The pressure-derived microvascular resistance reserve and its correlation to Doppler MRR measurement-a proof of concept study.

Background: Microvascular resistance reserve (MRR) is a recently introduced specific index of coronary microcirculation. MRR calculation can utilize parameters deriving from coronary flow reserve (CFR) assessment, provided that intracoronary pressure data are also available. The previously proposed pressure-bounded CFR (CFRpb) defines the possible CFR interval on the basis of resting and hyperemic pressure gradients in the epicardial vessel, however, its correlation to the Doppler wire measurement was reported to be rather poor without the correction for hydrostatic pressure. Purpose: We aimed to determine the pressure-bounded coronary MRR interval with hydrostatic pressure correction according to the previously established equations of CFRpb adapted for the MRR concept. Furthermore, we also aimed to design a prediction model using the actual MRR value within the pressure-bounded interval and validate the results against the gold-standard Doppler wire technique. Methods: Hydrostatic pressure between the tip of the catheter and the sensor of the pressure wire was calculated by height difference measurement from a lateral angiographic view. In the derivation cohort the pressure-bounded MRR interval (between MRRpbmin and MRRpbmax) was determined solely from hydrostatic pressure-corrected intracoronary pressure data. The actual MRR was calculated by simple hemodynamic equations incorporating the anatomical data of the three-dimensionally reconstructed coronary artery (MRRp-3D). These results were analyzed by regression analyses to find relations between the MRRpb bounds and the actual MRRp-3D. Results: In the derivation cohort of 23 measurements, linear regression analysis showed a tight relation between MRRpbmax and MRRp-3D (r 2 = 0.74, p < 0.0001). Using this relation (MRRp-3D = 1.04 + 0.51 × MRRpbmax), the linear prediction of the MRR was tested in the validation cohort of 19 measurements against the gold standard Doppler wire technique. A significant correlation was found between the linearly predicted and the measured values (r = 0.54, p = 0.01). If the area stenosis (AS%) was included to a quadratic prediction model, the correlation was improved (r = 0.63, p = 0.004). Conclusions: The MRR can be predicted reliably to assess microvascular function by our simple model. After the correction for hydrostatic pressure error, the pressure data during routine FFR measurement provides a simultaneous physiological assessment of the macro- and microvasculature.

Non-Invasive Tools in Perioperative Stroke Risk Assessment for Asymptomatic Carotid Artery Stenosis with a Focus on the Circle of Willis.

This review aims to explore advancements in perioperative ischemic stroke risk estimation for asymptomatic patients with significant carotid artery stenosis, focusing on Circle of Willis (CoW) morphology based on the CTA or MR diagnostic imaging in the current preoperative diagnostic algorithm. Functional transcranial Doppler (fTCD), near-infrared spectroscopy (NIRS), and optical coherence tomography angiography (OCTA) are discussed in the context of evaluating cerebrovascular reserve capacity and collateral vascular systems, particularly the CoW. These non-invasive diagnostic tools provide additional valuable insights into the cerebral perfusion status. They support biomedical modeling as the gold standard for the prediction of the potential impact of carotid artery stenosis on the hemodynamic changes of cerebral perfusion. Intraoperative risk assessment strategies, including selective shunting, are explored with a focus on CoW variations and their implications for perioperative ischemic stroke and cognitive function decline. By synthesizing these insights, this review underscores the potential of non-invasive diagnostic methods to support clinical decision making and improve asymptomatic patient outcomes by reducing the risk of perioperative ischemic neurological events and preventing further cognitive decline.

Comparison of Flow Reduction Efficacy of Nominal and Oversized Flow Diverters Using a Novel Measurement-assisted in Silico Method.

