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In this study a frequency scaling law for 3D anatomically representative supravalvular aortic stenosis (SVAS) cases is proposed. The law is uncovered for stethoscopy's preferred auscultation range (70-120 Hz). LES simulations are performed on the CFD solver Fluent, leveraging Simulia's Living Heart Human Model (LHHM), modified to feature hourglass stenoses that range between 30 to 80 percent (mild to severe) in addition to the descending aorta. For physiological hemodynamic boundary conditions the Windkessel model is implemented via a UDF subroutine. The flow-generated acoustic signal is then extracted using the FW-H model and analyzed using FFT. A preferred receiver location that matches clinical practice is confirmed (right intercostal space) and a correlation between the degree of stenosis and a corresponding acoustic frequency is obtained. Five clinical auscultation signals are tested against the scaling law, with the findings interpreted in relation to the NHS classification of stenosis and to the assessments of experienced cardiologists. The scaling law is thus shown to succeed as a potential quantitative decision-support tool for clinicians, enabling them to reliably interpret stethoscopic auscultations for all degrees of stenosis, which is especially useful for moderate degrees of SVAS. Computational investigation of more complex stenotic cases would enhance the clinical relevance of this proposed scaling law, and will be explored in future research., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Cardiotoxicity limits the use of anthracyclines as potent chemotherapeutics. We employ classical molecular dynamics to explore anthracycline interactions with a realistic myocardial membrane and compare to an ideal membrane widely used in literature. The interaction of these two membranes with four anthracyclines; doxorubicin, epirubicin, daunorubicin, and idarubicin are studied. Careful analysis was conducted on three forms of each drug; pristine, primary metabolite, and cationic salt. By examining the molecular residence time near the membrane's surface, the average number of molecule/membrane hydrogen bonds, the immobilization of the molecules near the membrane, and the location of those molecules relative to the mid-plane of the membrane we found out that salt forms exhibit the highest cardiotoxic probability, followed by the metabolites and pristine forms. Additionally, all forms have more affinity to the upper layer of the realistic myocardial membrane. Meanwhile, an ideal membrane consisting of a single type of phospholipids is not capable of capturing the specific interactions of each drug form. These findings confirm that cardiotoxic mechanisms are membrane-layer and drug-form dependent., (© 2023. The Author(s).)

This study explores the negative impact of cyclophosphamide (CP) on cardiac contractility by specifically examining its effect on the active and passive tension of the cardiac muscle in-vitro and revealing the mechanism through which CP induces myocardial insult in-vivo. In young male Sprague-Dawley rats, cardiac toxicity was induced by a single intraperitoneal injection of CP (150 mg/kg body weight). Axial heart tissue slices were electrically stimulated, and the total isometric contraction force was measured at varying pretension levels. Blood and tissue biochemical assays, and histological/ immuno-histological assessments were conducted to evaluate the underlying molecular mechanisms. Statistical analysis shows that there is a significant difference between the drugged and the control groups in terms of the active tension values. Moreover, the pre-tension stress significantly affects both the active and passive tension values. CP altered heart, body, and heart-to-body weight, desolated cardiac muscle architecture, surged cardiac enzymes (CK-MB, LDH, and cTn l), augmented myocardial oxidative stressors (MDA), and weakened myocardial antioxidant status (SOD and GSH). Mechanistically, cyclophosphamide prompted the necroptotic trajectory evidenced by the activation of RIPK1, RIPK3, MLKL and TRPM7, the inhibition of caspase 8 and BCL2 and the upregulation of the protein/mRNA expression of TNF-α and TNFR1. This study identifies necroptosis as a key factor in cyclophosphamide-evoked myocardial contractility impairment, highlighting its potential as a target for alleviating antitumor-related myocardial damage. This innovative approach to investigating the underlying mechanisms of CP-induced cardiac toxicity offers valuable insights into the potential of developing new therapies to mitigate cyclophosphamide's negative impact., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

