Hydrodynamic effects of compliance mismatch in stented arteries

Cardiovascular diseases are the number one cause of death in the world, making the understanding of hemodynamics and development of treatment options imperative. The most common modality for treatment of occlusive coronary artery diseases is the use of stents. Stent design profoundly influences the postprocedural hemodynamic and solid mechanical environment of the stented artery. However, despite their wide acceptance, the incidence of stent late restenosis is still high (Zwart et al., 2010, "Coronary Stent Thrombosis in the Current Era: Challenges and Opportunities for Treatment," Current Treatment Options in Cardiovascular Medicine, 12(1), pp. 46-57), and it is most prevailing at the proximal and distal ends of the stent. In this work, we focus our investigation on the localized hemodynamic effects of compliance mismatch due to the presence of a stent in an artery. The compliance mismatch in a stented artery is maximized at the proximal and distal ends of the stent. Hence, it is our objective to understand and reveal the mechanism by which changes in compliance contribute to the generation of nonphysiological wall shear stress (WSS). Such adverse hemodynamic conditions could have an effect on the onset of restenosis. Three-dimensional, spatiotemporally resolved computational fluid dynamics simulations of pulsatile flow with fluid-structure interaction were carried out for a simplified coronary artery with physiologically relevant flow parameters. A model with uniform elastic modulus is used as the baseline control case. In order to study the effect of compliance variation on local hemodynamics, this baseline model is compared with models where the elastic modulus was increased by two-, five-, and tenfold in the middle of the vessel. The simulations provided detailed information regarding the recirculation zone dynamics formed during flow reversals. The results suggest that discontinuities in compliance cause critical changes in local hemodynamics, namely, altering the local pressure and velocity gradients. The change in pressure gradient at the discontinuity was as high as 90%. The corresponding changes in WSS and oscillatory shear index calculated were 9% and 15%, respectively. We demonstrate that these changes are attributed to the physical mechanism associating the pressure gradient discontinuities to the production of vorticity (vorticity flux) due to the presence of the stent. The pressure gradient discontinuities and augmented vorticity flux are affecting the wall shear stresses. As a result, this work reveals how compliance variations act to modify the near wall hemodynamics of stented arteries.     

DPIV measurements of flow disturbances in stented artery models: adverse affects of compliance mismatch

Vascular stents influence the post-procedural hemodynamic environment in ways that may encourage restenosis. Understanding how stents influence flow patterns may lead to more hemodynamically compatible stent designs that alleviate thrombus formation and promote endothelialization. This study employed time-resolved Digital Particle Image Velocimetry (DPIV) to compare the hemodynamic performance of two stents in a compliant vessel. The first stent was a rigid insert, representing an extreme compliance mismatch. The second stent was a commercially available nitinol stent with some flexural characteristics. DPIV showed that compliance mismatch promotes the formation of a ring vortex in the vicinity of the stent. Larger compliance mismatch increased both the size and residence time of the ring vortex, and introduced in-flow stagnation points. These results provide detailed quantitative evidence of the hemodynamic effect of stent mechanical properties. Better understanding of these characteristics will provide valuable information for modifying stent design in order to promote long-term patency.     

Effects of compliance mismatch on blood flow in an artery with endovascular prosthesis

The objective of this paper is to study the mechanical effects caused by the local stiffening of an artery (due to the vascular prosthesis, for instance). At the junction of the host artery and the more rigid implantant, the abrupt change in compliance creates an abnormal stress concentration that initiates an adaptive response in the vascular tissue. The roles of both fluid and solid mechanical phenomena must be considered in the prosthesis design optimization. In this context, even the simple models could provide helpful tools for designing process. We present here a model of blood flow in compliant vessel. The artery is supposed to be an orthotropical thin elastic shell. We obtain the solution by matched asymptotic expansions. The results prove the high flexure concentration close to the compliance jump. It is shown that the use of orthotropical graft may reduce the peak value of these shear forces to a remarkable extent. Waves reflected from the suture and pressure increase in the prosthesis are discussed. Compliance mismatch is shown to reduce the peak value of maximal wall shear stress.     