PURPOSE: The high efficacy of flow diverters (FD) in the case of wide-neck aneurysms is well demonstrated, yet new challenges have arisen because of reported posttreatment failures and the growing number of new generation of devices. Our aim is to present a measurement-supported in silico workflow that automates the virtual deployment and subsequent hemodynamic analysis of FDs. In this work, the objective is to analyze the effects of FD deployment variability of two manufacturers on posttreatment flow reduction. METHODS: The virtual deployment procedure is based on detailed mechanical calibration of the flow diverters, while the flow representation is based on hydrodynamic resistance (HR) measurements. Computational fluid dynamic simulations resulted in 5 untreated and 80 virtually treated scenarios, including 2 FD designs in nominal and oversized deployment states. The simulated aneurysmal velocity reduction (AMVR) is correlated with the HR values and deployment scenarios. RESULTS: The linear HR coefficient and AMVR revealed a power-law relationship considering all 80 deployments. In nominal deployment scenarios, a significantly larger average AMVR was obtained (60.3%) for the 64-wire FDs than for 48-wire FDs (51.9%). In oversized deployments, the average AMVR was almost the same for 64-wire and 48-wire device types, 27.5% and 25.7%, respectively. CONCLUSION: The applicability of our numerical workflow was demonstrated, also in large-scale hemodynamic investigations. The study revealed a robust power-law relationship between a HR coefficient and AMVR. Furthermore, the 64 wire configurations in nominal sizing produced a significantly higher posttreatment flow reduction, replicating the results of other in vitro studies.

Potential Clinical Usefulness of Post-Valvular Contrast Densities to Determine the Severity of Aortic Valve Stenosis Using Computed Tomography.

BACKGROUND: Different methods are established for the changes in aortic valve stenosis with cardiac computed tomography angiography (CCTA), but the effect of the grade of stenosis on contrast densities around the valve has not been investigated. AIMS/METHODS: Using the information from flow dynamics in cases of increased velocity through narrowed lumen, the hypothesis was formed that flow changes can alter the contrast densities in stenotic post-valvular regions, and the density changes might correlate with the grade of stenosis. Forty patients with severe aortic stenosis and fifteen with a normal aortic valve were enrolled. With echocardiography, the peak/mean transvalvular gradients, peak transvalvular velocity, and aortic valve opening area were obtained. With CCTA, densities 4-5 mm above the aortic valve; at the junction of the left, right, and noncoronary cusp to the annulus; at the middle level of the left, right, and noncoronary sinuses of Valsalva in the center and the lateral points; at the sinotubular junction; and 4 cm from the sinotubular junction at the midline were measured. First, a comparison of the densities between the normal and stenotic valve was performed, and then possible correlations between echocardiography and CCTA values were investigated in the stenotic group. RESULTS: In all CCTA regions, significantly lower-density values were detected among stenotic valve patients compared to the normal aortic valve population. Additionally, in both groups, higher densities were measured in the peri-jet regions than in the lateral ones. Furthermore, a good correlation was found between the aortic valve opening area and the densities in almost all perivalvular areas. With regard to the densities at the junction of the non-coronary leaflet to the fibrotic annulus and at the most lateral point of the right sinus of Valsalva, a high level of correlation was found between all echocardiography and CCTA parameters. Lastly, with receiver operating characteristic curve measurements, area under the curve values were between 0.857 and 0.930. CONCLUSION: Certain CCTA density values, especially 4-5mm above the valve opening, can serve as auxiliary information to echocardiography when the severity of aortic valve stenosis is unclear.

Simplified coronary flow reserve calculations based on three-dimensional coronary reconstruction and intracoronary pressure data.

BACKGROUND: Measurements of fractional flow reserve (FFR) and/or coronary flow reserve (CFR) are widely used for hemodynamic characterization of coronary lesions. The frequent combination of the epicardial and microvascular disease may indicate a need for complex hemodynamic evaluation of coronary lesions. This study aims at validating the calculation of CFR based on a simple hemodynamic model to detailed computational fluid dynamics (CFD) analysis. METHODS: Three-dimensional (3D) morphological data and pressure values from FFR measurements were used to calculate the target vessel. Nine patients with one intermediate stenosis each, measured by pressure wire, were included in this study. RESULTS: A correlation was found between the determined CFR from simple equations and from a steady flow simulation (r = 0.984, p < 10-5). There was a significant correlation between the CFR values calculated by transient and steady flow simulations (r = 0.94, p < 10-3). CONCLUSIONS: Feasibility was demonstrated of a simple hemodynamic calculation of CFR based on 3D-angiography and intracoronary pressure measurements. A simultaneous determination of both the FFR and CFR values provides the capability to diagnose microvascular dysfunction: the CFR/FFR ratio characterizes the microvascular reserve.

