John F. LaDisa

On Coupling a Lumped Parameter Heart Model and a Three-Dimensional Finite Element Aorta Model

Aortic flow and pressure result from the interactions between the heart and arterial system. In this work, we considered these interactions by utilizing a lumped parameter heart model as an inflow boundary condition for three-dimensional finite element simulations of aortic blood flow and vessel wall dynamics. The ventricular pressure–volume behavior of the lumped parameter heart model is approximated using a time varying elastance function scaled from a normalized elastance function. When the aortic valve is open, the coupled multidomain method is used to strongly couple the lumped parameter heart model and three-dimensional arterial models and compute ventricular volume, ventricular pressure, aortic flow, and aortic pressure. The shape of the velocity profiles of the inlet boundary and the outlet boundaries that experience retrograde flow are constrained to achieve a robust algorithm. When the aortic valve is closed, the inflow boundary condition is switched to a zero velocity Dirichlet condition. With this method, we obtain physiologically realistic aortic flow and pressure waveforms. We demonstrate this method in a patient-specific model of a normal human thoracic aorta under rest and exercise conditions and an aortic coarctation model under pre- and post-interventions.

Mechanism of Preconditioning by Isoflurane in Rabbits: A Direct Role for Reactive Oxygen Species

Background Reactive oxygen species (ROS) contribute to myocardial protection during ischemic preconditioning, but the role of the ROS in protection against ischemic injury produced by volatile anesthetics has only recently been explored. We tested the hypothesis that ROS mediate isoflurane-induced preconditioning in vivo. Methods Pentobarbital-anesthetized rabbits were instrumented for measurement of hemodynamics and were subjected to a 30 min coronary artery occlusion followed by 3 h reperfusion. Rabbits were randomly assigned to receive vehicle (0.9% saline), or the ROS scavengers N-acetylcysteine (NAC; 150 mg/kg) or N-2-mercaptopropionyl glycine (2-MPG; 1 mg · kg−1· min−1), in the presence or absence of 1.0 minimum alveolar concentration (MAC) isoflurane. Isoflurane was administered for 30 min and then discontinued 15 min before coronary artery occlusion. A fluorescent probe for superoxide anion production (dihydroethidium, 2 mg) was administered in the absence of the volatile anesthetic or 5 min before exposure to isoflurane in 2 additional groups (n = 8). Myocardial infarct size and superoxide anion production were assessed using triphenyltetrazolium staining and confocal fluorescence microscopy, respectively. Results Isoflurane (P < 0.05) decreased infarct size to 24 ± 4% (mean ± SEM; n = 10) of the left ventricular area at risk compared with control experiments (43 ± 3%; n = 8). NAC (43 ± 3%; n = 7) and 2-MPG (42 ± 5%; n = 8) abolished this beneficial effect, but had no effect on myocardial infarct size (47 ± 3%; n = 8 and 46 ± 3; n = 7, respectively) when administered alone. Isoflurane increased superoxide anion production as compared with control experiments (28 ± 12 vs. −6 ± 9 fluorescence units;P < 0.05). Conclusions The results indicate that ROS produced following administration of isoflurane contribute to protection against myocardial infarction in vivo.

Alterations in regional vascular geometry produced by theoretical stent implantation influence distributions of wall shear stress: analysis of a curved coronary artery using 3D computational fluid dynamics modeling

