Computational modeling of blood component transport related to coronary artery thrombosis in Kawasaki disease.

Coronary artery thrombosis is the major risk associated with Kawasaki disease (KD). Long-term management of KD patients with persistent aneurysms requires a thrombotic risk assessment and clinical decisions regarding the administration of anticoagulation therapy. Computational fluid dynamics has demonstrated that abnormal KD coronary artery hemodynamics can be associated with thrombosis. However, the underlying mechanisms of clot formation are not yet fully understood. Here we present a new model incorporating data from patient-specific simulated velocity fields to track platelet activation and accumulation. We use a system of Reaction-Advection-Diffusion equations solved with a stabilized finite element method to describe the evolution of non-activated platelets and activated platelet concentrations [AP], local concentrations of adenosine diphosphate (ADP) and poly-phosphate (PolyP). The activation of platelets is modeled as a function of shear-rate exposure and local concentration of agonists. We compared the distribution of activated platelets in a healthy coronary case and six cases with coronary artery aneurysms caused by KD, including three with confirmed thrombosis. Results show spatial correlation between regions of higher concentration of activated platelets and the reported location of the clot, suggesting predictive capabilities of this model towards identifying regions at high risk for thrombosis. Also, the concentration levels of ADP and PolyP in cases with confirmed thrombosis are higher than the reported critical values associated with platelet aggregation (ADP) and activation of the intrinsic coagulation pathway (PolyP). These findings suggest the potential initiation of a coagulation pathway even in the absence of an extrinsic factor. Finally, computational simulations show that in regions of flow stagnation, biochemical activation, as a result of local agonist concentration, is dominant. Identifying the leading factors to a pro-coagulant environment in each case-mechanical or biochemical-could help define improved strategies for thrombosis prevention tailored for each patient.

Decoding thrombosis through code: a review of computational models.

From the molecular level up to a blood vessel, thrombosis and hemostasis involves many interconnected biochemical and biophysical processes over a wide range of length and time scales. Computational modeling has gained eminence in offering insights into these processes beyond what can be obtained from in vitro or in vivo experiments, or clinical measurements. The multiscale and multiphysics nature of thrombosis has inspired a wide range of modeling approaches that aim to address how a thrombus forms and dismantles. Here, we review recent advances in computational modeling with a focus on platelet-based thrombosis. We attempt to summarize the diverse range of modeling efforts straddling the wide-spectrum of physical phenomena, length scales, and time scales; highlighting key advancements and insights from existing studies. Potential information gleaned from models is discussed, ranging from identification of thrombus-prone regions in patient-specific vasculature to modeling thrombus deformation and embolization in response to fluid forces. Furthermore, we highlight several limitations of current models, future directions in the field, and opportunities for clinical translation, to illustrate the state-of-the-art. There are a plethora of opportunity areas for which models can be expanded, ranging from topics of thromboinflammation to platelet production and clearance. Through successes demonstrated in existing studies described here, as well as continued advancements in computational methodologies and computer processing speeds and memory, in silico investigations in thrombosis are poised to bring about significant knowledge growth in the years to come.

Integrating local and distant radiation-induced lung injury: Development and validation of a predictive model for ventilation loss.

BACKGROUND: Investigations on radiation-induced lung injury (RILI) have predominantly focused on local effects, primarily those associated with radiation damage to lung parenchyma. However, recent studies from our group and others have revealed that radiation-induced damage to branching serial structures such as airways and vessels may also have a substantial impact on post-radiotherapy (RT) lung function. Furthermore, recent results from multiple functional lung avoidance RT trials, although promising, have demonstrated only modest toxicity reduction, likely because they were primarily focused on dose avoidance to lung parenchyma. These observations emphasize the critical need for predictive dose-response models that effectively incorporate both local and distant RILI effects. PURPOSE: We develop and validate a predictive model for ventilation loss after lung RT. This model, referred to as P+A, integrates local (parenchyma [P]) and distant (central and peripheral airways [A]) radiation-induced damage, modeling partial (narrowing) and complete (collapse) obstruction of airways. METHODS: In an IRB-approved prospective study, pre-RT breath-hold CTs (BHCTs) and pre- and one-year post-RT 4DCTs were acquired from lung cancer patients treated with definitive RT. Up to 13 generations of airways were automatically segmented on the BHCTs using a research virtual bronchoscopy software. Ventilation maps derived from the 4DCT scans were utilized to quantify pre- and post-RT ventilation, serving, respectively, as input data and reference standard (RS) in model validation. To predict ventilation loss solely due to parenchymal damage (referred to as P model), we used a normal tissue complication probability (NTCP) model. Our model used this NTCP-based estimate and predicted additional loss due radiation-induced partial or complete occlusion of individual airways, applying fluid dynamics principles and a refined version of our previously developed airway radiosensitivity model. Predictions of post-RT ventilation were estimated in the sublobar volumes (SLVs) connected to the terminal airways. To validate the model, we conducted a k-fold cross-validation. Model parameters were optimized as the values that provided the lowest root mean square error (RMSE) between predicted post-RT ventilation and the RS for all SLVs in the training data. The performance of the P+A and the P models was evaluated by comparing their respective post-RT ventilation values with the RS predictions. Additional evaluation using various receiver operating characteristic (ROC) metrics was also performed. RESULTS: We extracted a dataset of 560 SLVs from four enrolled patients. Our results demonstrated that the P+A model consistently outperformed the P model, exhibiting RMSEs that were nearly half as low across all patients (13 ± 3 percentile for the P+A model vs. 24 ± 3 percentile for the P model on average). Notably, the P+A model aligned closely with the RS in ventilation loss distributions per lobe, particularly in regions exposed to doses ≥13.5 Gy. The ROC analysis further supported the superior performance of the P+A model compared to the P model in sensitivity (0.98 vs. 0.07), accuracy (0.87 vs. 0.25), and balanced predictions. CONCLUSIONS: These early findings indicate that airway damage is a crucial factor in RILI that should be included in dose-response modeling to enhance predictions of post-RT lung function.

