Non-invasive estimation of the parameters of a three-element windkessel model of aortic arch arteries in patients undergoing thoracic endovascular aortic repair.

Background: Image-based computational hemodynamic modeling and simulations are important for personalized diagnosis and treatment of cardiovascular diseases. However, the required patient-specific boundary conditions are often not available and need to be estimated. Methods: We propose a pipeline for estimating the parameters of the popular three-element Windkessel (WK3) models (a proximal resistor in series with a parallel combination of a distal resistor and a capacitor) of the aortic arch arteries in patients receiving thoracic endovascular aortic repair of aneurysms. Pre-operative and post-operative 1-week duplex ultrasound scans were performed to obtain blood flow rates, and intra-operative pressure measurements were also performed invasively using a pressure transducer pre- and post-stent graft deployment in arch arteries. The patient-specific WK3 model parameters were derived from the flow rate and pressure waveforms using an optimization algorithm reducing the error between simulated and measured pressure data. The resistors were normalized by total resistance, and the capacitor was normalized by total resistance and heart rate. The normalized WK3 parameters can be combined with readily available vessel diameter, brachial blood pressure, and heart rate data to estimate WK3 parameters of other patients non-invasively. Results: Ten patients were studied. The medians (interquartile range) of the normalized proximal resistor, distal resistor, and capacitor parameters are 0.10 (0.07-0.15), 0.90 (0.84-0.93), and 0.46 (0.33-0.58), respectively, for common carotid artery; 0.03 (0.02-0.04), 0.97 (0.96-0.98), and 1.91 (1.63-2.26) for subclavian artery; 0.18 (0.08-0.41), 0.82 (0.59-0.92), and 0.47 (0.32-0.85) for vertebral artery. The estimated pressure showed fairly high tolerance to patient-specific inlet flow rate waveforms using the WK3 parameters estimated from the medians of the normalized parameters. Conclusion: When patient-specific outflow boundary conditions are not available, our proposed pipeline can be used to estimate the WK3 parameters of arch arteries.

Distinct Temporal Pattern of the Prediction of Lumen Remodeling of Lower Extremity Vein Bypass Grafts by Initial Local Hemodynamics.

We predicted human lower extremity vein bypass graft remodeling by hemodynamics. Computed tomography and duplex ultrasound scans of 55 patients were performed at 1 week and 1, 6, and 12 months post-implantation to obtain wall shear stress (WSS) and oscillatory shear index (OSI) at 1-mm intervals via computational fluid dynamics simulations. Graft remodeling was quantified by computed tomography-measured lumen diameter changes in the early (1 week-1 month), intermediate (1-6 months), and late (6-12 months) periods. Linear mixed-effect models were constructed to examine the overall relationship between remodeling and initial hemodynamics using the average data of all cross sections within the same graft. A significant association of graft remodeling with WSS (p < 0.001) and time (p = 0.001) was found; however, the effect size decreased with time (every 2.7 dyne/cm2 increase of WSS was associated with a 0.39, 0.35, 0.002 mm diameter increase in the three periods, respectively). The association of remodeling with OSI was significant only in the intermediate period (every 0.1 increase of OSI was associated with a 0.25 mm lumen diameter decrease, p = 0.004). Therefore, the association of graft lumen remodeling with local hemodynamics has a distinct temporal pattern; WSS and OSI are predictive of remodeling only in certain postoperative periods.

Heterogeneous and dynamic lumen remodeling of the entire infrainguinal vein bypass grafts in patients.