Novel Method to Detect Pitfalls of Intracoronary Pressure Measurements by Pressure Waveform Analysis.

Potential pitfalls of fractional flow reserve (FFR) measurements are well-known drawbacks of invasive physiology measurement, e.g., significant drift of the distal pressure trace may lead to the misclassification of stenoses. Thus, a simultaneous waveform analysis of the pressure traces may be of help in the quality control of these measurements by online detection of such artefacts as the drift or the wedging of the catheter. In the current study, we analysed the intracoronary pressure waveform with a dedicated program. In 130 patients, 232 FFR measurements were performed and derivative pressure curves were calculated. Local amplitude around the dicrotic notch was calculated from the distal intracoronary pressure traces (δdPn/dt). A unidimensional arterial network model of blood flow was employed to simulate the intracoronary pressure traces at different flow rates. There was a strong correlation between δdPn/dt values measured during hyperaemia and FFR (r = 0.88). Diagnostic performance of distal δdPn/dt ≤ 3.52 for the prediction of FFR ≤ 0.80 was 91%. The correlation between the pressure gradient and the corresponding δdPn/dt values obtained from all measurements independently of the physiological phase was also significant (r = 0.80). During simulation, the effect of flow rate on δdPn/dt further supported the close correlation between the pressure ratios and δdPn/dt. Discordance between the FFR and the δdPn/dt can be used as an indicator of possible technical problems of FFR measurements. Hence, an online calculation of the δdPn/dt may be helpful in avoiding some pitfalls of FFR evaluation.

Pressure- and 3D-Derived Coronary Flow Reserve with Hydrostatic Pressure Correction: Comparison with Intracoronary Doppler Measurements.

Purpose: To develop a method of coronary flow reserve (CFR) calculation derived from three-dimensional (3D) coronary angiographic parameters and intracoronary pressure data during fractional flow reserve (FFR) measurement. Methods: Altogether 19 coronary arteries of 16 native and 3 stented vessels were reconstructed in 3D. The measured distal intracoronary pressures were corrected to the hydrostatic pressure based on the height differences between the levels of the vessel orifice and the sensor position. Classical fluid dynamic equations were applied to calculate the flow during the resting state and vasodilatation based on morphological data and intracoronary pressure values. 3D-derived coronary flow reserve (CFRp-3D) was defined as the ratio between the calculated hyperemic and the resting flow and was compared to the CFR values simultaneously measured by the Doppler sensor (CFRDoppler). Results: Haemodynamic calculations using the distal coronary pressures corrected for hydrostatic pressures showed a strong correlation between the individual CFRp-3D values and the CFRDoppler measurements (r = 0.89, p < 0.0001). Hydrostatic pressure correction increased the specificity of the method from 46.1% to 92.3% for predicting an abnormal CFRDoppler < 2. Conclusions: CFRp-3D calculation with hydrostatic pressure correction during FFR measurement facilitates a comprehensive hemodynamic assessment, supporting the complex evaluation of macro-and microvascular coronary artery disease.

Impact of Design and Deployment Technique on the Hydrodynamic Resistance of Flow Diverters : An in Vitro Experimental Study.