Fluid-structure interaction effects on sac-blood pressure and wall stress in a stented aneurysm

An aneurysm is a local artery ballooning greater than 50% of its nominal diameter with a risk of sudden rupture. Minimally invasive repair can be achieved by inserting surgically a stent-graft, called an endovascular graft (EVG), which is either straight tubular curved tubular or bifurcating. However post-procedural complications may arise because of elevated stagnant blood pressure in the cavity, i.e., the sac formed by the EVG and the weakened aneurysm wall In order to investigate the underlying mechanisms leading to elevated sac-pressures and hence to potentially dangerous wall stress levels and aneurysm rupture, a transient 3-D stented abdominal aortic aneurysm model and a coupled fluid-structure interaction solver were employed. Simulation results indicate that, even without the presence of endoleaks (blood flowing into the cavity), elevated sac pressure can occur due to complex fluid-structure interactions between the luminal blood flow, EVG wall, intra-sac stagnant blood, including an intra-luminal thrombus, and the aneurysm wall. Nevertheless, the impact of sac-blood volume changes due to leakage on the sac pressure and aneurysm wall stress was analyzed as well. While blood flow conditions, EVG and aneurysm geometries as well as wall mechanical properties play important roles in both sac pressure and wall stress generation, it is always the maximum wall stress that is one of the most critical parameters in aneurysm rupture prediction. All simulation results are in agreement with experimental data and clinical observations.     

Sequential structural and fluid dynamic numerical simulations of a stented bifurcated coronary artery

Despite their success, stenting procedures are still associated to some clinical problems like sub-acute thrombosis and in-stent restenosis. Several clinical studies associate these phenomena to a combination of both structural and hemodynamic alterations caused by stent implantation. Recently, numerical models have been widely used in the literature to investigate stenting procedures but always from either a purely structural or fluid dynamic point of view. The aim of this work is the implementation of sequential structural and fluid dynamic numerical models to provide a better understanding of stenting procedures in coronary bifurcations. In particular, the realistic geometrical configurations obtained with structural simulations were used to create the fluid domains employed within transient fluid dynamic analyses. This sequential approach was applied to investigate the final kissing balloon (FKB) inflation during the provisional side branch technique. Mechanical stresses in the arterial wall and the stent as well as wall shear stresses along the arterial wall were examined before and after the FKB deployment. FKB provoked average mechanical stresses in the arterial wall almost 2.5 times higher with respect to those induced by inflation of the stent in the main branch only. Results also enlightened FKB benefits in terms of improved local blood flow pattern for the side branch access. As a drawback, the FKB generates a larger region of low wall shear stress. In particular, after FKB the percentage of area characterized by wall shear stresses lower than 0.5?Pa was 79.0%, while before the FKB it was 62.3%. For these reasons, a new tapered balloon dedicated to bifurcations was proposed. The inclusion of the modified balloon has reduced the mechanical stresses in the proximal arterial vessel to 40% and the low wall shear stress coverage area to 71.3%. In conclusion, these results show the relevance of the adopted sequential approach to study the wall mechanics and the hemodynamics created by stent deployment.     

Accurate prediction of wall shear stress in a stented artery: newtonian versus non-newtonian models

A significant amount of evidence linking wall shear stress to neointimal hyperplasia has been reported in the literature. As a result, numerical and experimental models have been created to study the influence of stent design on wall shear stress. Traditionally, blood has been assumed to behave as a Newtonian fluid, but recently that assumption has been challenged. The use of a linear model; however, can reduce computational cost, and allow the use of Newtonian fluids (e.g., glycerine and water) instead of a blood analog fluid in an experimental setup. Therefore, it is of interest whether a linear model can be used to accurately predict the wall shear stress caused by a non-Newtonian fluid such as blood within a stented arterial segment. The present work compares the resulting wall shear stress obtained using two linear and one nonlinear model under the same flow waveform. All numerical models are fully three-dimensional, transient, and incorporate a realistic stent geometry. It is shown that traditional linear models (based on blood's lowest viscosity limit, 3.5 Pa s) underestimate the wall shear stress within a stented arterial segment, which can lead to an overestimation of the risk of restenosis. The second linear model, which uses a characteristic viscosity (based on an average strain rate, 4.7 Pa s), results in higher wall shear stress levels, but which are still substantially below those of the nonlinear model. It is therefore shown that nonlinear models result in more accurate predictions of wall shear stress within a stented arterial segment.     