OBJECTIVE: To examine the regional variation and temporal change in lumen size along the entire autogenous vein bypass graft used for treating arterial occlusive disease in lower extremity and to explore the factors associated with graft expansive or constrictive remodeling. METHODS: Patients were prospectively scanned using contrast-enhanced computed tomography at 1 week and 1, 6, and 12 months postoperatively to obtain lumen cross-sectional areas at 1-mm intervals along the entire grafts. Graft lumen remodeling characteristics and the associated demographic and clinical factors were examined. RESULTS: Fifty-six patients with at least two consecutive computed tomography scans were analyzed. Patients with a composite or longer graft, or with diabetes, had a larger lumen cross-sectional area variation along the graft. The mean lumen cross-sectional areas of all the grafts demonstrated no significant changes through 12 months. However, individually, graft remodeling was time dependent and there was a more dramatic change in lumen cross-sectional area within the first postoperative month. At 12 months, a near equal distribution between expansive and constrictive grafts existed. A negative relation between the initial lumen diameters and the subsequent lumen diameter changes was observed. Eleven grafts failed within 12 months; failed and patent grafts had similar mean lumen cross-sectional areas at all four time points, but failed grafts had a larger maximal local cross-sectional area reduction from 1 week to 1 month (58.0 ± 6.7% vs 38.1 ± 3.1%, mean ± standard error of the mean, failed vs patent, P = .004). Black patients had a smaller mean lumen cross-sectional area than white patients at all four time points and also had a higher early percent mean area reduction (-20.5 ± 6.3% vs -1.0 ± 3.7%, black vs white, P = .018). Cilostazol use was associated with early expansive graft remodeling. CONCLUSIONS: Vein grafts remodel heterogeneously and dynamically. Remodeling is associated with initial graft lumen size, race, and cilostazol use. It is found that remodeling that produces some critical minimum area or maximal percent reduction during the first postoperative month may predispose to vein graft failure. These findings offer insight into further investigation to examine the underlying mechanisms and opportunities to improve graft remodeling and durability.

Haemodynamics of Different Configurations of a Left Subclavian Artery Stent Graft for Thoracic Endovascular Aortic Repair.

OBJECTIVE: Branched stent grafts represent a viable option for left subclavian artery (LSA) revascularisation in patients treated by thoracic endovascular aortic repair (TEVAR) for Zone 2 lesions. This study investigated the haemodynamic performance of different LSA branched stent graft configurations as potential determinants of thrombotic and stroke risks. METHODS: A three dimensional aortic arch geometry extracted from post-operative computed tomography images of a TEVAR patient using a single LSA branched aortic endograft was modified in silico to obtain ten potential LSA branched stent graft configurations: five down facing (0-5 - 10 mm aortic protrusion with 10-12 mm internal diameter), four curved (30-60° with antegrade/retrograde orientation), and one LSA orifice misalignment. The 0 mm down facing stent graft was considered base configuration. Computational fluid dynamic analyses were performed to identify differences in pressure, energy, and wall shear stress (WSS) based parameters. RESULTS: Total pressure drop and energy loss variations among configurations were not greater than 5 mmHg (6% of mean arterial pressure) and 5.7 mW (0.7% of cardiac power), respectively. Protrusions up to 5 mm created clinically insignificant flow disturbances. However, stent graft protrusions further into the aortic lumen created more complex haemodynamics, characterised by larger energy loss and more prominent flow recirculation. Protrusion greater than 5 mm into the lumen was associated with larger areas of elevated maximum WSS (>20 Pa) along the outer surface of the branched stent graft. CONCLUSION: Arterial haemodynamic characteristics are affected by LSA branched stent graft configurations, with pressure drops and energy losses likely to be clinically insignificant. The length of the stent graft protrusion into the aortic lumen generated the largest haemodynamic variations in the aortic system. Protrusions up to 5 mm have smaller risk of potential thrombus generation. Conversely, larger protrusions into the aortic lumen showed more disturbed haemodynamics, suggesting a greater risk of potential thrombus formation, which may be clinically important over time.

Anatomic and hemodynamic investigation of an occluded common carotid chimney stent graft for hybrid thoracic aortic aneurysm repair.