BackgroundThe success of stent implantation in the restoration of blood flow through areas of vascular narrowing is limited by restenosis. Several recent studies have suggested that the local geometric environment created by a deployed stent may influence regional blood flow characteristics and alter distributions of wall shear stress (WSS) after implantation, thereby rendering specific areas of the vessel wall more susceptible to neointimal hyperplasia and restenosis. Stents are most frequently implanted in curved vessels such as the coronary arteries, but most computational studies examining blood flow patterns through stented vessels conducted to date use linear, cylindrical geometric models. It appears highly probable that restenosis occurring after stent implantation in curved arteries also occurs as a consequence of changes in fluid dynamics that are established immediately after stent implantation.MethodsIn the current investigation, we tested the hypothesis that acute changes in stent-induced regional geometry influence distributions of WSS using 3D coronary artery CFD models implanted with stents that either conformed to or caused straightening of the primary curvature of the left anterior descending coronary artery. WSS obtained at several intervals during the cardiac cycle, time averaged WSS, and WSS gradients were calculated using conventional techniques.ResultsImplantation of a stent that causes straightening, rather than conforms to the natural curvature of the artery causes a reduction in the radius of curvature and subsequent increase in the Dean number within the stented region. This straightening leads to modest skewing of the velocity profile at the inlet and outlet of the stented region where alterations in indices of WSS are most pronounced. For example, time-averaged WSS in the proximal portion of the stent ranged from 8.91 to 11.7 dynes/cm2 along the pericardial luminal surface and 4.26 to 4.88 dynes/cm2 along the myocardial luminal surface of curved coronary arteries as compared to 8.31 dynes/cm2 observed throughout the stented region of a straight vessel implanted with an equivalent stent.ConclusionThe current results predicting large spatial and temporal variations in WSS at specific locations in curved arterial 3D CFD simulations are consistent with clinically observed sites of restenosis. If the findings of this idealized study translate to the clinical situation, the regional geometry established immediately after stent implantation may predispose portions of the stented vessel to a higher risk of neointimal hyperplasia and subsequent restenosis.

Computational Simulations for Aortic Coarctation: Representative Results From a Sampling of Patients

Treatments for coarctation of the aorta (CoA) can alleviate blood pressure (BP) gradients (Δ), but long-term morbidity still exists that can be explained by altered indices of hemodynamics and biomechanics. We introduce a technique to increase our understanding of these indices for CoA under resting and nonresting conditions, quantify their contribution to morbidity, and evaluate treatment options. Patient-specific computational fluid dynamics (CFD) models were created from imaging and BP data for one normal and four CoA patients (moderate native CoA: Δ12 mmHg, severe native CoA: Δ25 mmHg and postoperative end-to-end and end-to-side patients: Δ0 mmHg). Simulations incorporated vessel deformation, downstream vascular resistance and compliance. Indices including cyclic strain, time-averaged wall shear stress (TAWSS), and oscillatory shear index (OSI) were quantified. Simulations replicated resting BP and blood flow data. BP during simulated exercise for the normal patient matched reported values. Greatest exercise-induced increases in systolic BP and mean and peak ΔBP occurred for the moderate native CoA patient (SBP: 115 to 154 mmHg; mean and peak ΔBP: 31 and 73 mmHg). Cyclic strain was elevated proximal to the coarctation for native CoA patients, but reduced throughout the aorta after treatment. A greater percentage of vessels was exposed to subnormal TAWSS or elevated OSI for CoA patients. Local patterns of these indices reported to correlate with atherosclerosis in normal patients were accentuated by CoA. These results apply CFD to a range of CoA patients for the first time and provide the foundation for future progress in this area.

Local hemodynamic changes caused by main branch stent implantation and subsequent virtual side branch balloon angioplasty in a representative coronary bifurcation

Abnormal blood flow patterns promoting inflammation, cellular proliferation, and thrombosis may be established by local changes in vessel geometry after stent implantation in bifurcation lesions. Our objective was to quantify altered hemodynamics due to main vessel (MV) stenting and subsequent virtual side branch (SB) angioplasty in a coronary bifurcation by using computational fluid dynamics (CFD) analysis. CFD models were generated from representative vascular dimensions and intravascular ultrasound images. Time-averaged wall shear stress (TAWSS), oscillatory shear index (OSI), and fractional flow reserve (FFR) were quantified. None of the luminal surface was exposed to low TAWSS (<4 dyn/cm(2)) in the nondiseased bifurcation model. MV stenting introduced eccentric areas of low TAWSS along the lateral wall of the MV. Virtual SB angioplasty resulted in a more concentric region of low TAWSS in the MV distal to the carina and along the lateral wall of the SB. The luminal surface exposed to low TAWSS was similar before and after virtual SB angioplasty (rest: 43% vs. 41%; hyperemia: 18% vs. 21%) and primarily due to stent-induced flow alterations. Sites of elevated OSI (>0.1) were minimal but more impacted by general vessel geometry established after MV stenting. FFR measured at a jailed SB was within the normal range despite angiographic stenosis of 54%. These findings indicate that the most commonly used percutaneous interventional strategy for a bifurcation lesion causes abnormal local hemodynamic conditions. These results may partially explain the high clinical event rates in bifurcation lesions.