Computational analysis of type II endoleaks in a stented abdominal aortic aneurysm model

Insertion of a stent-graft into an aneurysm to form a new (synthetic) blood vessel and prevent the weakened artery wall from rupture is an attractive surgical intervention when compared to traditional open surgery. However, focusing on a stented abdominal aortic aneurysm (AAA), post-operative complications such as endoleaks may occur. An endoleak is the net influx of blood during the cardiac cycle into the cavity (or sac) formed by the stent-graft and the AAA wall. A natural endoleak source may stem from one or two secondary branches leading to and from the aneurysm, labeled types IIa and IIb endoleaks. Employing experimentally validated fluid-structure interaction solvers, the transient 3-D lumen and cavity blood flows, wall movements, pressure variations, maximum wall stresses and migration forces were computed for types IIa and IIb endoleaks. Simulation results indicate that the sac pressure caused by these endoleaks depends largely on the inlet branch pressure, where the branch inlet pressure increases, the sac pressure may reach the systemic level and AAA-rupture is possible. The maximum wall stress is typically located near the anterior-distal side in this model, while the maximum stent-graft stress occurs near the bifurcating point, in both cases, due to local stress concentrations. The time-varying leakage rate depends on the pressure difference between AAA sac and inlet branch. In contrast, the stent-graft migration force is reduced by type II endoleaks because it greatly depends on the pressure difference between the stent-graft and the aneurysm cavity.     

A molecular model for lipid-protein interaction in membranes: the role of hydrophobic mismatch.

The interaction free energy between a hydrophobic, transmembrane, protein and the surrounding lipid environment is calculated based on a microscopic model for lipid organization. The protein is treated as a rigid hydrophobic solute of thickness dP, embedded in a lipid bilayer of unperturbed thickness doL. The lipid chains in the immediate vicinity of the protein are assumed to adjust their length to that of the protein (e.g., they are stretched when dP > doL) in order to bridge over the lipid-protein hydrophobic mismatch (dP-doL). The bilayer's hydrophobic thickness is assumed to decay exponentially to its asymptotic, unperturbed, value. The lipid deformation free energy is represented as a sum of chain (hydrophobic core) and interfacial (head-group region) contributions. The chain contribution is calculated using a detailed molecular theory of chain packing statistics, which allows the calculation of conformational properties and thermodynamic functions (in a mean-field approximation) of the lipid tails. The tails are treated as single chain amphiphiles, modeled using the rotational isometric state scheme. The interfacial free energy is represented by a phenomenological expression, accounting for the opposing effects of head-group repulsions and hydrocarbon-water surface tension. The lipid deformation free energy delta F is calculated as a function of dP-doL. Most calculations are for C14 amphiphiles which, in the absence of a protein, pack at an average area per head-group ao approximately equal to 32 A2 (doL approximately 24.5 A), corresponding to the fluid state of the membrane. When dP = doL, delta F > 0 and is due entirely to the loss of conformational entropy experienced by the chains around the protein. When dP > doL, the interaction free energy is further increased due to the enhanced stretching of the tails. When dP < doL, chain flexibility (entropy) increases, but this contribution to delta F is overcounted by the increase in the interfacial free energy. Thus, delta F obtains a minimum at dP-doL approximately 0. These qualitative interpretations are supported by detailed numerical calculations of the various contributions to the interaction free energy, and of chain conformational properties. The range of the perturbation of lipid order extends typically over few molecular diameters. A rather detailed comparison of our approach to other models is provided in the discussion.     

Coronary artery compliance in the dog

Measurement of left anterior descending coronary arterial pressure, phasic coronary flow, and intramyocardial pressure in an open-chest dog provided data, which when entered into the computer model of the coronary circulation, permitted calculation of coronary artery compliance and resistance during systole and diastole. Resting in vivo compliance averaged 0.21 x 10(-3) mL/mmHg (1 mmHg = 133.322 Pa) while systolic resistance averaged 4.05 mmHg X min-1 X mL-1 and during diastole 2.06 mmHg X min-1 X mL-1. Left stellate ganglion stimulation or vasodilation caused minimal changes in compliance but glutaraldehyde applied to arterial wall caused a decrease in compliance. Sympathetic stimulation and vasodilation decreased both diastolic and systolic resistance. Transmural distribution of coronary flow was not significantly altered by the experimental changes in compliance and resistance.     