We examined the possible reasons for common carotid artery chimney stent graft occlusion through computational fluid dynamics analyses of follow-up imaging of a patient-specific aortic configuration reconstructed from computed tomography aortography. Anatomic and hemodynamic parameters were extracted for the bilateral common carotid and subclavian arteries before and after endograft placement. Results suggested that postoperative reduction in lumen diameter within the chimney stent graft combined with an increased flow rate led to complex hemodynamics with high wall shear stress, probably resulting in high-shear thrombogenesis and chimney stent graft occlusion 2.6 years after the primary repair. Early postoperative duplex ultrasound imaging might help identify at-risk conditions.

Hemodynamic and Anatomic Predictors of Renovisceral Stent-Graft Occlusion Following Chimney Endovascular Repair of Juxtarenal Aortic Aneurysms.

PURPOSE: To identify anatomic and hemodynamic changes associated with impending visceral chimney stent-graft occlusion after endovascular aneurysm repair (EVAR) with the chimney technique (chEVAR). METHODS: A retrospective evaluation was performed of computed tomography scans from 41 patients who underwent juxtarenal chEVAR from 2008 to 2012 to identify stent-grafts demonstrating conformational changes following initial placement. Six subjects (mean age 74 years; 3 men) were selected for detailed reconstruction and computational hemodynamic analysis; 4 had at least 1 occluded chimney stent-graft. This subset of repairs was systematically analyzed to define the anatomic and hemodynamic impact of these changes and identify signature patterns associated with impending renovisceral stent-graft occlusion. Spatial and temporal analyses of cross-sectional area, centerline angle, intraluminal pressure, and wall shear stress (WSS) were performed within the superior mesenteric and renal artery chimney grafts used for repair. RESULTS: Conformational changes in the chimney stent-grafts and associated perturbations, in both local WSS and pressure, were responsible for the 5 occlusions in the 13 stented branches. Anatomic and hemodynamic signatures leading to occlusion were identified within 1 month postoperatively, with a lumen area <14 mm2 (p=0.04), systolic pressure gradient >25 Pa/mm (p=0.03), and systolic WSS >45 Pa (p=0.03) associated with future chimney stent-graft occlusion. CONCLUSION: Chimney stent-grafts at increased risk for occlusion demonstrated anatomic and hemodynamic signatures within 1 month of juxtarenal chEVAR. Analysis of these parameters in the early postoperative period may be useful for identifying and remediating these high-risk stent-grafts.

Hemodynamic Influence on Smooth Muscle Cell Kinetics and Phenotype During Early Vein Graft Adaptation.

Pathologic vascular adaptation following local injury is the primary driver for accelerated intimal hyperplasia and an occlusive phenotype. Smooth muscle cell (SMC) proliferation within the wall, and migration into the developing intima, is a major component of this remodeling response. The primary objective in the current study was to investigate the effect of the local biomechanical forces on early vein graft adaptation, specifically focusing on the spatial and temporal response of SMC proliferation and conversion from a contractile to synthetic architecture. Taking advantage of the differential adaptation that occurs during exposure to divergent flow environments, vein grafts were implanted in rabbits to create two distinct flow environments and harvested at times ranging from 2 h to 28 days. Using an algorithm for the virtual reconstruction of unfixed, histologic specimens, immunohistochemical tracking of DNA synthesis, and high-throughput transcriptional analysis, the spatial and temporal changes in graft morphology, cell proliferation, and SMC phenotype were catalogued. Notable findings include a burst of cell proliferation at 7 days post-implantation, which was significantly augmented by exposure to a reduced flow environment. Compared to the adjacent media, proliferation rates were 3-fold greater in the intima, and a specific spatial distribution of these proliferating cells was identified, with a major peak in the sub-endothelial region and a second peak centering on the internal elastic lamina. Genomic markers of a contractile SMC phenotype were reduced as early as 2 h post-implantation and reached a nadir at 7 days. Network analysis of upstream regulatory pathways identified GATA6 and KLF5 as important transcription factors that regulate this shift in SMC phenotype.

Multi-scale Modeling of the Cardiovascular System: Disease Development, Progression, and Clinical Intervention.

