Cancer cell extravasation requires iplectin-mediated delivery of MT1-MMP at invadopodia.

BACKGROUND: Invadopodia facilitate cancer cell extravasation, but the molecular mechanism whereby invadopodia-specific proteases such as MT1-MMP are called to invadopodia is unclear. METHODS: Mass spectrometry and immunoprecipitation were used to identify interactors of MT1-MMP in metastatic breast cancer cells. After identification, siRNA and small molecule inhibitors were used to assess the effect these interactors had on cellular invasiveness. The chicken embryo chorioallantoic membrane (CAM) model was used to assess extravasation and invadopodia formation in vivo. RESULTS: In metastatic breast cancer cells, MT1-MMP was found to associate with plectin, a cytolinker and scaffolding protein. Complex formation between plectin and MT1-MMP launches invadopodia formation, a subtype we termed iplectin (i = invadopodial). iPlectin delivers MT1-MMP to invadopodia and is indispensable for regulating cell surface levels of the enzyme. Genetic depletion of plectin with siRNA reduced invadopodia formation and cell invasion in vitro. In vivo extravasation efficiency assays and intravital imaging revealed iplectin to be a key contributor to invadopodia ultrastructure and essential for extravasation. Pharmacologic inhibition of plectin using the small molecule Plecstatin-1 (PST-1) abrogated MT1-MMP delivery to invadopodia and extravasation efficiency. CONCLUSIONS: Anti-metastasis therapeutic approaches that target invadopodia are possible by disrupting interactions between MT1-MMP and iplectin. CLINICAL TRIAL REGISTRATION NUMBER: NCT04608357.

The application of exercise stress cardiovascular magnetic resonance in patients with suspected dilated cardiomyopathy.

OBJECTIVES: The imaging features of dilated cardiomyopathy (DCM) overlap with physiological exercise-induced cardiac remodeling in active and otherwise healthy individuals. Distinguishing the two conditions is challenging. This study examined the diagnostic and prognostic roles of exercise stress imaging in asymptomatic patients with suspected DCM. METHODS: Exercise stress cardiovascular magnetic resonance (CMR) was performed in 60 asymptomatic patients with suspected DCM (dilated left ventricle and/or impaired systolic function on CMR), who also underwent DNA sequencing for DCM-causing genetic variants. Confirmed DCM was defined as genotype- and phenotype-positive (G+P+). Another 100 healthy subjects were recruited to establish normal exercise capacities (peak exercise cardiac index; PeakCI). The primary outcome was a composite of all-cause mortality, cardiac decompensation and ventricular arrhythmic events. RESULTS: No patients with confirmed G+P+ DCM had PeakCI exceeding the 35th percentile specific for age and sex. Applying this threshold in G-P+ patients, those with PeakCI below 35th percentile had characteristics similar to confirmed DCM while patients with higher PeakCI were younger, more active and higher longitudinal strain. Adverse cardiovascular events occurred only in patients with low exercise capacity (P = 0.004). CONCLUSIONS: In individuals with suspected DCM, exercise stress CMR demonstrates diagnostic and prognostic potential in distinguishing between pathological DCM and physiological exercise-induced cardiac remodeling.

Mechanistic Study of the Reactions of Methyl Peroxy Radical with Methanol or Hydroxyl Methyl Radical.

An ab initio and direct dynamic study of the reactions of CH3O2 + CH3OH and CH3O2 + CH2OH has been carried out over the temperature range of 300-1500 K. All stationary points were calculated at the MP2/aug-cc-pVTZ level of theory for CH3O2 + CH3OH or at the M06-2X/MG3S level of theory for CH3O2 + CH2OH and identified for the local minimum. The energetic parameters were refined at the QCISD(T)/cc-pVTZ and CCSD(T)/aug-cc-pVTZ levels of theory. For the reaction of CH3OO + CH3OH, two hydrogen abstraction channels producing CH3OOH + CH2OH (R1) and CH3OOH + CH3O (R2) were confirmed. These two channels consist of the same reversible first step involving the formation of a prereactive complex in the entrance channel. The rate constants of these two channels have been calculated by canonical transition station theory (TST) and canonical variational transition station theory (VTST) with Eckart tunneling correction and compared with the available literature data. The positive temperature dependence of the rate constants was observed. The tunneling effect is important at low temperature and decreases with an increase of the temperature. The contribution of R1 to the total rate constant is dominant, with branching ratios of 0.93 at 500 K and 0.67 at 1000 K, although the branching ratio for R2 increases dramatically with the increase of the temperature from 500 K. For the reaction of CH3OO + CH2OH, eight channels were explored on the lowest singlet and triplet surfaces, and an excited intermediate was found to be formed on the singlet surface. A channel proceeding through the formation of an excited intermediate followed by its impulsive dissociation was confirmed as the dominant channels with a branching ratio more than 0.99 in the temperature range of 300-1500 K, where products of CH3O and OCH2OH were given. The rate constant of the dominant channel calculated by multichannel RRKM-VTST is comparable with the available literature data.

