The Association Between Time-Varying Wall Shear Stress and the Development of Plaque Ulcerations in Carotid Arteries From the Plaque at Risk Study

Background and Purpose: Shear stress (WSS) is involved in the pathophysiology of atherosclerotic disease and might affect plaque ulceration. In this case-control study, we compared carotid plaques that developed a new ulcer during follow-up and plaques that remained silent for their exposure to time-dependent oscillatory shear stress parameters at baseline.Materials and Methods: Eighteen patients who underwent CTA and MRI of their carotid arteries at baseline and 2 years follow-up were included. These 18 patients consisted of six patients who demonstrated a new ulcer and 12 control patients selected from a larger cohort with similar MRI-based plaque characteristics as the ulcer group. (Oscillatory) WSS parameters [time average WSS, oscillatory shear index (OSI), and relative residence time (RRT)] were calculated using computational fluid dynamics applying the MRI-based geometry of the carotid arteries and compared among plaques (wall thickness>2 mm) with and without ulceration (Mann–Whitney U test) and ulcer-site vs. non-ulcer-site within the plaque (Wilcoxon signed rank test). More detailed analysis on ulcer cases was performed and the predictive value of oscillatory WSS parameters was calculated using linear and logistic mixed-effect regression models.Results: The ulcer group demonstrated no difference in maximum WSS [9.9 (6.6–18.5) vs. 13.6 (9.7–17.7) Pa, p = 0.349], a lower maximum OSI [0.04 (0.01–0.10) vs. 0.12 (0.06–0.20) p = 0.019] and lower maximum RRT [1.25 (0.78–2.03) Pa−1 vs. 2.93 (2.03–5.28) Pa−1, p = 0.011] compared to controls. The location of the ulcer (ulcer-site) within the plaque was not always at the maximal WSS, but demonstrated higher average WSS, lower average RRT and OSI at the ulcer-site compared to the non-ulcer-sites. High WSS (WSS>4.3 Pa) and low RRT (RRT < 0.25 Pa) were associated with ulceration with an odds ratio of 3.6 [CI 2.1–6.3] and 2.6 [CI 1.54–4.44] respectively, which remained significant after adjustment for wall thickness.Conclusion: In this explorative study, ulcers were not exclusively located at plaque regions exposed to the highest WSS, OSI, or RRT, but high WSS and low RRT regions had a significantly higher odds to present ulceration within the plaque even after adjustment for wall thickness.

Effects of Patent Ductus Arteriosus on the Hemodynamics of Modified Blalock–Taussig Shunt Based on Patient-Specific Simulation

The question of preserving the patent ductus arteriosus (PDA) during the modified Blalock–Taussig shunt (MBTS) procedure remains controversial. The goal of this study was to investigate the effects of the PDA on the flow features of the MBTS to help with preoperative surgery design and postoperative prediction. In this study, a patient with pulmonary atresia and PDA was included. A patient-specific three-dimensional model was reconstructed, and virtual surgeries of shunt insertion and ductus ligation were performed using computer-aided design. Computational fluid dynamics was utilized to analyze the hemodynamic parameters of varied models based on the patient-specific anatomy and physiological data. The preservation of the PDA competitively reduced the shunt flow but increased total pulmonary perfusion. The shunt flow and ductal flow collided, causing significant and complicated turbulence in the pulmonary artery where low wall shear stress, high oscillatory shear index, and high relative residence time were distributed. The highest energy loss was found when the PDA was preserved. The preservation of PDA is not recommended during MBTS procedures because it negatively influences hemodynamics. This may lead to pulmonary overperfusion, inadequate systemic perfusion, and a heavier cardiac burden, thus increasing the risk of heart failure. Also, it seems to bring no benefit in terms of reducing the risk for thrombosis.