PURPOSE: Despite the high efficacy of flow diverters (FD) in treating sidewall intracranial aneurysms, failures are reported. One of the physical factors determining efficacy is the flow reducing capacity of the FD that is currently unknown to the operator. Our aim was to measure the flow reducing capacity expressed as the hydrodynamic resistance (HR), the metallic surface area (MSA) and pore density (PD) of two different FD designs and quantitatively investigate the impact of sizing and the deployment technique on these parameters. METHODS: Altogether 38 Pipeline (Medtronic) and P64 (Phenox) FD­s were implanted in holder tubes by a neurointerventionist in nominally sized, oversized and longitudinally compressed or elongated manners. The tubes were placed in a flow model with the flow directed across the FD through a side hole on the tube. HR was expressed by the measured pressure drop as the function of the flow rate. Deployed length, MSA and PD were also measured and correlated with the HR. RESULTS: Both PD and MSA changed with varying deployment length, which correlates well with the change in HR. Oversizing the device by 1 mm in diameter has reduced the HR on average to one fifth of the original value for both manufacturers. CONCLUSION: This study demonstrates experimentally that different FD designs have different flow diverting capacities (HR). Parameters are greatly influenced by radial sizing and longitudinal compression or elongation during implantation. Our results might be useful in procedure planning, predicting clinical outcome, and in patient-specific numerical flow simulations.

Nanonewton scale adhesion force measurements on biotinylated microbeads with a robotic micropipette.

Binding force between biomolecules has a crucial role in most biological processes. Receptor-ligand interactions transmit physical forces and signals simultaneously. Previously, we employed a robotic micropipette both in live cell and microbead adhesion studies to explore the adhesion force of biomolecules such as cell surface receptors including specific integrins on immune cells. Here we apply standard computational fluid dynamics simulations to reveal the detailed physical background of the flow generated by the micropipette when probing microbead adhesion on functionalized surfaces. Measuring the aspiration pressure needed to pick up the biotinylated 10 µm beads on avidin coated surfaces and converting it to a hydrodynamic lifting force on the basis of simulations, we found an unbinding force of 12 ± 2 nN, when targeting the beads manually; robotic targeting resulted in 9 ± 4 nN (mean ± SD). We measured and simulated the effect of the targeting offset, when the microbead was out of the axis (off-axis)of the micropipette. According to the simulations, the higher offset resulted in a higher lifting force acting on the bead. Considering this effect, we could readily correct the impact of the targeting offset to renormalize the experimental data. Horizontal force and torque also appeared in simulations in case of a targeting offset. Surprisingly, simulations show that the lifting force acting on the bead reaches a maximum at a flow rate of ~ 5 µl/s if the targeting offset is not very high (<5 µm). Further increasing the flow rate decreases the lifting force. We attribute this effect to the spherical geometry of the bead. We predict that higher flow rates cannot increase the hydrodynamic lifting force acting on the precisely targeted microbead, setting a fundamental force limit (16 nN in our setup) for manipulating microbeads with a micropipette perpendicular to the supporting surface. In order to extend the force range, we propose the offset targeting of microbeads.

The Holistic Coronary Physiology Display: Calculation of the Flow Separation Index in Vessel-Specific Individual Flow Range during Fractional Flow Reserve Measurement Using 3D Coronary Reconstruction.

In order to make optimal decisions on the treatment of atherosclerotic coronary heart disease (CHD), appropriate evaluation is necessary, including both the anatomical and physiological assessment of the coronary arteries. According to current guidelines, a fractional flow reserve (FFR)-based clinical decision is recommended, but coronary flow reserve (CFR) measurements and microvascular evaluation should also be considered in special cases for a detailed exploration of the coronary disease state. We aimed to generate an extended physiological evaluation during routine FFR measurement and define a new pathological flow-related prognostic factor. Fluid dynamic equations were applied to calculate CFR on the basis of the three-dimensional (3D) reconstruction of the invasively acquired coronary angiogram and the measured intracoronary pressure data. A new, potentially robust prognostic parameter of a coronary lesion called the "flow separation index" (FSi), which is thought to detect the pathological flow amount through a stenosis was introduced in a vessel-specific flow range. Correlations between FSi and the clinically established physiological indices (CFR and FFR) were determined. The FSi was calculated in 19 vessels of 16 patients, including data from the pre- and post-stent revascularization treatment of 3 patients. There was no significant correlation between the FSi and the CFR (r = -0.23, p = 0.34); however, there was significant negative correlation between the FSi and the FFR (r = -0.66, p = 0.002). An even stronger correlation was found between the FSi and the ratio of the resting pressure ratio and the FFR (r = 0.92, p < 0.0001). The diagnostic power of the FSi for predicting the FFR value of <0.80, as a gold standard prognostic factor, was tested by receiver operating characteristic analysis. FSi > 0.022 proved to be the cutoff value of the prediction of a pathologically low FFR with a 0.856 area under the curve (95% confidence interval: 0.620 to 0.972). The present flow-pressure-velocity display provides a comprehensive summary of patient-specific pathophysiology in CHD. The consequences of epicardial stenoses can be evaluated together with their complex relations to microvascular conditions. Based on these values, clinical decision-making concerning both pharmacological therapy and percutaneous or surgical revascularization may be more precisely guided.