Cardiac magnetic resonance T1 and extracellular volume mapping with motion correction and co-registration based on fast elastic image registration.

OBJECTIVE: Our aim was to investigate the technical feasibility of a novel motion compensation method for cardiac magntic resonance (MR) T1 and extracellular volume fraction (ECV) mapping. MATERIALS AND METHODS: Native and post-contrast T1 maps were obtained using modified look-locker inversion recovery (MOLLI) pulse sequences with acquisition scheme defined in seconds. A nonrigid, nonparametric, fast elastic registration method was applied to generate motion-corrected T1 maps and subsequently ECV maps. Qualitative rating was performed based on T1 fitting-error maps and overlay images. Local deformation vector fields were produced for quantitative assessment. Intra- and inter-observer reproducibility were compared with and without motion compensation. RESULTS: Eighty-two T1 and 39 ECV maps were obtained in 21 patients with diverse myocardial diseases. Approximately 60% demonstrated clear quality improvement after motion correction for T1 mapping, particularly for the poor-rating cases (23% before vs 2% after). Approximately 67% showed further improvement with co-registration in ECV mapping. Although T1 and ECV values were not clinically significantly different before and after motion compensation, there was improved intra- and inter-observer reproducibility after motion compensation. CONCLUSIONS: Automated motion correction and co-registration improved the qualitative assessment and reproducibility of cardiac MR T1 and ECV measurements, allowing for more reliable ECV mapping.

Fractal analysis of left ventricular trabeculations is associated with impaired myocardial deformation in healthy Chinese.

BACKGROUND: Left ventricular (LV) non-compaction (LVNC) is defined by extreme LV trabeculation, but is measured variably. Here we examined the relationship between quantitative measurement in LV trabeculation and myocardial deformation in health and disease and determined the clinical utility of semi-automated assessment of LV trabeculations. METHODS: Cardiovascular magnetic resonance (CMR) was performed in 180 healthy Singaporean Chinese (age 20-69 years; males, n = 91), using balanced steady state free precession cine imaging at 3T. The degree of LV trabeculation was assessed by fractal dimension (FD) as a robust measure of trabeculation complexity using a semi-automated technique. FD measures were determined in healthy men and women to derive normal reference ranges. Myocardial deformation was evaluated using feature tracking. We tested the utility of this algorithm and the normal ranges in 10 individuals with confirmed LVNC (non-compacted/compacted; NC/C ratio > 2.3 and ≥1 risk factor for LVNC) and 13 individuals with suspected disease (NC/C ratio > 2.3). RESULTS: Fractal analysis is a reproducible means of assessing LV trabeculation extent (intra-class correlation coefficient: intra-observer, 0.924, 95% CI [0.761-0.973]; inter-observer, 0.925, 95% CI [0.821-0.970]). The overall extent of LV trabeculation (global FD: 1.205 ± 0.031) was independently associated with increased indexed LV end-diastolic volume and mass (sß = 0.35; p < 0.001 and sß = 0.13; p < 0.01, respectively) after adjusting for age, sex and body mass index. Increased LV trabeculation was independently associated with reduced global circumferential strain (sß = 0.17, p = 0.013) and global diastolic circumferential and radial strain rates (sß = 0.25, p < 0.001 and sß = -0.15, p = 0.049, respectively). Abnormally high FD was observed in all patients with a confirmed diagnosis of LVNC. Five out of 13 individuals with suspected LVNC had normal FD, despite NC/C > 2.3. CONCLUSION: This study defines the normal range of LV trabeculation in healthy Chinese that can be used to make or refute a diagnosis of LVNC using the fractal analysis tool, which we make freely available. We also show that increased myocardial trabeculation is associated with higher LV volumes, mass and reduced myocardial strain.