Presence of Left Atrial Fibrosis May Contribute to Aberrant Hemodynamics and Increased Risk of Stroke in Atrial Fibrillation Patients

Atrial fibrillation (AF) patients are at high risk of stroke, with the left atrial appendage (LAA) found to be the most common site of clot formation. Presence of left atrial (LA) fibrosis has also been associated with higher stroke risk. However, the mechanisms for increased stroke risk in patients with atrial fibrotic remodeling are poorly understood. We sought to explore these mechanisms using fluid dynamic analysis and to test the hypothesis that the presence of LA fibrosis leads to aberrant hemodynamics in the LA, contributing to increased stroke risk in AF patients. We retrospectively collected late-gadolinium-enhanced MRI (LGE-MRI) images of eight AF patients (four persistent and four paroxysmal) and reconstructed their 3D LA surfaces. Personalized computational fluid dynamic simulations were performed, and hemodynamics at the LA wall were quantified by wall shear stress (WSS, friction of blood), oscillatory shear index (OSI, temporal directional change of WSS), endothelial cell activation potential (ECAP, ratio of OSI and WSS), and relative residence time (RRT, residence time of blood near the LA wall). For each case, these hemodynamic metrics were compared between fibrotic and non-fibrotic portions of the wall. Our results showed that WSS was lower, and OSI, ECAP, and RRT was higher in the fibrotic region as compared to the non-fibrotic region, with ECAP (p = 0.001) and RRT (p = 0.002) having significant differences. Case-wise analysis showed that these differences in hemodynamics were statistically significant for seven cases. Furthermore, patients with higher fibrotic burden were exposed to larger regions of high ECAP, which represents regions of low WSS and high OSI. Consistently, high ECAP in the vicinity of the fibrotic wall suggest that local blood flow was slow and oscillating that represents aberrant hemodynamic conditions, thus enabling prothrombotic conditions for circulating blood. AF patients with high LA fibrotic burden had more prothrombotic regions, providing more sites for potential clot formation, thus increasing their risk of stroke.

Hemodynamic Comparison of Stent-Grafts for the Treatment of Aortoiliac Occlusive Disease

Purpose: To compare the flow patterns and hemodynamics of the AFX stent-graft and the covered endovascular reconstruction of aortic bifurcation (CERAB) configuration using laser particle image velocimetry (PIV) experiments. Materials and Methods: Two anatomically realistic aortoiliac phantoms were constructed using polydimethylsiloxane polymer. An AFX stent-graft with a transparent cover made with a new method was inserted into one phantom. A CERAB configuration using Atrium’s Avanta V12 with transparent covers made with a previously established method was inserted into the other phantom, both modified stent-grafts were suitable for laser PIV, enabling visualization of the flow fields and quantification of time average wall shear stress (TAWSS), oscillatory shear index (OSI), and relative residence time (RRT). Results: Disturbed flow was observed at the bifurcation region of the AFX, especially at the end systolic velocity (ESV) time-point where recirculation was noticeable due to vortical flow. In contrast, predominantly unidirectional flow was observed at the CERAB bifurcation. These observations were confirmed by the quantified hemodynamic results from PIV analysis where mean TAWSS of 0.078 Pa (range: 0.009–0.242 Pa) was significantly lower in AFX as compared with 0.229 Pa (range: 0.013–0.906 Pa) for CERAB (p<0.001). Mean OSI of 0.318 (range: 0.123–0.496) in AFX was significantly higher than 0.252 (range: 0.055–0.472) in CERAB (p<0.001). Likewise, mean RRT of 180 Pa−1 (range: 9–3603 Pa−1) in AFX was also significantly higher than 88 Pa−1 (range: 2–840 Pa−1) in CERAB (p=0.0086). Conclusion: In this in vitro study, the flow pattern of a modified AFX stent-graft was found to be more disturbed especially at the end systolic phase, its hemodynamic outcomes less desirable than CERAB configuration. Clinical Relevance: While the AFX stent-graft has an advantage over the CERAB configuration in eliminating radial mismatch, and maintaining the anatomical bifurcation for future endovascular intervention, this in vitro study revealed that the associated lower TAWSS, higher OSI and RRT may predispose to thrombosis and are, thus, less desirable as compared to a CERAB configuration. Further investigation is warranted to confirm whether these findings translate into the clinical setting.