Axial stent strut angle influences wall shear stress after stent implantation: analysis using 3D computational fluid dynamics models of stent foreshortening

IntroductionThe success of vascular stents in the restoration of blood flow is limited by restenosis. Recent data generated from computational fluid dynamics (CFD) models suggest that the vascular geometry created by an implanted stent causes local alterations in wall shear stress (WSS) that are associated with neointimal hyperplasia (NH). Foreshortening is a potential limitation of stent design that may affect stent performance and the rate of restenosis. The angle created between axially aligned stent struts and the principal direction of blood flow varies with the degree to which the stent foreshortens after implantation.MethodsIn the current investigation, we tested the hypothesis that stent foreshortening adversely influences the distribution of WSS and WSS gradients using time-dependent 3D CFD simulations of normal arteries based on canine coronary artery measurements of diameter and blood flow. WSS and WSS gradients were calculated using conventional techniques in ideal (16 mm) and progressively foreshortened (14 and 12 mm) stented computational vessels.ResultsStent foreshortening increased the intrastrut area of the luminal surface exposed to low WSS and elevated spatial WSS gradients. Progressive degrees of stent foreshortening were also associated with strut misalignment relative to the direction of blood flow as indicated by analysis of near-wall velocity vectors.ConclusionThe current results suggest that foreshortening may predispose the stented vessel to a higher risk of neointimal hyperplasia.

COMPUTATIONAL SIMULATIONS DEMONSTRATE ALTERED WALL SHEAR STRESS IN AORTIC COARCTATION PATIENTS TREATED BY RESECTION WITH END-TO-END ANASTOMOSIS

BACKGROUND Atherosclerotic plaque in the descending thoracic aorta (dAo) is related to altered wall shear stress (WSS) for normal patients. Resection with end-to-end anastomosis (RWEA) is the gold standard for coarctation of the aorta (CoA) repair, but may lead to altered WSS indices that contribute to morbidity. METHODS Computational fluid dynamics (CFD) models were created from imaging and blood pressure data for control subjects and age- and gender-matched CoA patients treated by RWEA (four males, two females, 15 ± 8 years). CFD analysis incorporated downstream vascular resistance and compliance to generate blood flow velocity, time-averaged WSS (TAWSS), and oscillatory shear index (OSI) results. These indices were quantified longitudinally and circumferentially in the dAo, and several visualization methods were used to highlight regions of potential hemodynamic susceptibility. RESULTS The total dAo area exposed to subnormal TAWSS and OSI was similar between groups, but several statistically significant local differences were revealed. Control subjects experienced left-handed rotating patterns of TAWSS and OSI down the dAo. TAWSS was elevated in CoA patients near the site of residual narrowings and OSI was elevated distally, particularly along the left dAo wall. Differences in WSS indices between groups were negligible more than 5 dAo diameters distal to the aortic arch. CONCLUSIONS Localized differences in WSS indices within the dAo of CoA patients treated by RWEA suggest that plaque may form in unique locations influenced by the surgical repair. These regions can be visualized in familiar and intuitive ways allowing clinicians to track their contribution to morbidity in longitudinal studies.

Optimization of Cardiovascular Stent Design Using Computational Fluid Dynamics

Coronary stent design affects the spatial distribution of wall shear stress (WSS), which can influence the progression of endothelialization, neointimal hyperplasia, and restenosis. Previous computational fluid dynamics (CFD) studies have only examined a small number of possible geometries to identify stent designs that reduce alterations in near-wall hemodynamics. Based on a previously described framework for optimizing cardiovascular geometries, we developed a methodology that couples CFD and three-dimensional shape-optimization for use in stent design. The optimization procedure was fully-automated, such that solid model construction, anisotropic mesh generation, CFD simulation, and WSS quantification did not require user intervention. We applied the method to determine the optimal number of circumferentially repeating stent cells (N(C)) for slotted-tube stents with various diameters and intrastrut areas. Optimal stent designs were defined as those minimizing the area of low intrastrut time-averaged WSS. Interestingly, we determined that the optimal value of N(C) was dependent on the intrastrut angle with respect to the primary flow direction. Further investigation indicated that stent designs with an intrastrut angle of approximately 40 deg minimized the area of low time-averaged WSS regardless of vessel size or intrastrut area. Future application of this optimization method to commercially available stent designs may lead to stents with superior hemodynamic performance and the potential for improved clinical outcomes.