Assessing exercise cardiac reserve using real-time cardiovascular magnetic resonance.

BACKGROUND: Exercise cardiovascular magnetic resonance (ExCMR) has great potential for clinical use but its development has been limited by a lack of compatible equipment and robust real-time imaging techniques. We developed an exCMR protocol using an in-scanner cycle ergometer and assessed its performance in differentiating athletes from non-athletes. METHODS: Free-breathing real-time CMR (1.5T Aera, Siemens) was performed in 11 athletes (5 males; median age 29 [IQR: 28-39] years) and 16 age- and sex-matched healthy volunteers (7 males; median age 26 [interquartile range (IQR): 25-33] years). All participants underwent an in-scanner exercise protocol on a CMR compatible cycle ergometer (Lode BV, the Netherlands), with an initial workload of 25W followed by 25W-increment every minute. In 20 individuals, exercise capacity was also evaluated by cardiopulmonary exercise test (CPET). Scan-rescan reproducibility was assessed in 10 individuals, at least 7 days apart. RESULTS: The exCMR protocol demonstrated excellent scan-rescan (cardiac index (CI): 0.2 ± 0.5L/min/m2) and inter-observer (ventricular volumes: 1.2 ± 5.3mL) reproducibility. CI derived from exCMR and CPET had excellent correlation (r = 0.83, p < 0.001) and agreement (1.7 ± 1.8L/min/m2). Despite similar values at rest (P = 0.87), athletes had increased exercise CI compared to healthy individuals (at peak exercise: 12.2 [IQR: 10.2-13.5] L/min/m2 versus 8.9 [IQR: 7.5-10.1] L/min/m2, respectively; P < 0.001). Peak exercise CI, where image acquisition lasted 13-17 s, outperformed that at rest (c-statistics = 0.95 [95% confidence interval: 0.87-1.00] versus 0.48 [95% confidence interval: 0.23-0.72], respectively; P < 0.0001 for comparison) in differentiating athletes from healthy volunteers; and had similar performance as VO2max (c-statistics = 0.84 [95% confidence interval = 0.62-1.00]; P = 0.29 for comparison). CONCLUSIONS: We have developed a novel in-scanner exCMR protocol using real-time CMR that is highly reproducible. It may now be developed for clinical use for physiological studies of the heart and circulation.

Heart blood flow simulation: a perspective review.

Cardiovascular disease (CVD), the leading cause of death today, incorporates a wide range of cardiovascular system malfunctions that affect heart functionality. It is believed that the hemodynamic loads exerted on the cardiovascular system, the left ventricle (LV) in particular, are the leading cause of CVD initiation and propagation. Moreover, it is believed that the diagnosis and prognosis of CVD at an early stage could reduce its high mortality and morbidity rate. Therefore, a set of robust clinical cardiovascular assessment tools has been introduced to compute the cardiovascular hemodynamics in order to provide useful insights to physicians to recognize indicators leading to CVD and also to aid the diagnosis of CVD. Recently, a combination of computational fluid dynamics (CFD) and different medical imaging tools, image-based CFD (IB-CFD), has been widely employed for cardiovascular functional assessment by providing reliable hemodynamic parameters. Even though the capability of CFD to provide reliable flow dynamics in general fluid mechanics problems has been widely demonstrated for many years, up to now, the clinical implications of the IB-CFD patient-specific LVs have not been applicable due to its limitations and complications. In this paper, we review investigations conducted to numerically simulate patient-specific human LV over the past 15 years using IB-CFD methods. Firstly, we divide different studies according to the different LV types (physiological and different pathological conditions) that have been chosen to reconstruct the geometry, and then discuss their contributions, methodologies, limitations, and findings. In this regard, we have studied CFD simulations of intraventricular flows and related cardiology insights, for (i) Physiological patient-specific LV models, (ii) Pathological heart patient-specific models, including myocardial infarction, dilated cardiomyopathy, hypertrophic cardiomyopathy and hypoplastic left heart syndrome. Finally, we discuss the current stage of the IB-CFD LV simulations in order to mimic realistic hemodynamics of patient-specific LVs. We can conclude that heart flow simulation is on the right track for developing into a useful clinical tool for heart function assessment, by (i) incorporating most of heart structures' (such as heart valves) operations, and (ii) providing useful diagnostic indices based hemodynamic parameters, for routine adoption in clinical usage.