Cardiovascular diseases (CVDs) are the leading cause of death in the western world. With the current development of clinical diagnostics to more accurately measure the extent and specifics of CVDs, a laudable goal is a better understanding of the structure-function relation in the cardiovascular system. Much of this fundamental understanding comes from the development and study of models that integrate biology, medicine, imaging, and biomechanics. Information from these models provides guidance for developing diagnostics, and implementation of these diagnostics to the clinical setting, in turn, provides data for refining the models. In this review, we introduce multi-scale and multi-physical models for understanding disease development, progression, and designing clinical interventions. We begin with multi-scale models of cardiac electrophysiology and mechanics for diagnosis, clinical decision support, personalized and precision medicine in cardiology with examples in arrhythmia and heart failure. We then introduce computational models of vasculature mechanics and associated mechanical forces for understanding vascular disease progression, designing clinical interventions, and elucidating mechanisms that underlie diverse vascular conditions. We conclude with a discussion of barriers that must be overcome to provide enhanced insights, predictions, and decisions in pre-clinical and clinical applications.

Rule-based model of vein graft remodeling.

When vein segments are implanted into the arterial system for use in arterial bypass grafting, adaptation to the higher pressure and flow of the arterial system is accomplished thorough wall thickening and expansion. These early remodeling events have been found to be closely coupled to the local hemodynamic forces, such as shear stress and wall tension, and are believed to be the foundation for later vein graft failure. To further our mechanistic understanding of the cellular and extracellular interactions that lead to global changes in tissue architecture, a rule-based modeling method is developed through the application of basic rules of behaviors for these molecular and cellular activities. In the current method, smooth muscle cell (SMC), extracellular matrix (ECM), and monocytes are selected as the three components that occupy the elements of a grid system that comprise the developing vein graft intima. The probabilities of the cellular behaviors are developed based on data extracted from in vivo experiments. At each time step, the various probabilities are computed and applied to the SMC and ECM elements to determine their next physical state and behavior. One- and two-dimensional models are developed to test and validate the computational approach. The importance of monocyte infiltration, and the associated effect in augmenting extracellular matrix deposition, was evaluated and found to be an important component in model development. Final model validation is performed using an independent set of experiments, where model predictions of intimal growth are evaluated against experimental data obtained from the complex geometry and shear stress patterns offered by a mid-graft focal stenosis, where simulation results show good agreements with the experimental data.

Reconstructing regulatory networks from the dynamic plasticity of gene expression by mutual information.

The capacity of an organism to respond to its environment is facilitated by the environmentally induced alteration of gene and protein expression, i.e. expression plasticity. The reconstruction of gene regulatory networks based on expression plasticity can gain not only new insights into the causality of transcriptional and cellular processes but also the complex regulatory mechanisms that underlie biological function and adaptation. We describe an approach for network inference by integrating expression plasticity into Shannon's mutual information. Beyond Pearson correlation, mutual information can capture non-linear dependencies and topology sparseness. The approach measures the network of dependencies of genes expressed in different environments, allowing the environment-induced plasticity of gene dependencies to be tested in unprecedented details. The approach is also able to characterize the extent to which the same genes trigger different amounts of expression in response to environmental changes. We demonstrated the usefulness of this approach through analysing gene expression data from a rabbit vein graft study that includes two distinct blood flow environments. The proposed approach provides a powerful tool for the modelling and analysis of dynamic regulatory networks using gene expression data from distinct environments.

The dynamics of vein graft remodeling induced by hemodynamic forces: a mathematical model.