Hemodynamics in stented vertebral artery ostial stenosis based on computational fluid dynamics simulations

Hemodynamic factors may affect the potential occurrence of in-stent restenosis (ISR) after intervention procedure of vertebral artery ostial stenosis (VAOS). The purpose of the present study is to investigate the influence of stent protrusion length in implantation strategy on the local hemodynamics of the VAOS. CTA images of a 58-year-old female patient with posterior circulation transient ischemic attack were used to perform a 3D reconstruction of the vertebral artery. Five models of the vertebral artery before and after the stent implantation were established. Model 1 was without stent implantation, Model 2–5 was with stent protruding into the subclavian artery for 0, 1, 2, 3 mm, respectively. Computational fluid dynamics simulations based on finite element analysis were employed to mimic the blood flow in arteries and to assess hemodynamic conditions, particularly the blood flow velocity and wall shear stress (WSS). The WSS and the blood flow velocity at the vertebral artery ostium were reduced by 85.33 and 35.36% respectively after stents implantation. The phenomenon of helical flow disappeared. Hemodynamics comparison showed that stent struts that protruded 1 mm into the subclavian artery induced the least decrease in blood speed and WSS. The results suggest that stent implantation can improve the hemodynamics of VAOS, while stent struts that had protruded 1 mm into the subclavian artery would result in less thrombogenesis and neointimal hyperplasia and most likely decrease the risk of ISR.     

Charge transport in a DNA model with solvent interaction

The charge transport in the modified DNA model is studied by taking into account the factor of solvent and the effect of coupling motions of nucleotides. We report on the presence of the modulational instability (MI) of a plane wave for charge migration in DNA and the generation of soliton-like excitations in DNA nucleotides. By applying the continuum approximation, we show that the original differential-difference equation for the DNA dynamics can be reduced to a set of three coupled nonlinear equations. The linear stability analysis of wave solutions of the coupled systems is performed and the growth rate of instability is found numerically. We also investigate the impact of solvent interaction. The solvent factor introduces a new behavior to the wave patterns, modifying also the intrinsic properties of localized structures. In the numerical simulations, we show that the solitons exists when taking into account the effect of solvent and confirms an highest propagation of localized structures in the systems. The effect of solvent forces introduces a robustness behavior to the formed patterns, reinforcing the idea that the information in the DNA model is confined and concentrated to specific regions for efficiency. We also show that the localized structures can be disappeared with the highest value of solvent factor and thereafter the information within the molecule is not perceptible or not transmitted to another sites.     

ATP-dependent interaction of human mismatch repair proteins and dual role of PCNA in mismatch repair.

DNA mismatch repair ensures genomic stability by correcting biosynthetic errors and by blocking homologous recombination. MutS-like and MutL-like proteins play important roles in these processes. In Escherichia coli and yeast these two types of proteins form a repair initiation complex that binds to mismatched DNA. However, whether human MutS and MutL homologs interact to form a complex has not been elucidated. Using immunoprecipitation and Western blot analysis we show here that human MSH2, MLH1, PMS2 and proliferating cell nuclear antigen (PCNA) can be co-immunoprecipitated, suggesting formation of a repair initiation complex among these proteins. Formation of the initiation complex is dependent on ATP hydrolysis and at least functional MSH2 and MLH1 proteins, because the complex could not be detected in tumor cells that produce truncated MLH1 or MSH2 protein. We also demonstrate that PCNA is required in human mismatch repair not only at the step of repair initiation, but also at the step of repair DNA re-synthesis.     

The interaction of DNA mismatch repair proteins with human exonuclease I.

Exonucleolytic degradation of DNA is an essential part of many DNA metabolic processes including DNA mismatch repair (MMR) and recombination. Human exonuclease I (hExoI) is a member of a family of conserved 5' --> 3' exonucleases, which are implicated in these processes by genetic studies. Here, we demonstrate that hExoI binds strongly to hMLH1, and we describe interaction regions between hExoI and the MMR proteins hMSH2, hMSH3, and hMLH1. In addition, hExoI forms an immunoprecipitable complex with hMLH1/hPMS2 in vivo. The study of interaction regions suggests a biochemical mechanism of the involvement of hExoI as a downstream effector in MMR and/or DNA recombination.     