Automated quantitative assessment of cardiovascular magnetic resonance-derived atrioventricular junction velocities.

The assessment of atrioventricular junction (AVJ) deformation plays an important role in evaluating left ventricular systolic and diastolic function in clinical practice. This study aims to demonstrate the effectiveness and consistency of cardiovascular magnetic resonance (CMR) for quantitative assessment of AVJ velocity compared with tissue Doppler echocardiography (TDE). A group of 145 human subjects comprising 21 healthy volunteers, 8 patients with heart failure, 17 patients with hypertrophic cardiomyopathy, 52 patients with myocardial infarction, and 47 patients with repaired Tetralogy of Fallot were prospectively enrolled and underwent TDE and CMR scan. Six AVJ points were tracked with three CMR views. The peak systolic velocity (Sm1), diastolic velocity during early diastolic filling (Em), and late diastolic velocity during atrial contraction (Am) were extracted and analyzed. All CMR-derived septal and lateral AVJ velocities correlated well with TDE measurements (Sm1: r = 0.736; Em: r = 0.835; Am: r = 0.701; Em/Am: r = 0.691; all p < 0.001) and demonstrated excellent reproducibility [intrastudy: r = 0.921-0.991, intraclass correlation coefficient (ICC): 0.918-0.991; interstudy: r = 0.900-0.970, ICC: 0.887-0.957; all p < 0.001]. The evaluation of three-dimensional AVJ motion incorporating measurements from all views better differentiated normal and diseased states [area under the curve (AUC) = 0.918] and provided further insights into mechanical dyssynchrony diagnosis in HF patients (AUC = 0.987). These findings suggest that the CMR-based method is feasible, accurate, and consistent in quantifying the AVJ deformation, and subsequently in diagnosing systolic and diastolic cardiac dysfunction.

Numerical analysis of the hemodynamic performance of bileaflet mechanical heart valves at different implantation angles.

BACKGROUND AND AIM OF THE STUDY: The effects of the implantation angle of bileaflet mechanical heart valves (BMHVs) on the sinus region and downstream flow profiles were investigated. Three-dimensional numerical simulations of BMHVs were performed under physiologic pulsatile flow conditions. The study aim was to examine how the flow fields of different aortic sinus shapes and the downstream aortic arch geometry would be affected by implantation angle. METHODS: Two geometric models of sinus were investigated: a simplified axisymmetric sinus; and a three-sinus aortic root model, with two different downstream geometries, namely a straight pipe and a simplified curved aortic arch. A 29 mm St. Jude Medical BMHV geometric model was used and positioned at four different angles (0 degrees, 30 degrees, 60 degrees and 90 degrees). RESULTS: The simulation results showed variation in downstream flow profiles at different implantation angles. Generally, at position Z = 1D along the centerline (where Z refers to the axis normal to the x-y plane and D is the inlet diameter), the triple-jet structures were observed with a slight shift of the center jet for three-sinus aortic cases. Apparent differences were observed at position Z = 2D and 4D, such as higher velocity profiles at the inner arch wall. The flow field downstream of the valve implanted at 0 degrees (anatomic position) showed the smallest overall asymmetry at peak systole, while the flow field downstream of the valve implanted at 90 degrees (anti-anatomic position) exhibited high regions of recirculation. CONCLUSION: Valve orientation was found not to affect the shear stress distribution significantly in the downstream aorta, and this was in agreement with the findings of earlier studies.

Numerical Study on the Impact of Central Venous Catheter Placement on Blood Flow in the Cavo-Atrial Junction.