Although vein bypass grafting is one of the primary options for the treatment of arterial occlusive disease and provides satisfactory results at an early stage of the treatment, the patency is limited to a few months in many patients. When the vein is implanted in the arterial system, it adapts to the high flow rate and high pressure of the arterial environment by changing the sizes of its layers, and this remodeling is believed to be a precursor of future graft failure. Hemodynamic forces, such as wall shear stress (WSS) and wall tension, have been recognized as major factors impacting vein graft remodeling. Although a wide range of experimental evidence relating hemodynamic forces to vein graft remodeling has been reported, a comprehensive mathematical model describing the relationship among WSS, wall tension, and the structural adaptation of each individual layer of the vein graft wall is lacking. The current manuscript presents a comprehensive and robust framework for treating the complex interaction between the WSS, wall tension, and the structural adaptation of each individual layer of the vein graft wall. We modeled the intimal and medial area and the radius of external elastic lamina, which in combination dictate luminal narrowing and the propensity for graft occlusion. Central to our model is a logistic relationship between independent and dependent variables to describe the initial increase and later decrease in the growth rate. The detailed understanding of the temporal changes in vein graft morphology that can be extracted from the current model is critical in identifying the dominant contributions to vein graft failure and the further development of strategies to improve their longevity.

Development of a calcium alginate tympanostomy tube.

OBJECTIVES/HYPOTHESIS: Tympanostomy tubes (TTs) are prone to complications resulting in part from the unpredictable duration that the TT remains in the tympanic membrane. General anesthesia may be necessary to remove TTs that fail to extrude. The purpose of this study was to develop a TT that could be dissolved on demand but remain functional with exposure to common otologic exposures. STUDY DESIGN: Prospective in vitro analysis. METHODS: Dissolvable TTs were developed from calcium alginate. Mechanical properties and occlusion susceptibility were optimized by varying ingredient concentrations and compared to commonly used commercial TTs using in vitro measures. RESULTS: Alginate TTs had a greater compressive strength than commercial silicone tubes. TTs composed of 0.5 M CaCl were stronger than high molarity CaCl concentrations. Uncoated alginate TTs showed a 20% reduction in occlusion propensity. Exposure of alginate TTs to otological solutions for 24 hours resulted in degradation of their mechanical properties, but they remained superior to commercial silicone TTs. CONCLUSIONS: Alginate TTs appear to be a good alternative to commercial tubes based on high mechanical strength and low occlusion propensity. Furthermore, unlike commercial TTs, alginate TTs have the potential to be dissolved in vivo if retained.

In vitro testing of tympanostomy tube occlusion.

OBJECTIVE: Tympanostomy tubes (TTs) are commonly rendered nonfunctional by mucus plug formation. The purpose of this study was to determine whether an in vitro model could be developed to assess TT plug formation with results consistent with human trials. STUDY DESIGN: An ear chamber was designed to mimic middle ear air and mucus flow conditions in post-TT otorrhea. TT occlusion was tested and correlated to published in vivo results. METHODS: TTs that had previously been studied in vivo (Goode "T" and Reuter Bobbin collar buttons) were placed in the model chamber. Pooled, homogenized human middle ear mucus and an analog, egg white, were delivered at 80 muL per hour through the TTs. An air bolus was delivered every two minutes to simulate swallowing. Chamber pressure was monitored over 2.5 hours. Occlusion was determined by a pressure peak and visual confirmation. RESULTS: Obstruction was found in 60 percent of the Reuter Bobbin and 40 percent of the Goode TTs using the mucus analog. These results are similar to those reported from previous in vivo studies. No plugging was reported for either TT using homogenized human ear mucus. CONCLUSIONS: The in vitro TT chamber simulates the in vivo environment and yields results consistent with in vivo observations. This model system may allow for rapid prototyping and evaluation of new TTs that may be less vulnerable to occlusion.

Hemodynamically driven vein graft remodeling: a systems biology approach.

Despite intense investigation over several decades to understand the mechanisms of vein graft failure, few therapeutic modalities have emerged. Emphasis using standard reductionist approaches has been focused on cataloging the components involved in the early events following vein graft implantation, but limited insight has been gained in understanding the dynamic interaction of these components. We propose that the application of systems theory offers the opportunity for significant advances in this area. Focused on modeling the dynamic relationships that define living organisms, systems biology provides the necessary tools to further our understanding of the complex series of overlapping biologic events on surgical implantation of the vein graft. Through the use of ordinary differential equation and agent-based modeling techniques, we present our ongoing efforts to define the nonlinear interactions between hemodynamics and vascular adaptation.