Thiamine: a mechanistic model of interaction with protein

Mechanistic model of thiamine-binding protein functioning which is based on the potential role of prototropic groups and hydrophobic environment around 5-beta-hydroxyethyl substituent of ligand has been proposed. As a model the chemical transformations of thiamine and its structural O-acyl substituted analogues in the presence of ferricyanide and phosphatic buffer in pH range 7,2-7,8 were investigated. The oxidation to the thiochrome and thiochrome derivatives is first order in substrate and ferricyanide concentrations. It is found that the reciprocal of the pseudo-first-order rate constant increases in ferrocyanide concentration at the constant oxidant concentration. Rate constants and partition ratios for reaction of thiamine, O-benzoylthiamine, O-(4-nitrobenzoyl)thiamine, O-(2-norbornoyl) thiamine, O-(1-norbornoyl)thiamine, O-(1-adamantoyl) thiamine, O-(2-adamantoyl) thiamine, O-(5-methyl-1-adamantyl)acetylthiamine, O-(2-adamantyl)acetylthiamine, O-(1-adamantyl)acetylthiamine were determined. The acceleration effect of hydrophobic fragment of O-acyl substituent is attributed to the formation of neutral tricyclic form in the step followed by electron transfer to ferricyanide. Mechanistic implications for possible transformation of thiamine in neutral tricyclic form at interaction with thiamine-binding protein are discussed.     

The MutSalpha-proliferating cell nuclear antigen interaction in human DNA mismatch repair

We have examined the interaction parameters, conformation, and functional significance of the human MutSalpha(.) proliferating cell nuclear antigen (PCNA) complex in mismatch repair. The two proteins associate with a 1:1 stoichiometry and a K(D) of 0.7 microm in the absence or presence of heteroduplex DNA. PCNA does not influence the affinity of MutSalpha for a mismatch, and mismatch-bound MutSalpha binds PCNA. Small angle x-ray scattering studies have established the molecular parameters of the complex, which are consistent with an elongated conformation in which the two proteins associate in an end-to-end fashion in a manner that does not involve an extended unstructured tether, as has been proposed for yeast MutSalpha and PCNA ( Shell, S. S., Putnam, C. D., and Kolodner, R. D. (2007) Mol. Cell 26, 565-578 ). MutSalpha variants lacking the PCNA interaction motif are functional in 3'- or 5'-directed mismatch-provoked excision, but display a partial defect in 5'-directed mismatch repair. This finding is consistent with the modest mutability conferred by inactivation of the MutSalpha PCNA interaction motif and suggests that interaction of the replication clamp with other repair protein(s) accounts for the essential role of PCNA in MutSalpha-dependent mismatch repair.     

Numerical simulation of hemodynamics in stented internal carotid aneurysm based on patient-specific model

There is still a considerable lack of quantitative information concerning the effects of stent structures on blood flow in an aneurismal cavity. In this paper, five virtual stents with different structures and wire cross-sections were designed for incorporation into the same patient-specific aneurysm model. Computational fluid dynamics simulations were performed so as to study how these five types of stents modified hemodynamic parameters. Numerical results demonstrated that the mean flow rate in the aneurismal cavity decreased the most in the model that used a stent with a rectangular wire cross-section, and that the wall shear stresses at the dome and neck of the aneurysm decreased more in models that used a stent with a circular wire cross-section or a spiral stent with a rectangular wire cross-section compared to other models. In addition, the wall pressure on the aneurysm increased slightly after implantation of the stent in all five models. This result differs from that previously published, and may help guide the design and assist clinicians in selecting an appropriate stent for treating cerebral aneurysms.     

