear forces exerted on circulating cells, particularly on the largest circulating cells, monocytes, while passing through stenotic aortic valves results in pro-inflammatory effects that are resolved with TAVI.
Methods:
TAVI provides a unique opportunity to compare the activation status of monocytes under high shear stress (before TAVI) and under low shear stress (after TAVI). The activation status of monocytes was determined using a single-chain antibody MAN-1 which is specific for the activated β2-integrin Mac-1. Monocyte function was further characterized by their adhesion to stimulated endothelial cells, phagocytic activity, uptake of oxidized LDL, and cytokine expression. In addition, we designed a microfluidic system to recapitulate the shear rate conditions before and after TAVI. We used this tool in combination with functional assays, Ca
2+
imaging, siRNA gene silencing, and pharmacological agonists and antagonists to identify the key mechanoreceptor mediating the shear stress sensitivity of monocytes. Finally, we stained for monocytes in explanted stenotic aortic human valves.
Results:
The resolution of high shear stress via TAVI reduces Mac-1 activation, cellular adhesion, phagocytosis, oxidized LDL uptake, and expression of inflammatory markers in monocytes and plasma. Using microfluidics, pharmacological and genetic studies, we could recapitulate high shear stress effects on isolated human monocytes under highly controlled conditions, showing that shear stress-dependent calcium influx and monocyte adhesion are mediated by the mechanosensitive ion channel Piezo-1. We also demonstrate that expression of this receptor is shear stress-dependent and downregulated in patients receiving TAVI. Finally, we show monocyte accumulation at the aortic side of leaflets of explanted aortic valves.
Conclusions:
We demonstrate that high shear stress, as present in patients with aortic valve stenosis, activates multiple monocyte functions and we identify Piezo-1 as the mainly responsible mechanoreceptor, representing a potentially druggable target. Importantly, we demonstrate an anti-inflammatory effect and therefore a novel therapeutic benefit of TAVI.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.