An in silico study is performed to investigate fluid dynamic effects of central venous catheter (CVC) placement within patient-specific cavo-atrial junctions. Prior studies show the CVC infusing a liquid, but this study focuses on the placement without any liquid emerging from the CVC. A 7 or 15-French double-lumen CVC is placed virtually in two patient-specific models; the CVC tip location is altered to understand its effect on the venous flow field. Results show that the CVC impact is trivial on flow in the superior vena cava when the catheter-to-vein ratio ranges from 0.15 to 0.33. Results further demonstrate that when the CVC tip is directly in the right atrium, flow vortices in the right atrium result in elevated wall shear stress near the tip hole. A recirculation region characterizes a spatially variable flow field inside the CVC side hole. Furthermore, flow stagnation is present near the internal side hole corners but an elevated wall shear stress near the curvature of the side hole's exit. These results suggest that optimal CVC tip location is within the superior vena cava, so as to lower the potential for platelet activation due to elevated shear stresses and that CVC geometry and location depth in the central vein significantly influences the local CVC fluid dynamics. A thrombosis model also shows thrombus formation at the side hole and tip hole. After modifying the catheter design, the hemodynamics change, which alter thrombus formation. Future studies are warranted to study CVC design and placement location in an effort to minimize CVC-induced thrombosis incidence.

E-cadherin interacts with EGFR resulting in hyper-activation of ERK in multiple models of breast cancer.

The loss of intercellular adhesion molecule E-cadherin is a hallmark of the epithelial-mesenchymal transition (EMT), during which tumor cells transition into an invasive phenotype. Accordingly, E-cadherin has long been considered a tumor suppressor gene; however, E-cadherin expression is paradoxically correlated with breast cancer survival rates. Using novel multi-compartment organoids and multiple in vivo models, we show that E-cadherin promotes a hyper-proliferative phenotype in breast cancer cells via interaction with the transmembrane receptor EGFR. The E-cad and EGFR interaction results in activation of the MEK/ERK signaling pathway, leading to a significant increase in proliferation via activation of transcription factors, including c-Fos. Pharmacological inhibition of MEK activity in E-cadherin positive breast cancer significantly decreases both tumor growth and macro-metastasis in vivo. This work provides evidence for a novel role of E-cadherin in breast tumor progression and identifies a new target to treat hyper-proliferative E-cadherin-positive breast tumors, thus providing the foundation to utilize E-cadherin as a biomarker for specific therapeutic success.

Unraveling the Role of EV-Derived miR-150-5p in Prostate Cancer Metastasis and Its Association with High-Grade Gleason Scores: Implications for Diagnosis.

Metastasis remains the leading cause of mortality in prostate cancer patients. The presence of tumor cells in lymph nodes is an established prognostic indicator for several cancer types, such as melanoma, breast, oral, pancreatic, and cervical cancers. Emerging evidence highlights the role of microRNAs enclosed within extracellular vesicles as facilitators of molecular communication between tumors and metastatic sites in the lymph nodes. This study aims to investigate the potential diagnostic utility of EV-derived microRNAs in liquid biopsies for prostate cancer. By employing microarrays on paraffin-embedded samples, we characterized the microRNA expression profiles in metastatic lymph nodes, non-metastatic lymph nodes, and primary tumor tissues of prostate cancer. Differential expression of microRNAs was observed in metastatic lymph nodes compared to prostate tumors and non-metastatic lymph node tissues. Three microRNAs (miR-140-3p, miR-150-5p, and miR-23b-3p) were identified as differentially expressed between tissue and plasma samples. Furthermore, we evaluated the expression of these microRNAs in exosomes derived from prostate cancer cells and plasma samples. Intriguingly, high Gleason score samples exhibited the lowest expression of miR-150-5p compared to control samples. Pathway analysis suggested a potential regulatory role for miR-150-5p in the Wnt pathway and bone metastasis. Our findings suggest EV-derived miR-150-5p as a promising diagnostic marker for identifying patients with high-grade Gleason scores and detecting metastasis at an early stage.

Validation of an axial flow blood pump: computational fluid dynamics results using particle image velocimetry.

A magnetically suspended axial flow blood pump is studied experimentally in this article. The pump casing enclosed a three-blade straightener, a two-blade impeller shrouded by a permanent magnet-embedded cylinder, and a three-blade diffuser. The internal flow fields were simulated earlier using computational fluid dynamics (CFD), and the pump characteristic curves were determined. The simulation results showed that the internal flow field was basically streamlined, except the diffuser region. Particle image velocimetry (PIV) measurement of the 1:1 pump model was conducted to validate the CFD result. In order to ensure the optical access, an acrylic prototype was fabricated with the impeller driven by a servomotor instead, as the magnet is opaque. In addition to the transparent model, the blood analog fluid with the refractive index close to that of acrylic was used to avoid refraction. According to the CFD results, the axial flow blood pump could generate adequate pressure head at the rotating speed of 9500rpm and flow rate of 5L/min, and the same flow condition was applied during the PIV measurement. Through the comparisons, it was found that the experimental results were close to those obtained by CFD and had thus validated the CFD model, which could complement the limitation of the measurement in assessing the more detailed flow fields of the axial flow pump.

