Vartan Kurtcuoglu

Choosing the optimal wall shear parameter for the prediction of plaque location—A patient-specific computational study in human right coronary arteries

OBJECTIVEnWhile the correlation of atherosclerotic plaque locations with local wall shear stress magnitude has been evaluated previously by other investigators in both right (RCA) and left coronary arteries (LCA), the relative performance of average wall shear stress (AWSS), average wall shear stress gradient (AWSSG), oscillatory shear index (OSI) and relative residence time (RRT) as indicators of potential atherosclerotic plaque locations has not been studied for the LCA. Here we determine the performance of said wall shear parameters in the LCA for the prediction of plaque development locations and compare these results to those previously found in the RCA.nnnMETHODSnWe obtained 30 patient-specific geometries (mean age 67.1 (± 9.2) years, all with stable angina) of the LCA using dual-source computed tomography and virtually removed any plaque present. We then performed computational fluid dynamics simulations to calculate the wall shear parameters.nnnRESULTSnFor the 96 total plaques, AWSS had a higher sensitivity for the prediction of plaque locations (86 ± 25%) than AWSSG (65 ± 37%, p<0.05), OSI (67 ± 32%, p<0.01) or RRT (48 ± 38%, p<0.001). RRT had a higher PPV (49 ± 36%) than AWSS (31 ± 20%, p<0.05) or AWSSG (16 ± 12%, p<0.001). Segment 5 of the LCA presented with overall low values for sensitivity and PPV. Parameter performance in the remainder of the LCA was comparable to that in the RCA.nnnCONCLUSIONSnAWSS features remarkably high sensitivity, but does not reach the PPV of RRT. This may indicate that while low wall shear stress is necessary for plaque formation, its presence alone is not sufficient to predict future plaque locations. Time dependent factors have to be taken into account as well.

Control of initial endothelial spreading by topographic activation of focal adhesion kinase

The time required to re-establish a functioning endothelial cell layer after vascular implant placement is critical to the success of the respective cardiologic or surgical intervention. Topographic modifications of implant surfaces promise to expedite endothelial regeneration by triggering the activation of cellular machineries that facilitate cell spreading. Exploiting nanoimprint lithography techniques on cyclic olefin copolymer foils, we engineered biocompatible submicron- and micro-structured gratings with groove and ridge width of 1 or 5 µm and groove depth ranging from 0.1 to 2 µm. Our results reveal that both the onset of endothelial spreading and subsequent texture-guided cell polarization critically depend on the feature size of the underlying topography, yet are independently modulated by the surface texture. Specifically, we demonstrate that on gratings with ridge and groove width of 1 µm and groove depth of 1 µm or deeper, the onset of endothelial spreading is 40% faster than on flat substrates, and that the cells align within ten degrees to the gratings. On this topography, we identify two independently regulated phases: acceleration of the onset of spreading supported by the rapid activation of integrin signaling proceeding viaFocal Adhesion Kinase, and contact guidance which requires ROCK1/2 and myosin-II dependent cell contractility and focal adhesion maturation.

Ex vivo and in vivo coronary ostial locations in humans

PurposeKnowledge of the normal in vivo distribution and variation of coronary ostial locations is essential in the planning of various interventional and surgical procedures. However, all studies to date have reported the distribution of coronary ostia locations only in cadaver hearts. In this study, we sought to assess the distribution of coronary ostial locations in patients using cardiac dual-source computed tomography (CT) and compare these values to those of human cadaveric specimens.MethodsMeasurements of the coronary ostia location were performed in 150 patients undergoing dual-source CT and in 75 cadavers using open measurement techniques. All 150 patients had a normal aortic valve function and no previous cardiac intervention or surgery. The location of the right and left coronary origin in relation to the aortic annulus and the height of the sinus of Valsalva were measured.ResultsMean ostial locations at CT were 17.0 (±3.6)xa0mm and 15.3 (±3.1)xa0mm for the right and left coronary ostia, with large variations of both sides (right: 10.4–28.5xa0mm; left: 9.8–29.3xa0mm). In cadavers, mean locations were 14.9 (±4.3)xa0mm [5–24xa0mm] for right and 16.0 (±3.6)xa0mm [9–24xa0mm] for left coronary ostia. Comparison of CT and cadaver data showed statistically significant differences for right (Pxa0<xa00.0001) but not left (Pxa0=xa00.1675) coronary ostia.ConclusionsThis study provides data of normal coronary ostial origins and demonstrates significant differences between in vivo and ex vivo measurements regarding the right coronary ostium. The observed large variations of coronary ostia origins emphasize the importance of considering such anatomic variations in the development of treatments.