A novel virtual flow diverter implantation method with realistic deployment mechanics and validated force response.

Virtual flow diverter deployment techniques underwent significant development during the last couple of years. Each existing technique displays advantageous features, as well as significant limitations. One common drawback is the lack of quantitative validation of the mechanics of the device. In the following work, we present a new spring-mass-based method with validated mechanical responses that combines many of the useful capabilities of previous techniques. The structure of the virtual braids naturally incorporates the axial length changes as a function of the local expansion diameter. The force response of the model was calibrated using the measured response of real FDs. The mechanics of the model allows to replicate the expansion process during deployment, including additional effects such as the push-pull technique that is required for the deployment of braided FDs to achieve full opening and proper wall apposition. Furthermore, it is a computationally highly efficient solution that requires little pre-processing and has a run-time of a few seconds on a general laptop and thus allows for exploratory analyses. The model was applied in a patient-specific geometry, where corresponding accurate control measurements in a 3D-printed model were also available. The analysis shows the effects of FD oversizing and push-pull application on the radial expansion, surface density, and on the wall contact pressure.

Hydrodynamic Resistance of Intracranial Flow-Diverter Stents: Measurement Description and Data Evaluation.

PURPOSE: Intracranial aneurysms are malformations forming bulges on the walls of brain arteries. A flow diverter device is a fine braided wire structure used for the endovascular treatment of brain aneurysms. This work presents a rig and a protocol for the measurement of the hydrodynamic resistance of flow diverter stents. Hydrodynamic resistance is interpreted here as the pressure loss versus volumetric flow rate function through the mesh structure. The difficulty of the measurement is the very low flow rate range and the extreme sensitivity to contamination and disturbances. METHODS: Rigorous attention was paid to reproducibility, hence a strict protocol was designed to ensure controlled circumstances and accuracy. Somewhat unusually, the history of the development of the rig, including the pitfalls was included in the paper. In addition to the hydrodynamic resistance measurements, the geometrical properties-metallic surface area, pore density, deployed and unconstrained length and diameter-of the stent deployment were measured. RESULTS: Based on our evaluation method a confidence band can be determined for a given deployment scenario. Collectively analysing the hydrodynamic resistance and the geometric indices, a deeper understanding of an implantation can be obtained. Our results suggest that to correctly interpret the hydrodynamic resistance of a scenario, the deployment length has to be considered. To demonstrate the applicability of the measurement, as a pilot study the results of four intracranial flow diverter stents of two types and sizes have been reported in this work. The results of these measurements even on this small sample size provide valuable information on differences between stent types and deployment scenarios.

Multiple Aneurysms AnaTomy CHallenge 2018 (MATCH)-phase II: rupture risk assessment.

