Transcatheter Aortic Valve Implantation Represents an Anti-Inflammatory Therapy Via Reduction of Shear Stress–Induced, Piezo-1–Mediated Monocyte Activation

Abstract

<jats:p> <jats:bold>Background:</jats:bold> 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. </jats:p> <jats:p> <jats:bold>Methods:</jats:bold> 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 <jats:sup>2+</jats:sup> 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. </jats:p> <jats:p> <jats:bold>Results:</jats:bold> 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. </jats:p> <jats:p> <jats:bold>Conclusions:</jats:bold> 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. </jats:p>

Tunable Harmonic Flow Patterns in Microfluidic Systems through Simple Tube Oscillation

“…The simplicity, controllability, versatility, and biocompatibility of the newly described technology make it highly suitable for multiple applications. These include important applications in physics (e.g., studying complex fluids and soft materials [5][6][7] and generation of droplets [58,59] ), chemistry (e.g., synthesis of various molecules and compounds [11,12] ), and biology (e.g., manipulation of cells, [60,61] performing multistep assays, [13] diagnostics, [62] and developing organ-on-a-chip platforms [63] for studying the mechanobiology of cells [64,65] and the human circulatory system [17,19,66] ). Notably, both customized harmonic and disturbed flow patterns can be created and studied using the newly described technology.…”

“…This includes studying mechanical and rheological properties of complex fluids and soft materials such as polymers, emulsions, colloids, liquid crystals, and their biological counterparts, [5][6][7][8][9][10] chemical synthesis of hazardous chemical compounds, pharmaceutical agents, and micro/nanomaterials, [11][12][13][14] and mimicking harmonic/disturbed flows occurring in the natural systems, such as the human circulatory system, where they may cause dysfunction or disease. [15][16][17][18][19] Passive and active mechanisms have been used to generate disturbed flow patterns in microfluidic systems. [20] The passive mechanisms take advantage of asymmetric geometries or sudden changes in the geometry to generate secondary flows.…”

“…This includes studying mechanical and rheological properties of complex fluids and soft materials such as polymers, emulsions, colloids, liquid crystals, and their biological counterparts, [ 5–10 ] chemical synthesis of hazardous chemical compounds, pharmaceutical agents, and micro/nanomaterials, [ 11–14 ] and mimicking harmonic/disturbed flows occurring in the natural systems, such as the human circulatory system, where they may cause dysfunction or disease. [ 15–19 ]…”

Determination of the Empirical Electrokinetic Equilibrium Condition of Microorganisms in Microfluidic Devices

“…Additionally, it must be noted that while the focus of this study is the use of microscale EK techniques, microfluidic devices are currently being used across a wide range of fields. One such example, as presented by Baratchi et al [ 22 ], is the in vitro study of cell mechanobiology, including the effects of shear stress on cells. These developments in iEK techniques could be combined with other cell characterization systems, such as the one presented by Baratchi et al [ 22 ], which can result in a more comprehensive cell characterization process.…”

Transcatheter Aortic Valve Implantation, Atrial Fibrillation, and Bleeding: A Surprisingly Fatal Attraction

“…Recently, it has been shown that monocytes, which play an important role in coagulation, exhibit an activated phenotype in AS patients which reverses post-TAVI. 33 Although it is well accepted that platelets can be activated and desensitized by shear stress, there is a lack of data currently available regarding the effects of AS, and indeed TAVI, on platelet function. Therefore, mechanistic studies on the role of shear stress-induced effects on circulating blood cells will likely provide additional insights into the links between the potential prothrombotic effects and bleeding risk observed in patients undergoing TAVI.…”