A Rapid and Computationally Inexpensive Method to Virtually Implant Current and Next-Generation Stents into Subject-Specific Computational Fluid Dynamics Models

Computational modeling is often used to quantify hemodynamic alterations induced by stenting, but frequently uses simplified device or vascular representations. Based on a series of Boolean operations, we developed an efficient and robust method for assessing the influence of current and next-generation stents on local hemodynamics and vascular biomechanics quantified by computational fluid dynamics. Stent designs were parameterized to allow easy control over design features including the number, width and circumferential or longitudinal spacing of struts, as well as the implantation diameter and overall length. The approach allowed stents to be automatically regenerated for rapid analysis of the contribution of design features to resulting hemodynamic alterations. The applicability of the method was demonstrated with patient-specific models of a stented coronary artery bifurcation and basilar trunk aneurysm constructed from medical imaging data. In the coronary bifurcation, we analyzed the hemodynamic difference between closed-cell and open-cell stent geometries. We investigated the impact of decreased strut size in stents with a constant porosity for increasing flow stasis within the stented basilar aneurysm model. These examples demonstrate the current method can be used to investigate differences in stent performance in complex vascular beds for a variety of stenting procedures and clinical scenarios.

Carotid plaque regression following 6-month statin therapy assessed by 3T cardiovascular magnetic resonance: comparison with ultrasound intima media thickness

BackgroundCardiovascular magnetic resonance (CMR) allows volumetric carotid plaque measurement that has advantage over 2-dimensional ultrasound (US) intima-media thickness (IMT) in evaluating treatment response. We tested the hypothesis that 6-month statin treatment in patients with carotid plaque will lead to plaque regression when measured by 3 Tesla CMR but not by IMT.MethodsTwenty-six subjects (67 ± 2 years, 7 females) with known carotid plaque (> 1.1 mm) and coronary or cerebrovascular atherosclerotic disease underwent 3T CMR (T1, T2, proton density and time of flight sequences) and US at baseline and following 6 months of statin therapy (6 had initiation, 7 had increase and 13 had maintenance of statin dosing). CMR plaque volume (PV) was measured in the region 12 mm below and up to 12 mm above carotid flow divider using software. Mean posterior IMT in the same region was measured. Baseline and 6-month CMR PV and US IMT were compared. Change in lipid rich/necrotic core (LR/NC) and calcification plaque components from CMR were related to change in PV.ResultsLow-density lipoprotein cholesterol decreased (86 ± 6 to 74 ± 4 mg/dL, p = 0.046). CMR PV decreased 5.8 ± 2% (1036 ± 59 to 976 ± 65 mm3, p = 0.018). Mean IMT was unchanged (1.12 ± 0.06 vs. 1.14 ± 0.06 mm, p = NS). Patients with initiation or increase of statins had -8.8 ± 2.8% PV change (p = 0.001) while patients with maintenance of statin dosing had -2.7 ± 3% change in PV (p = NS). There was circumferential heterogeneity in CMR plaque thickness with greatest thickness in the posterior carotid artery, in the region opposite the flow divider. Similarly there was circumferential regional difference in change of plaque thickness with significant plaque regression in the anterior carotid region in region of the flow divider. Change in LR/NC (R = 0.62, p = 0.006) and calcification (R = 0.45, p = 0.03) correlated with PV change.ConclusionsSix month statin therapy in patients with carotid plaque led to reduced plaque volume by 3T CMR, but ultrasound posterior IMT did not show any change. The heterogeneous spatial distribution of plaque and regional differences in magnitude of plaque regression may explain the difference in findings and support volumetric measurement of plaque. 3T CMR has potential advantage over ultrasound IMT to assess treatment response in individuals and may allow reduced sample size, duration and cost of clinical trials of plaque regression.