The interaction of prostaglandins with high-density lipoproteins: a non-equilibrium model of ligand-receptor interaction

Using high-density lipoproteins (HDL) labeled with a fluorescent phospholipid probe (an anthrylvinyl-labeled analogue of sphingomyelin) it was found that low amounts (10(-12) M) of the prostaglandins E1 and F2 alpha induced different structural changes of the HDL surface, whereas prostaglandin E2 had no effect. The effects of prostaglandin E1 on HDL were largely paralleled by those of this prostaglandin on synthetic recombinants prepared from apolipoprotein A1, phospholipids and cholesterol. The prostaglandin E1-HDL interaction resembled that of a ligand with a receptor site because it was specific, reversible, concentration- and temperature-dependent and saturable. However, the maximal HDL retaining capacity for prostaglandin E1 as determined by equilibrium dialysis was very low, and a single prostaglandin E1 molecule was able to induce structural changes in a large number of discrete lipoprotein particles. To explain this remarkable fact, a non-equilibrium model of ligand-receptor interaction is proposed. According to this model in open systems characterized by a short life-time of the ligand-receptor complex, high diffusion rates of the ligand and long relaxation times which exceed the interval between two successive ligand-receptor occupations, the ligand-induced changes will accumulate, resulting in amplification of the primary biological signal. It is emphasized that the low mobility of lipids constituting the environment of the receptor protein plays a critical role in this type of signal amplification.     

Rad9 plays an important role in DNA mismatch repair through physical interaction with MLH1

Rad9 is conserved from yeast to humans and plays roles in DNA repair (homologous recombination repair, and base-pair excision repair) and cell cycle checkpoint controls. It has not previously been reported whether Rad9 is involved in DNA mismatch repair (MMR). In this study, we have demonstrated that both human and mouse Rad9 interacts physically with the MMR protein MLH1. Disruption of the interaction by a single-point mutation in Rad9 leads to significantly reduced MMR activity. This disruption does not affect S/M checkpoint control and the first round of G₂/M checkpoint control, nor does it alter cell sensitivity to UV light, gamma rays or hydroxyurea. Our data indicate that Rad9 is an important factor in MMR and carries out its MMR function specifically through interaction with MLH1.     

Identification of mismatch repair protein complexes in HeLa nuclear extracts and their interaction with heteroduplex DNA

Deficiencies in DNA mismatch repair (MMR) have been found in hereditary colon cancers (hereditary non-polyposis colon cancer, HNPCC) as well as in sporadic cancers, illustrating the importance of MMR in maintaining genomic integrity. We have examined the interactions of specific mismatch repair proteins in human nuclear extracts. Western blot and co-immunoprecipitation studies indicate two complexes as follows: one consisting of hMSH2, hMSH6, hMLH1, and hPMS2 and the other consisting of hMSH2, hMSH6, hMLH1, and hPMS1. These interactions occur without the addition of ATP. Furthermore, the protein complexes specifically bind to mismatched DNA and not to a similar homoduplex oligonucleotide. The protein complex-DNA interactions occur primarily through hMSH6, although hMSH2 can also become cross-linked to the mismatched substrate when not participating in the MMR protein complex. In the presence of ATP the binding of hMSH6 to mismatched DNA is decreased. In addition, hMLH1, hPMS2, and hPMS1 no longer interact with each other or with the hMutSalpha complex (hMSH2 and hMSH6). However, the ability of hMLH1 to co-immunoprecipitate mismatched DNA increases in the presence of ATP. This interaction is dependent on the presence of the mismatch and does not appear to involve a direct binding of hMLH1 to the DNA.     

Numerical simulation of the urine flow in a stented ureter

When a stent is implanted in a blocked ureter, the urine passing from the kidney to the bladder must traverse a very complicated flow path. That path consists of two parallel passages, one of which is the bore of the stent and the other is the annular space between the external surface of the stent and the inner wall of the ureter. The flow path is further complicated by the presence of numerous pass-through holes that are deployed along the length of the stent. These holes allow urine to pass between the annulus and the bore. Further complexity in the pattern of the urine flow occurs because the coiled "pig tails," which hold the stent in place, contain multiple ports for fluid ingress and egress. The fluid flow in a stented ureter has been quantitatively analyzed here for the first time using numerical simulation. The numerical solutions obtained here fully reveal the details of the urine flow throughout the entire stented ureter. It was found that in the absence of blockages, most of the pass-through holes are inactive. Furthermore, only the port in each coiled pig tail that is nearest the stent proper is actively involved in the urine flow. Only in the presence of blockages, which may occur due to encrustation or biofouling, are the numerous pass-through holes activated. The numerical simulations are able to track the urine flow through the pass-through holes as well as adjacent to the blockages. The simulations are also able to provide highly accurate results for the kidney-to-bladder urine flow rate. The simulation method presented here constitutes a powerful new tool for rational design of ureteral stents in the future.