Longitudinal investigation of aortic dissection in mice with computational fluid dynamics.

Predicting late adverse events in aortic dissections is challenging. One commonly observed risk factor is partial thrombosis of the false lumen. In this study we investigated false lumen thrombus progression over 7 days in four mice with angiotensin II-induced aortic dissection. We performed computational fluid dynamic simulations with subject-specific boundary conditions from velocity and pressure measurements. We investigated endothelial cell activation potential, mean velocity, thrombus formation potential, and other hemodynamic factors. Our findings support the hypothesis that flow stagnation is the predominant hemodynamic factor driving a large thrombus ratio in false lumina, particularly those with a single fenestration.

A 1D-3D Hybrid Model of Patient-Specific Coronary Hemodynamics.

PURPOSE: Coronary flow is affected by evolving events such as atherosclerotic plaque formation, rupture, and thrombosis, resulting in myocardial ischemia and infarction. Highly resolved 3D hemodynamic data at the stenosis is essential to model shear-sensitive thrombotic events in coronary artery disease. METHODS: We developed a hybrid 1D-3D simulation framework to compute patient-specific coronary hemodynamics efficiently. A 1D model of the coronary flow is coupled to an image-based 3D model of the region of interest. This framework affords the advantages of reduced-order modeling, decreasing the global computational cost, without sacrificing the accuracy of the quantities of interest. RESULTS: We validated our 1D-3D model against full 3D coronary simulations in healthy and diseased conditions. Our results showed good agreement between the 3D and the 1D-3D models while reducing the computational cost by 40-fold compared to the 3D simulation. The 1D-3D model predicted left/right coronary flow distribution within 3% and provided an accurate estimation of fractional flow reserve and wall shear stress distribution at the stenosis comparable to the 3D simulation. CONCLUSION: Savings in computational cost may be significant in situations with changing geometry, such as growing thrombosis. Also, this approach would allow quantifying the time-dependent effect of thrombotic growth and occlusion on the global coronary circulation.

Thrombosis and Hemodynamics: external and intrathrombus gradients.

Distinct from dilute, isotropic, and homogeneous reaction systems typically used in laboratory kinetic assays, blood is concentrated, two-phase, flowing, and highly anisotropic when clotting on a surface. This review focuses on spatial gradients that are generated and can dictate thrombus structure and function. Novel experimental and computational tools have recently emerged to explore reaction-transport coupling during clotting. Multiscale simulations help bridge tissue length scales (the coronary arteries) to millimeter scales of a growing clot to the microscopic scale of single-cell signaling and adhesion. Microfluidic devices help create and control pathological velocity profiles, albeit at a low Reynolds number. Since rate processes and force loading are often coupled, this review highlights prevailing convective-diffusive transport physics that modulate cellular and molecular processes during thrombus formation.

Hemodynamic variables in aneurysms are associated with thrombotic risk in children with Kawasaki disease.