Hemodynamic Abnormalities in the Aorta of Turner Syndrome Girls

Congenital abnormalities in girls and women with Turner syndrome (TS), alongside an underlying predisposition to obesity and hypertension, contribute to an increased risk of cardiovascular disease and ultimately reduced life expectancy. We observe that children with TS present a greater variance in aortic arch morphology than their healthy counterparts, and hypothesize that their hemodynamics is also different. In this study, computational fluid dynamic (CFD) simulations were performed for four TS girls, and three age-matched healthy girls, using patient-specific inlet boundary conditions, obtained from phase-contrast MRI data. The visualization of multidirectional blood flow revealed an increase in vortical flow in the arch, supra-aortic vessels, and descending aorta, and a correlation between the presence of aortic abnormalities and disturbed flow. Compared to the relatively homogeneous pattern of time-averaged wall shear stress (TAWSS) on the healthy aortae, a highly heterogeneous distribution with elevated TAWSS values was observed in the TS geometries. Visualization of further shear stress parameters, such as oscillatory shear index (OSI), normalized relative residence time (RRTn), and transverse WSS (transWSS), revealed dissimilar heterogeneity in the oscillatory and multidirectional nature of the aortic flow. Taking into account the young age of our TS cohort (average age 13 ± 2 years) and their obesity level (75% were obese or overweight), which is believed to accelerate the initiation and progression of endothelial dysfunction, these findings may be an indication of atherosclerotic disease manifesting earlier in life in TS patients. Age, obesity and aortic morphology may, therefore, play a key role in assessing cardiovascular risk in TS children.

Contact Map Fingerprints of Protein-Ligand Unbinding Trajectories Reveal Mechanisms Determining Residence Times Computed from Scaled Molecular Dynamics

<div>The binding kinetic properties of potential drugs may significantly influence their subsequent clinical efficacy. Predictions of these properties based on computer simulations provide a useful alternative to their expensive and time-demanding experimental counterparts, even at an early drug discovery stage.</div><div>Herein, we perform Scaled Molecular Dynamics (ScaledMD) simulations on a set of 27 ligands of HSP90 belonging to more than 7 chemical series in order to estimate their relative residence time. We introduce two new techniques for the analysis and the classification of the simulated unbinding trajectories. The first technique, which helps in estimating the limits of the free energy well around the bound state and the second one, based on a new contact map fingerprint, allows the description and the comparison of the paths that lead to unbinding.</div><div>Using these analyses, we find that ScaledMD’s relative residence time generally enables the identification of the slowest unbinders. We propose an explanation for the underestimation of the residence times of a subset of compounds and we investigate how the biasing in ScaledMD can affect the mechanistic insights that can be gained from the simulations.</div>

Contact Map Fingerprints of Protein-Ligand Unbinding Trajectories Reveal Mechanisms Determining Residence Times Computed from Scaled Molecular Dynamics

<div>The binding kinetic properties of potential drugs may significantly influence their subsequent clinical efficacy. Predictions of these properties based on computer simulations provide a useful alternative to their expensive and time-demanding experimental counterparts, even at an early drug discovery stage.</div><div>Herein, we perform Scaled Molecular Dynamics (ScaledMD) simulations on a set of 27 ligands of HSP90 belonging to more than 7 chemical series in order to estimate their relative residence time. We introduce two new techniques for the analysis and the classification of the simulated unbinding trajectories. The first technique, which helps in estimating the limits of the free energy well around the bound state and the second one, based on a new contact map fingerprint, allows the description and the comparison of the paths that lead to unbinding.</div><div>Using these analyses, we find that ScaledMD’s relative residence time generally enables the identification of the slowest unbinders. We propose an explanation for the underestimation of the residence times of a subset of compounds and we investigate how the biasing in ScaledMD can affect the mechanistic insights that can be gained from the simulations.</div>