The remodelling index risk stratifies patients with hypertensive left ventricular hypertrophy.

AIMS: Hypertensive left ventricular hypertrophy (LVH) is associated with increased cardiovascular events. We previously developed the remodelling index (RI) that incorporated left ventricular (LV) volume and wall-thickness in a single measure of advanced hypertrophy in hypertensive patients. This study examined the prognostic potential of the RI in reference to contemporary LVH classifications. METHODS AND RESULTS: Cardiovascular magnetic resonance was performed in 400 asymptomatic hypertensive patients. The newly derived RI (EDV3t, where EDV is LV end-diastolic volume and t is the maximal wall thickness across 16 myocardial segments) stratified hypertensive patients: no LVH, LVH with normal RI (LVHNormal-RI), and LVH with low RI (LVHLow-RI). The primary outcome was a composite of all-cause mortality, acute coronary syndromes, strokes, and decompensated heart failure. LVHLow-RI was associated with increased LV mass index, fibrosis burden, impaired myocardial function and elevated biochemical markers of myocardial injury (high-sensitive cardiac troponin I), and wall stress. Over 18.3 ± 7.0 months (601.3 patient-years), 14 adverse events occurred (2.2 events/100 patient-years). Patients with LVHLow-RI had more than a five-fold increase in adverse events compared to those with LVHNormal-RI (11.6 events/100 patient-years vs. 2.0 events/100 patient-years, respectively; log-rank P < 0.001). The RI provided incremental prognostic value over and above a model consisting of clinical variables, LVH and concentricity; and predicted adverse events independent of clinical variables, LVH, and other prognostic markers. Concentric and eccentric LVH were associated with adverse prognosis (log-rank P = 0.62) that was similar to the natural history of hypertensive LVH (5.1 events/100 patient-years). CONCLUSION: The RI provides prognostic value that improves risk stratification of hypertensive LVH.

Evaluation of the impeller shroud performance of an axial flow ventricular assist device using computational fluid dynamics.

Generally, there are two types of impeller design used in the axial flow blood pumps. For the first type, which can be found in most of the axial flow blood pumps, the magnet is embedded inside the impeller hub or blades. For the second type, the magnet is embedded inside the cylindrical impeller shroud, and this design has not only increased the rotating stability of the impeller but has also avoided the flow interaction between the impeller blade tip and the pump casing. Although the axial flow blood pumps with either impeller design have been studied individually, the comparisons between these two designs have not been conducted in the literature. Therefore, in this study, two axial flow blood pumps with and without impeller shrouds were numerically simulated with computational fluid dynamics and compared with each other in terms of hydraulic and hematologic performances. For the ease of comparison, these two models have the same inner components, which include a three-blade straightener, a two-blade impeller, and a three-blade diffuser. The simulation results showed that the model with impeller shroud had a lower static pressure head with a lower hydraulic efficiency than its counterpart. It was also found that the blood had a high possibility to deposit on the impeller shroud inner surface, which greatly enhanced the possibility of thrombus formation. The blood damage indices in both models were around 1%, which was much lower than the 13.1% of the axial flow blood pump of Yano et al. with the corresponding experimental hemolysis of 0.033 g/100 L.

Generating wall shear stress for coronary artery in real-time using neural networks: Feasibility and initial results based on idealized models.

Computational fluid dynamics (CFD) and medical imaging can be integrated to derive some important hemodynamic parameters such as wall shear stress (WSS). However, CFD suffers from a relatively long computational time that usually varies from dozens of minutes to hours. Machine learning is a popular tool that has been applied to many fields, and it can predict outcomes fast and even instantaneously in most applications. This study aims to use machine learning as an alternative to CFD for generating hemodynamic parameters in real-time diagnosis during medical examinations. To perform the feasibility study, we used CFD to model the blood flow in 2000 idealized coronary arteries, and the calculated WSS values in these models were used as the dataset for training and testing. The preparation of the dataset was automated by scripts programmed in Python, and OpenFOAM was used as the CFD solver. We have explored multivariate linear regression, multi-layer perceptron, and convolutional neural network architectures to generate WSS values from coronary artery geometry directly without CFD. These architectures were implemented in TensorFlow 2.0. Our results showed that these algorithms were able to generate results in less than 1 s, proving its capability in real-time applications, in terms of computational time. Based on the accuracy, convolutional neural network outperformed the other architectures with a normalized mean absolute error of 2.5%. Although this study is based on idealized models, to the best of our knowledge, it is the first attempt to predict WSS in a stenosed coronary artery using machine learning approaches.