BACKGROUND: Thrombosis is a major adverse outcome associated with coronary artery aneurysms (CAAs) resulting from Kawasaki disease (KD). Clinical guidelines recommend initiation of anticoagulation therapy with maximum CAA diameter (Dmax) ≥8 mm or Z-score ≥ 10. Here, we investigate the role of aneurysm hemodynamics as a superior method for thrombotic risk stratification in KD patients. METHODS AND RESULTS: We retrospectively studied ten KD patients with CAAs, including five patients who developed thrombosis. We constructed patient-specific anatomic models from cardiac magnetic resonance images and performed computational hemodynamic simulations using SimVascular. Our simulations incorporated pulsatile flow, deformable arterial walls and boundary conditions automatically tuned to match patient-specific arterial pressure and cardiac output. From simulation results, we derived local hemodynamic variables including time-averaged wall shear stress (TAWSS), low wall shear stress exposure, and oscillatory shear index (OSI). Local TAWSS was significantly lower in CAAs that developed thrombosis (1.2 ±â€¯0.94 vs. 7.28 ±â€¯9.77 dynes/cm2, p = 0.006) and the fraction of CAA surface area exposed to low wall shear stress was larger (0.69 ±â€¯0.17 vs. 0.25 ±â€¯0.26%, p = 0.005). Similarly, longer residence times were obtained in branches where thrombosis was confirmed (9.07 ±â€¯6.26 vs. 2.05 ±â€¯2.91 cycles, p = 0.004). No significant differences were found for OSI or anatomical measurements such us Dmax and Z-score. Assessment of thrombotic risk according to hemodynamic variables had higher sensitivity and specificity compared to standard clinical metrics (Dmax, Z-score). CONCLUSIONS: Hemodynamic variables can be obtained non-invasively via simulation and may provide improved thrombotic risk stratification compared to current diameter-based metrics, facilitating long-term clinical management of KD patients with persistent CAAs.

Assessment of Coronary Artery Aneurysms Caused by Kawasaki Disease Using Transluminal Attenuation Gradient Analysis of Computerized Tomography Angiograms.

Patients with coronary artery aneurysms (CAAs) resulting from Kawasaki disease (KD) are at risk for thrombosis and myocardial infarction. Current guidelines recommend CAA diameter ≥8 mm as the criterion for initiating systemic anticoagulation. Transluminal attenuation gradient (TAG) analysis has been proposed as a noninvasive method for evaluating functional significance of coronary stenoses using computerized tomography angiography (CTA), but has not previously been used in CAA. We hypothesized that abnormal hemodynamics in CAA caused by KD could be quantified using TAG analysis. We studied 23 patients with a history of KD who had undergone clinically indicated CTA. We quantified TAG in the major coronary arteries and aneurysm geometry was characterized using maximum diameter, aneurysm shape index, and sphericity index. A total of 55 coronary arteries were analyzed, 25 of which had at least 1 aneurysmal region. TAG in aneurysmal arteries was significantly lower than in normal arteries (-23.5 ± 10.7 vs -10.5 ± 9.0, p = 0.00002). Aneurysm diameter, aneurysm shape index, and sphericity index were weakly correlated with TAG (r2 = 0.01, p = 0.6; r2 = 0.15, p = 0.06; r2 = 0.16, p = 0.04). This is the first application of TAG analysis to CAA caused by KD, and demonstrates significantly different TAG values in aneurysmal versus normal arteries. Lack of correlation between TAG and CAA geometry suggests that TAG may provide hemodynamic information not available from anatomy alone. TAG represents a possible extension to standard CTA for KD patients who may improve thrombotic risk stratification and aid in clinical decision making.

Intraocular and intracranial pressures during head-down tilt with lower body negative pressure.

BACKGROUND: Seven astronauts after 6-mo missions to the International Space Station showed unexpected vision problems. Lumbar punctures performed in the four astronauts with optic disc edema showed moderate elevations of cerebral spinal fluid pressure after returning to Earth. We hypothesized that lower body negative pressure (LBNP) imposed during head-down tilt (HDT) would reduce intraocular pressure (IOP) and transcranial ultrasound pulse amplitude, a noninvasive intracranial pressure (ICP) surrogate. METHODS: Participating in this study were 25 normal healthy nonsmoking volunteers (mean age: 36 yr). Subjects were positioned supine (5 min), sitting (5 min), 15° whole body HDT (5 min), and 10 min of HDT with LBNP (25 mmHg). The order of HDT and HDT+LBNP tests was balanced. Right and left IOP, transcranial ultrasound pulse amplitude, arm blood pressure, and heart rate were measured during the last minute (steady state) of each testing condition. RESULTS: IOP significantly decreased from supine to sitting posture by 3.2 ± 1.4 mmHg (mean ± SD: N = 25), and increased by 0.9 ± 1.3 mmHg from supine to the HDT position. LBNP during HDT significantly lowered IOP to supine levels. In addition, LBNP significantly reduced transcranial ultrasound pulse amplitudes by 38% as compared to the HDT condition (N = 9). Sitting mean blood pressure (BP) was significantly higher (+5 mmHg) than BP values after 10 min of LBNP during HDT. However, heart rate was not significantly different across all conditions. DISCUSSION: These data suggest that short duration exposures to LBNP attenuate HDT-induced increases in IOP and ICP. Macias BR, Liu JHK, Grande-Gutierrez N, Hargens AR. Intraocular and intracranial pressures during head-down tilt with lower body negative pressure.