PURPOSE: Assessing the rupture probability of intracranial aneurysms (IAs) remains challenging. Therefore, hemodynamic simulations are increasingly applied toward supporting physicians during treatment planning. However, due to several assumptions, the clinical acceptance of these methods remains limited. METHODS: To provide an overview of state-of-the-art blood flow simulation capabilities, the Multiple Aneurysms AnaTomy CHallenge 2018 (MATCH) was conducted. Seventeen research groups from all over the world performed segmentations and hemodynamic simulations to identify the ruptured aneurysm in a patient harboring five IAs. Although simulation setups revealed good similarity, clear differences exist with respect to the analysis of aneurysm shape and blood flow results. Most groups (12/71%) included morphological and hemodynamic parameters in their analysis, with aspect ratio and wall shear stress as the most popular candidates, respectively. RESULTS: The majority of groups (7/41%) selected the largest aneurysm as being the ruptured one. Four (24%) of the participating groups were able to correctly select the ruptured aneurysm, while three groups (18%) ranked the ruptured aneurysm as the second most probable. Successful selections were based on the integration of clinically relevant information such as the aneurysm site, as well as advanced rupture probability models considering multiple parameters. Additionally, flow characteristics such as the quantification of inflow jets and the identification of multiple vortices led to correct predictions. CONCLUSIONS: MATCH compares state-of-the-art image-based blood flow simulation approaches to assess the rupture risk of IAs. Furthermore, this challenge highlights the importance of multivariate analyses by combining clinically relevant metadata with advanced morphological and hemodynamic quantification.

A new hypothesis on the role of vessel topology in cerebral aneurysm initiation.

Aneurysm pathogenesis is thought to be strongly linked with hemodynamical effects. According to our current knowledge, the formation process is initiated by locally disturbed flow conditions. The aim of the current work is to provide a numerical investigation on the role of the flow field at the stage of the initiation, before the aneurysm formation. Digitally reconstructed pre-aneurysmal geometries are used to examine correlations of the flow patterns to the location and direction of the aneurysms formed later. We argue that a very specific rotational flow pattern is present in all the investigated cases marking the location of the later aneurysm and that these flow patterns provide the mechanical load on the wall that can lead to a destructive remodelling in the vessel wall. Furthermore, these patterns induce elevated vessel surface related variables (e.g. wall shear stress (WSS), wall shear stress gradient (WSSG) and oscillatory shear index (OSI)), in agreement with the previous findings. We emphasise that the analysis of the flow patterns provides a deeper insight and a more robust numerical methodology compared to the sole examination of the aforementioned surface quantities.

Multiple Aneurysms AnaTomy CHallenge 2018 (MATCH): Phase I: Segmentation.

PURPOSE: Advanced morphology analysis and image-based hemodynamic simulations are increasingly used to assess the rupture risk of intracranial aneurysms (IAs). However, the accuracy of those results strongly depends on the quality of the vessel wall segmentation. METHODS: To evaluate state-of-the-art segmentation approaches, the Multiple Aneurysms AnaTomy CHallenge (MATCH) was announced. Participants carried out segmentation in three anonymized 3D DSA datasets (left and right anterior, posterior circulation) of a patient harboring five IAs. Qualitative and quantitative inter-group comparisons were carried out with respect to aneurysm volumes and ostia. Further, over- and undersegmentation were evaluated based on highly resolved 2D images. Finally, clinically relevant morphological parameters were calculated. RESULTS: Based on the contributions of 26 participating groups, the findings reveal that no consensus regarding segmentation software or underlying algorithms exists. Qualitative similarity of the aneurysm representations was obtained. However, inter-group differences occurred regarding the luminal surface quality, number of vessel branches considered, aneurysm volumes (up to 20%) and ostium surface areas (up to 30%). Further, a systematic oversegmentation of the 3D surfaces was observed with a difference of approximately 10% to the highly resolved 2D reference image. Particularly, the neck of the ruptured aneurysm was overrepresented by all groups except for one. Finally, morphology parameters (e.g., undulation and non-sphericity) varied up to 25%. CONCLUSIONS: MATCH provides an overview of segmentation methodologies for IAs and highlights the variability of surface reconstruction. Further, the study emphasizes the need for careful processing of initial segmentation results for a realistic assessment of clinically relevant morphological parameters.