Study of Coronary Atherosclerosis Using Blood Residence Time

Computational fluid dynamic-based modeling is commonly used in stenosed and stented coronary artery to characterize blood flow and identify hemodynamics factors that could lead to coronary stenosis. One such factor is the residence time (RT), which is important for investigating stenosis and restenosis progression. The current method to calculate RT, known as the relative residence time (RRT) method, does not provide the original scale of RT and only provides a relative value. We recently introduced a novel method, designated as RT method, based on developing the advection-diffusion equation with a scalar to calculate the absolute residence time. The goal of this study was to compare both methods. Our results show that both could detect regions with a high risk of stenosis and restenosis, but the RT method is also able to show the recirculation zone using pathlines in the lumen and quantify actual RT. Moreover, RT method also provided blood flow pathlines, and is correlated to wall shear stress (WSS), oscillatory shear index (OSI), RRT, and Localized Normalized Helicity (LNH) which are other critical factors to gauge stenosis severity and assess stenting in bifurcations coronary.

Hemodynamic Parameters Predict In-stent Thrombosis After Multibranched Endovascular Repair of Complex Abdominal Aortic Aneurysms: A Retrospective Study of Branched Stent-Graft Thrombosis

Background: Branch vessel occlusion is reported in endovascular repair of aortic pathology. This study aimed to evaluate the hemodynamic indicators associated with in-stent thrombosis (IST) of a branched stent-graft (BSG) after endovascular aortic repair (EVAR) of a complex abdominal aortic aneurysm.Methods: A retrospective evaluation was performed based on the computed tomography (CT) scans and clinical data of three patients who underwent multi-branched endovascular repair. Patient-specific 3-dimensional models were reconstructed, and hemodynamic analysis was performed for IST. Hemodynamics-related parameters including time-averaged wall shear stress (TAWSS), oscillatory shear stress index (OSI), and relative residence time (RRT) were compared among the individual patients.Results: The flow velocity, TAWSS, OSI, and RRT were radically changed in the area of the IST. In BSGs, IST tended to occur in the regions of hemodynamic alteration near the bends in the device, where a decreased flow velocity (&lt;0.6 m/s) and TAWSS (&lt;0.8 Pa) and an elevated OSI (&gt;0.2) and RRT (&gt;5 s) were consistently observed.Conclusions: Hemodynamic perturbations in BSGs cause a predisposition to IST, which can be predicted by a series of changes in the flow parameters. Early hemodynamic analysis might be useful for identifying and remediating IST after multibranched endovascular repair.

Impact of Malapposed and Overlapping Stents on Hemodynamics: A 2D Parametric Computational Fluid Dynamics Study

Despite significant progress, malapposed or overlapped stents are a complication that affects daily percutaneous coronary intervention (PCI) procedures. These malapposed stents affect blood flow and create a micro re-circulatory environment. These disturbances are often associated with a change in Wall Shear Stress (WSS), Time-averaged WSS (TAWSS), relative residence time (RRT) and oscillatory character of WSS and disrupt the delicate balance of vascular biology, providing a possible source of thrombosis and restenosis. In this study, 2D axisymmetric parametric computational fluid dynamics (CFD) simulations were performed to systematically analyze the hemodynamic effects of malapposition and stent overlap for two types of stents (drug-eluting stent and a bioresorbable stent). The results of the modeling are mainly analyzed using streamlines, TAWSS, oscillatory shear index (OSI) and RRT. The risks of restenosis and thrombus are evaluated according to commonly accepted thresholds for TAWSS and OSI. The small malapposition distances (MD) cause both low TAWSS and high OSI, which are potential adverse outcomes. The region of low OSI decrease with MD. Overlap configurations produce areas with low WSS and high OSI. The affected lengths are relatively insensitive to the overlap distance. The effects of strut size are even more sensitive and adverse for overlap configurations compared to a well-applied stent.