Effects of left atrium on intraventricular flow in numerical simulations.

With the aid of cardiac imaging techniques, recent numerical simulations of left ventricular flow can be patient-specific to better mimic physiological conditions. However, studies with a dynamic mitral valve (MV) remain extremely limited. Even so, the left atrium (LA) is usually simplified to be tubular regardless of its complex structure. Studies on the effect of this simplification are limited and observations are controversial. In this study, both tubular and generic atriums were incorporated in patient-specific simulations with and without the MV to qualitatively and quantitatively estimate the effects of the atrial model on downstream ventricular flow. The patient-specific model was generated based on cardiac magnetic resonance (CMR) images of a healthy volunteer, and the dynamic motion of the MV was defined by the contours acquired along long-axis images. Based on the simulations, the influence of the atrial vortices on ventricular flow was significant in the valveless models in terms of flow structure, kinetic energy (KE) and circulation. Although these effects were suppressed in the presence of the MV, the atrial vortices that survived the passage were not trivial, which was evidenced by reduced strength of circulation and undesired flow pattern in the apical region. The flow structure in the generic atrium also dominated the development of ventricular flow in the valveless model. After the MV was incorporated, its effects on the downstream ventricular flow were considerably reduced but not eliminated. Therefore, a proper modelling of atrial flow is necessary, especially for subjects with high ejection fraction (EF).

Application of Patient-Specific Computational Fluid Dynamics in Coronary and Intra-Cardiac Flow Simulations: Challenges and Opportunities.

The emergence of new cardiac diagnostics and therapeutics of the heart has given rise to the challenging field of virtual design and testing of technologies in a patient-specific environment. Given the recent advances in medical imaging, computational power and mathematical algorithms, patient-specific cardiac models can be produced from cardiac images faster, and more efficiently than ever before. The emergence of patient-specific computational fluid dynamics (CFD) has paved the way for the new field of computer-aided diagnostics. This article provides a review of CFD methods, challenges and opportunities in coronary and intra-cardiac flow simulations. It includes a review of market products and clinical trials. Key components of patient-specific CFD are covered briefly which include image segmentation, geometry reconstruction, mesh generation, fluid-structure interaction, and solver techniques.

Truncations of the titin Z-disc predispose to a heart failure with preserved ejection phenotype in the context of pressure overload.

Titin (TTN) Truncating variants (TTNtv) in the A-band of TTN predispose the mouse heart to systolic dysfunction when subjected to pressure-loading. However, the effects of TTNtv of the Z-disc are largely unexplored. A rat model of pressure-loaded heart is developed by trans-aortic constriction (TAC). Rats with TTNtv of the Z-disc were randomly assigned to TAC (Z-TAC) or sham-surgery (Z-Sham) and wildtype (WT) littermates served as controls (WT-TAC or WT-Sham). Left ventricular (LV) function was assessed by echocardiography. Pressure volume (PV) loops, histology and molecular profiling were performed eight months after surgery. Pressure-load by TAC increased LV mass in all cases when compared with Sham animals. Notably, systolic function was preserved in TAC animals throughout the study period, which was confirmed by terminal PV loops. Diastolic function was impaired in Z-disc TTNtv rats at baseline as compared to WT and became impaired further after TAC (dp/dtmin, mmHg/s): Z-TAC = -3435±763, WT-TAC = -6497±1299 (p<0.01). Z-TAC animals had greater cardiac fibrosis, with elevated collagen content and decreased vascular density as compared to WT-TAC animals associated with enhanced apoptosis of myocyte and non-myocyte populations. In the context of pressure overload, Z-disc TTNtv is associated with cardiac fibrosis, diastolic dysfunction, and capillary rarefaction in the absence of overt systolic dysfunction.