Rule-Based Simulation of Multi-Cellular Biological Systems-A Review of Modeling Techniques.

Emergent behaviors of multi-cellular biological systems (MCBS) result from the behaviors of each individual cells and their interactions with other cells and with the environment. Modeling MCBS requires incorporating these complex interactions among the individual cells and the environment. Modeling approaches for MCBS can be grouped into two categories: continuum models and cell-based models. Continuum models usually take the form of partial differential equations, and the model equations provide insight into the relationship among the components in the system. Cell-based models simulate each individual cell behavior and interactions among them enabling the observation of the emergent system behavior. This review focuses on the cell-based models of MCBS, and especially, the technical aspect of the rule-based simulation method for MCBS is reviewed. How to implement the cell behaviors and the interactions with other cells and with the environment into the computational domain is discussed. The cell behaviors reviewed in this paper are division, migration, apoptosis/necrosis, and differentiation. The environmental factors such as extracellular matrix, chemicals, microvasculature, and forces are also discussed. Application examples of these cell behaviors and interactions are presented.

Marrow cell therapies for cardiovascular diseases.

The nascent field of regenerative medicine has taken root in cardiovascular disease. Preclinical data demonstrating hemangioblast potential of marrow cells and cardioprotective effects of growth factors served as the basis for numerous early phase clinical trials. With the first wave of safety and efficacy trials complete, much is still unknown regarding optimal cell dose and type, timing of injection, route of administration, mechanisms of action, and achievable response measures. The next generation of studies will aim to answers these questions and make way for cellular therapies that result in effective cardiac repair.

An experiment-based model of vein graft remodeling induced by shear stress.

Vein graft intimal hyperplasia induced by shear stress is considered to be one of the major causes of vein graft failure. We have developed a mathematical model of vein graft intimal hyperplasia induced by shear stress based on experimental data. Intimal thickness and the rate of intimal thickness change are expressed as functions of shear stress and time. The model coefficients are derived from animal experiments where bilateral rabbit carotid vein grafts are exposed to different shear stress levels. Morphology data of the vein grafts are obtained over multiple time points. The model describes the well-known behavior of intimal thickening, which is inversely related to shear stress. It also depicts the time-dependent behavior of vein graft intimal hyperplasia. Finally, the model is used to simulate the intimal growth around a focal stenosis, which was created by ligating the middle of a vein graft using a suture. Simulation results and experimental data agree qualitatively, and demonstrate that the intima thickens more distal to the stenosed area. These experiments establish the potential of the general experiment-based approach for predicting human vein graft remodeling. Other mechanical and biological factors can be included following a similar approach in order to obtain a more accurate vein graft remodeling model.

A novel method for low load friction testing on living cells.

A low load tribology technique for studying the effects of friction on living cells was developed. Results show a direct relationship between the coefficient of friction (COF) and the extent of cell damage. The COF, mu, for a glass pin on an intact layer of human corneal epithelial cells is determined to be on the order of mu = 0.05 +/- 0.02 (n = 16). The correlations between applied normal load and extent of cell damage, as well as between number of reciprocation cycles and cell damage, are reported. It is also found that cell damage can occur when a loading force as low as 0.5 mN is applied, although the cells appear to be intact.

A model of vein graft intimal hyperplasia.

When vein graft is implanted in the arterial system, the vein graft wall becomes thicker as an adaptive process. We have developed a model of early adaptive vein graft intimal thickening induced by shear stress. Intimal thickness and the rate of intimal thickening are expressed as functions of shear stress and time based on experimental data. The model describes the behavior of intimal thickening which is inversely related to shear stress. It also depicts the time-dependent behavior of the vein graft intimal thickening.