In this paper, we identify a new (acoustic) frequency-stenosis relation whose frequencies lie within the recommended auscultation threshold of stethoscopy (< 120 Hz). We show that this relation can be used to extend the application of phonoangiography (quantifying the degree of stenosis from bruits) to widely accessible stethoscopes. The relation is successfully identified from an analysis restricted to the acoustic signature of the von Karman vortex street, which we automatically single out by means of a metric we propose that is based on an area-weighted average of the Q-criterion for the post-stenotic region. Specifically, we perform CFD simulations on internal flow geometries that represent stenotic blood vessels of different severities. We then extract their emitted acoustic signals using the Ffowcs Williams-Hawkings equation, which we subtract from a clean signal (stenosis free) at the same heart rate. Next, we transform this differential signal to the frequency domain and carefully classify its acoustic signatures per six (stenosis-)invariant flow phases of a cardiac cycle that are newly identified in this paper. We then automatically restrict our acoustic analysis to the sounds emitted by the von Karman vortex street (phase 4) by means of our Q-criterion-based metric. Our analysis of its acoustic signature reveals a strong linear relationship between the degree of stenosis and its dominant frequency, which differs considerably from the break frequency and the heart rate (known dominant frequencies in the literature). Applying our new relation to available stethoscopic data, we find that its predictions are consistent with clinical assessment. Our finding of this linear correlation is also unlike prevalent scaling laws in the literature, which feature a small exponent (i.e., low stenosis percentage sensitivity over much of the clinical range). They hence can only distinguish mild, moderate, and severe cases. Conversely, our linear law can identify variations in the degree of stenosis sensitively and accurately for the full clinical range, thus significantly improving the utility of the relevant scaling laws... Future research will investigate incorporating the vibroacoustic role of adjacent organs to expand the clinical applicability of our findings. Extending our approach to more complex 3D stenotic morphologies and including the vibroacoustic role of surrounding organs will be explored in future research to advance the clinical reach of our findings., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Hydrogels are nowadays widely used in various biomedical applications, and show great potential for the making of devices such as biosensors, drug- delivery vectors, carriers, or matrices for cell cultures in tissue engineering, etc. In these applications, due to the irregular complex surface of the human body or its organs/structures, the devices are often designed with a small thickness, and are required to be flexible when attached to biological surfaces. The devices will deform as driven by human motion and under external loading. In terms of mechanical modeling, most of these devices can be abstracted as shells. In this paper, we propose a mixed graph-finite element method (FEM) phase field approach to model the fracture of curved shells composed of hydrogels, for biomedical applications. We present herein examples for the fracture of a wearable biosensor, a membrane-coated drug, and a matrix for a cell culture, each made of a hydrogel. Used in combination with experimental material testing, our method opens a new pathway to the efficient modeling of fracture in biomedical devices with surfaces of arbitrary curvature, helping in the design of devices with tunable fracture properties.

Pulmonary hypertension (PH), a chronic and complex medical condition affecting 1% of the global population, requires clinical evaluation of right ventricular maladaptation patterns under various conditions. A particular challenge for clinicians is a proper quantitative assessment of the right ventricle (RV) owing to its intimate coupling to the left ventricle (LV). We, thus, proposed a patient-specific computational approach to simulate PH caused by left heart disease and its main adverse functional and structural effects on the whole heart. Information obtained from both prospective and retrospective studies of two patients with severe PH, a 72-year-old female and a 61-year-old male, is used to present patient-specific versions of the Living Heart Human Model (LHHM) for the pre-operative and post-operative cardiac surgery. Our findings suggest that before mitral and tricuspid valve repair, the patients were at risk of right ventricular dilatation which may progress to right ventricular failure secondary to their mitral valve disease and left ventricular dysfunction. Our analysis provides detailed evidence that mitral valve replacement and subsequent chamber pressure unloading are associated with a significant decrease in failure risk post-operatively in the context of pulmonary hypertension. In particular, right-sided strain markers, such as tricuspid annular plane systolic excursion (TAPSE) and circumferential and longitudinal strains, indicate a transition from a range representative of disease to within typical values after surgery. Furthermore, the wall stresses across the RV and the interventricular septum showed a notable decrease during the systolic phase after surgery, lessening the drive for further RV maladaptation and significantly reducing the risk of RV failure., (© 2022. International Federation for Medical and Biological Engineering.)

The present case study compares transmission Kikuchi diffraction (TKD) with electron back-scattering diffraction (EBSD) on the same area of an electron transparent cross-section of a twinning induced plasticity steel. While TKD expectedly provides better clarity of internal defect substructures in the band contrast map, EBSD returns orientation data that approaches the quality of the TKD map. This was rationalised by Monte Carlo simulations of the electron energy spreads, which showed that due to the geometry-based compromises associated with adapting a conventional EBSD detector (which is off-axis with respect to the incident electron beam) to TKD, a broadening in the electron energy distribution of the forward-scattered electrons collected on the detector phosphor screen, is unavoidable. In this circumstance, the values of the full-widths at half-maximum of the energy distributions for TKD and EBSD are of the same order. It follows that EBSD on electron transparent cross-sections may be a viable alternative to TKD when: (i) conventional EBSD detectors are adapted to TKD and, (ii) sample microstructures comprise features whose sizes do not mandate the application of TKD., (Copyright © 2017 Elsevier Ltd. All rights reserved.)