Hemodynamics in coronary arteries with overlapping stents

Coronary artery stenosis is commonly treated by stent placement via percutaneous intervention, at times requiring multiple stents that may overlap. Stent overlap is associated with increased risk of adverse clinical outcome. While changes in local blood flow are suspected to play a role therein, hemodynamics in arteries with overlapping stents remain poorly understood. In this study we analyzed six cases of partially overlapping stents, placed ex vivo in porcine left coronary arteries and compared them to five cases with two non-overlapping stents. The stented vessel geometries were obtained by micro-computed tomography of corrosion casts. Flow and shear stress distribution were calculated using computational fluid dynamics. We observed a significant increase in the relative area exposed to low wall shear stress (WSS<0.5 Pa) in the overlapping stent segments compared both to areas without overlap in the same samples, as well as to non-overlapping stents. We further observed that the configuration of the overlapping stent struts relative to each other influenced the size of the low WSS area: positioning of the struts in the same axial location led to larger areas of low WSS compared to alternating struts. Our results indicate that the overlap geometry is by itself sufficient to cause unfavorable flow conditions that may worsen clinical outcome. While stent overlap cannot always be avoided, improved deployment strategies or stent designs could reduce the low WSS burden.

On ultrasound-induced microbubble oscillation in a capillary blood vessel and its implications for the blood–brain barrier

The complex interaction between an ultrasound-driven microbubble and an enclosing capillary microvessel is investigated by means of a coupled, multidomain numerical model using the finite volume formulation. This system is of interest in the study of transient blood-brain barrier disruption (BBBD) for drug delivery applications. The compliant vessel structure is incorporated explicitly as a distinct domain described by a dedicated physical model. Red blood cells (RBCs) are taken into account as elastic solids in the blood plasma. We report the temporal and spatial development of transmural pressure (P(tm)) and wall shear stress (WSS) at the luminal endothelial interface, both of which are candidates for the yet unknown mediator of BBBD. The explicit introduction of RBCs shapes the P(tm) and WSS distributions and their derivatives markedly. While the peak values of these mechanical wall parameters are not affected considerably by the presence of RBCs, a pronounced increase in their spatial gradients is observed compared to a configuration with blood plasma alone. The novelty of our work lies in the explicit treatment of the vessel wall, and in the modelling of blood as a composite fluid, which we show to be relevant for the mechanical processes at the endothelium.

Age-specific characteristics and coupling of cerebral arterial inflow and cerebrospinal fluid dynamics.

The objective of this work is to quantify age-related differences in the characteristics and coupling of cerebral arterial inflow and cerebrospinal fluid (CSF) dynamics. To this end, 3T phase-contrast magnetic resonance imaging blood and CSF flow data of eleven young ( years) and eleven elderly subjects ( years) with a comparable sex-ratio were acquired. Flow waveforms and their frequency composition, transfer functions from blood to CSF flows and cross-correlations were analyzed. The magnitudes of the frequency components of CSF flow in the aqueduct differ significantly between the two age groups, as do the frequency components of the cervical spinal CSF and the arterial flows. The males aqueductal CSF stroke volumes and average flow rates are significantly higher than those of the females. Transfer functions and cross-correlations between arterial blood and CSF flow reveal significant age-dependence of phase-shift between these, as do the waveforms of arterial blood, as well as cervical-spinal and aqueductal CSF flows. These findings accentuate the need for age- and sex-matched control groups for the evaluation of cerebral pathologies such as hydrocephalus.

