Minki Hwang

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.

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.

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.

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.

Role of atrial wall thickness in wave-dynamics of atrial fibrillation

Background/Aims Atrial anatomy and thickness may affect the electrical wave-dynamics of atrial fibrillation (AF). We explored the relationship between left atrial (LA) wall thickness (LAWT) or LA geometry and AF wave-dynamics. Methods We included 15 patients with persistent AF (age, 62.3 ± 11.9 years) who underwent AF catheter ablation. We measured the LAWT, LA endocardial curvature, and SD-curvature (surface bumpiness) from preprocedural computed tomography images. We compared those anatomical characteristics with electrophysiologic parameters such as dominant frequency (DF), Shannon entropy (ShEn), or complex fractionated atrial electrogram (CFAE)-cycle length (CL), calculated from intracardiac bipolar electrograms (300–500 points, 5 s), acquired during ablation procedures. Results 1. LAWT (excluding fat) varied widely among patients, locations, and types of AF. LAWT was inversely correlated with LA volume (r = -0.565, p = 0.028) and positively correlated with SD-curvature (r = 0.272, p < 0.001). 2. LAWT was positively correlated with ShEn (r = 0.233, p < 0.001) and negatively correlated with CFAE-CL (r = -0.107, p = 0.038). 3. In the multivariate linear regression analyses for AF wave-dynamics parameters, DF (β = -0.29 [95% CI -0.44–-0.14], p < 0.001), ShEn (β = 0.19 [95% CI 0.12–0.25], p < 0.001), and CFAE-CL (β = 7.49 [95% CI 0.65–14.34], p = 0.032) were independently associated with LAWT. Conclusion Regional LAWT is associated with LA structural features, and has significant correlations with the wave-dynamics parameters associated with electrical wavebreaks or rotors in patients with persistent AF.

Ganglionated plexi stimulation induces pulmonary vein triggers and promotes atrial arrhythmogenecity: In silico modeling study

Background The role of the autonomic nervous system (ANS) on atrial fibrillation (AF) is difficult to demonstrate in the intact human left atrium (LA) due to technical limitations of the current electrophysiological mapping technique. We examined the effects of the ANS on the initiation and maintenance of AF by employing a realistic in silico human left atrium (LA) model integrated with a model of ganglionated plexi (GPs). Methods We incorporated the morphology of the GP and parasympathetic nerves in a three-dimensional (3D) realistic LA model. For the model of ionic currents, we used a human atrial model. GPs were stimulated by increasing the IK[ACh], and sympathetic nerve stimulation was conducted through a homogeneous increase in the ICa-L. ANS-induced wave-dynamics changes were evaluated in a model that integrated a patient’s LA geometry, and we repeated simulation studies using LA geometries from 10 different patients. Results The two-dimensional model of pulmonary vein (PV) cells exhibited late phase 3 early afterdepolarization-like activity under 0.05μM acetylcholine (ACh) stimulation. In the 3D simulation model, PV tachycardia was induced, which degenerated to AF via GP (0.05μM ACh) and sympathetic (7.0×ICa-L) stimulations. Under sustained AF, local reentries were observed at the LA-PV junction. We also observed that GP stimulation reduced the complex fractionated atrial electrogram (CFAE)-cycle length (CL, p<0.01) and the life span of phase singularities (p<0.01). GP stimulation also increased the overlap area of the GP and CFAE areas (CFAE-CL≤120ms, p<0.01). When 3 patterns of virtual ablations were applied to the 3D AF models, circumferential PV isolation including the GP was the most effective in terminating AF. Conclusion Cardiac ANS stimulations demonstrated triggered activity, automaticity, and local reentries at the LA-PV junction, as well as co-localized GP and CFAE areas in the 3D in silico GP model of the LA.

Modeling and Role of Leukocytes in Inflammation

Inflammation is a protective response of the body to infection or injury. When the body tissue is damaged by infection or injury, inflammatory response is triggered to remove the foreign invaders or start the healing process. In some diseases, such as atherosclerosis and rheumatoid arthritis, the inflammatory response is triggered inappropriately and the inflammatory cells damage the normal tissues. This suggests that those diseases can be treated by interfering with the inflammatory process.

Rule-Based Simulation of Vein Graft Remodeling

Vascular adaptation following local injury occurs through a combination of intimal hyperplasia and wall (inward/outward) remodeling. Over the past two decades, researchers have applied a wide variety of approaches to investigate neointimal hyperplasia and vascular remodeling in an effort to identify novel therapeutic strategies. However, despite incremental progress over these decades, specific cause/effect links between hemodynamic factors, inflammatory biochemical mediators, cellular effectors, and vascular occlusive phenotype remain lacking.