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Transcatheter aortic valve implantation (TAVI) can treat symptomatic patients with calcific aortic stenosis. However, the severity and distribution of the calcification of valve leaflets can impair the TAVI efficacy. Here we tackle this issue from a biomechanical standpoint, by finite element simulation of a widely adopted balloon-expandable TAVI in three models representing the aortic root with different scenarios of calcific aortic stenosis. We developed a modeling approach realistically accounting for aortic root pressurization and complex anatomy, detailed calcification patterns, and for the actual stent deployment through balloon-expansion.Numerical results highlighted the dependency on the specific calcification pattern of the “dog–boning” of the stent. Also, local stent distortions were associated with leaflet calcifications, and led to localized gaps between the TAVI stent and the aortic tissues, with potential implications in terms of paravalvular leakage. High stresses were found on calcium deposits, which may be a risk factor for stroke; their magnitude and the extent of the affected regions substantially increased for the case of an “arc–shaped” calcification, running from commissure to commissure. Moreover, high stresses due to the interaction between the aortic wall and the leaflet calcifications were computed in the annular region, suggesting an increased risk for annular damage.Our analyses suggest a relation between the alteration of the stresses in the native anatomical components and prosthetic implant with the presence and distribution of relevant calcifications. This alteration is dependent on the patient-specific features of the calcific aortic stenosis and may be a relevant indicator of suboptimal TAVI results.

BACKGROUND: We systematically analyzed the synergistic effect of: i) cytokine-mediated inflammatory activation of endothelial cells (ECs), and ii) shear-mediated platelet activation (SMPA) as a potential contributory mechanism to intraventricular thrombus formation in the setting of Left Ventricular Assist Device (LVAD) support. METHODS: Intact and shear-activated human platelets were exposed to nonactivated and cytokine-activated ECs. To modulate the level of LVAD-related shear activation, platelets were exposed to shear stress patterns of varying magnitude (30, 50, 70 dynes/cm(2), 10min) via a Hemodynamic Shearing Device. ECs were activated via exposure to inflammatory Tumor Necrosis Factor-α (TNF-α, 10 and 100 ng/mL, 24h), consistent with inflammatory activation recorded in patients on LVAD circulatory support. RESULTS: Adhesivity of shear-activated platelets to ECs was significantly higher than that of intact/unactivated platelets, regardless of the initial activation level (70 dynes/cm(2) shear-activated platelets vs. intact platelets: +80%, p

A microfluidic flow-based platform (μFP), able to stimulate platelets via exposure of shear stress patterns pertinent to cardiovascular devices and prostheses, was compared to the Hemodynamic Shearing Device (HSD) - a state-of-the-art bench-top system for exposure of platelets to defined levels and patterns of shear. Platelets were exposed to time-varying shear stress patterns in the two systems; in detail, platelets were recirculated in the μFP or stimulated in the HSD to replicate comparable exposure time. Shear-mediated platelet activation was evaluated via (i) the platelet activity state assay, allowing the measurement of platelet-mediated thrombin generation and associated prothrombotic tendencies, (ii) scanning electron microscopy to evaluate morphological changes of sheared platelets, and (iii) flow cytometry for the determination of platelet phosphatidylserine exposure as a marker of shear activation. The results revealed good matching and comparability between the two systems, with similar trends of platelet activation, formation of microaggregates, and analogous trends of activation marker exposure for both the HSD and microfluidic-stimulated samples. These findings support future translation of the microfluidic platform as a Point-of-Care facsimile system for the diagnosis of thrombotic risk in patients implanted with cardiovascular devices.

Thrombus formation is a major adverse event affecting patients implanted with ventricular assist devices (VADs). Despite anti-thrombotic drug administration, thrombotic events remain frequent within the first year post-implantation. Platelet activation (PA) is an essential process underling thrombotic adverse events in VAD systems. Indeed, abnormal shear forces, correlating with specific flow trajectories of VADs, are strong agonists mediating PA. To date, the ability to determine efficacy of anti-platelet (AP) agents under shear stress conditions is limited. Here, we present a novel microfluidic platform designed to replicate shear stress patterns of a clinical VAD, and use it to compare the efficacy of two AP agents in vitro. Gel-filtered platelets were incubated with i) acetylsalicylic acid (ASA) and ii) ticagrelor, at two different concentrations (ASA: 125 and 250[U+202F]μM; ticagrelor: 250 and 500[U+202F]nM) and were circulated in the VAD-emulating microfluidic platform using a peristaltic pump. GFP was collected after 4 and 52 repetitions of exposure to the VAD shear pattern and tested for shear-mediated PA. ASA significantly inhibited PA only at 2-fold higher concentration (250[U+202F]μM) than therapeutic dose (125[U+202F]μM). The effect of ticagrelor was not dependent on drug concentration, and did not show significant inhibition with respect to untreated control. This study demonstrates the potential use of microfluidic platforms as means of testing platelet responsiveness and AP drug efficacy under complex and realistic VAD-like shear stress conditions.