Mixing and modes of mass transfer in the third cerebral ventricle: a computational analysis.

Anatomic, velocimetric, and brain motion MRI scans were combined with a computational fluid dynamics model to investigate cerebrospinal fluid (CSF) mixing in the third cerebral ventricle of a healthy male adult. It was found that advection dominates over diffusion in most of the third ventricle. Three zones where diffusion plays an important role in the mixing process were identified. One of these zones, consisting of recessus infundibulus, recessus opticus and the adjacent regions up to commissura anterior, is likely to exist in the general population. We hypothesize that this zone may act as a buffer to flatten concentration peaks of pituitary gland hormones released into the CSF of the third ventricle. We further hypothesize that this zone may facilitate the communication between hypothalamus and the pituitary gland through the third ventricle cerebrospinal fluid by prolonging residence times of the communicated hormones.

Reconstruction of cerebrospinal fluid flow in the third ventricle based on MRI data

A finite-volume model of the cerebrospinal fluid (CSF) system encompassing the third ventricle and the aqueduct of Sylvius was used to reconstruct CSF velocity and pressure fields based on MRI data. The flow domain geometry was obtained through segmentation of MRI brain anatomy scans. The movement of the domain walls was interpolated from brain motion MRI scans. A constant pressure boundary condition (BC) was specified at the foramina of Monro. A transient velocity BC reconstructed from velocimetric MRI scans was employed at the inferior end of the aqueduct of Sylvius. It could be shown that a combination of MRI scans and computational fluid dynamics (CFD) simulation can be used to reconstruct the flow field in the third ventricle. Pre-interventional knowledge of patient-specific CSF flow has the potential to improve neurosurgical interventions such as shunt placement in case of hydrocephalus.

Compound Ex Vivo and In Silico Method for Hemodynamic Analysis of Stented Arteries

Hemodynamic factors such as low wall shear stress have been shown to influence endothelial healing and atherogenesis in stent-free vessels. However, in stented vessels, a reliable quantitative analysis of such relations has not been possible due to the lack of a suitable method for the accurate acquisition of blood flow. The objective of this work was to develop a method for the precise reconstruction of hemodynamics and quantification of wall shear stress in stented vessels. We have developed such a method that can be applied to vessels stented in or ex vivo and processed ex vivo. Here we stented the coronary arteries of ex vivo porcine hearts, performed vascular corrosion casting, acquired the vessel geometry using micro-computed tomography and reconstructed blood flow and shear stress using computational fluid dynamics. The method yields accurate local flow information through anatomic fidelity, capturing in detail the stent geometry, arterial tissue prolapse, radial and axial arterial deformation as well as strut malapposition. This novel compound method may serve as a unique tool for spatially resolved analysis of the relationship between hemodynamic factors and vascular biology. It can further be employed to optimize stent design and stenting strategies.

Computed high concentrations of low-density lipoprotein correlate with plaque locations in human coronary arteries

Subendothelial accumulation of low-density lipoprotein (LDL) in arterial walls is an initiator of atherosclerotic plaque formation. We report here on the correlation between healthy state subendothelial LDL concentration distribution and sites of subsequent plaque formation in coronary arteries of patients with coronary artery disease (CAD). We acquired left (LCA) and right coronary artery (RCA) and atherosclerotic plaque geometries of 60 patients with CAD using dual-source computed tomography angiography. After virtually removing all plaques to obtain an approximation of the arteries healthy state, we calculated LDL concentration in the artery walls as a function of local lumen-side shear stress. We found that maximum subendothelial LDL concentrations at plaque locations were, on average, 45% (RCA) and 187% (LCA) higher than the respective average subendothelial concentration. Our results demonstrate that locally elevated subendothelial LDL concentration correlates with subsequent plaque formation at the same location.