Wall shear stress-related plaque growth of lipid-rich plaques in human coronary arteries: an near-infrared spectroscopy and optical coherence tomography study.

AIMS: Low wall shear stress (WSS) is acknowledged to play a role in plaque development through its influence on local endothelial function. Also, lipid-rich plaques (LRPs) are associated with endothelial dysfunction. However, little is known about the interplay between WSS and the presence of lipids with respect to plaque progression. Therefore, we aimed to study the differences in WSS-related plaque progression between LRPs, non-LRPs, or plaque-free regions in human coronary arteries. METHODS AND RESULTS: In the present single-centre, prospective study, 40 patients who presented with an acute coronary syndrome successfully underwent near-infrared spectroscopy intravascular ultrasound (NIRS-IVUS) and optical coherence tomography (OCT) of at least one non-culprit vessel at baseline and completed a 1-year follow-up. WSS was computed applying computational fluid dynamics to a three-dimensional reconstruction of the coronary artery based on the fusion of the IVUS-segmented lumen with a CT-derived centreline, using invasive flow measurements as boundary conditions. For data analysis, each artery was divided into 1.5 mm/45° sectors. Plaque growth based on IVUS-derived percentage atheroma volume change was compared between LRPs, non-LRPs, and plaque-free wall segments, as assessed by both OCT and NIRS. Both NIRS- and OCT-detected lipid-rich sectors showed a significantly higher plaque progression than non-LRPs or plaque-free regions. Exposure to low WSS was associated with a higher plaque progression than exposure to mid or high WSS, even in the regions classified as a plaque-free wall. Furthermore, low WSS and the presence of lipids had a synergistic effect on plaque growth, resulting in the highest plaque progression in lipid-rich regions exposed to low shear stress. CONCLUSION: This study demonstrates that NIRS- and OCT-detected lipid-rich regions exposed to low WSS are subject to enhanced plaque growth over a 1-year follow-up. The presence of lipids and low WSS proves to have a synergistic effect on plaque growth.

Lipid-rich Plaques Detected by Near-infrared Spectroscopy Are More Frequently Exposed to High Shear Stress.

High wall shear stress (WSS) and near-infrared spectroscopy (NIRS) detected lipid-rich plaque (LRP) are both known to be associated with plaque destabilization and future adverse cardiovascular events. However, knowledge of spatial co-localization of LRP and high WSS is lacking. This study investigated the co-localization of LRP based on NIRS and high WSS. Fifty-three patients presenting acute coronary syndrome underwent NIRS-intravascular-ultrasound (NIRS-IVUS) imaging of a non-culprit coronary artery. WSS was obtained using WSS profiling in 3D-reconstructions of the coronary arteries based on fusion of IVUS-segmented lumen and CT-derived 3D-centerline. Thirty-eight vessels were available for final analysis and divided into 0.5 mm/45° sectors. LRP sectors, as identified by NIRS, were more often colocalized with high WSS than sectors without LRP. Moreover, there was a dose-dependent relationship between lipid content and high WSS exposure. This study is a first step in understanding the evolution of LRPs to vulnerable plaques. Graphical Abstract.

The impact of helical flow on coronary atherosclerotic plaque development.

BACKGROUND AND AIMS: Atherosclerosis has been associated with near-wall hemodynamics and wall shear stress (WSS). However, the role of coronary intravascular hemodynamics, in particular of the helical flow (HF) patterns that physiologically develop in those arteries, is rarely considered. The purpose of this study was to assess how HF affects coronary plaque initiation and progression, definitively demonstrating its atheroprotective nature. METHODS: The three main coronary arteries of five adult hypercholesterolemic mini-pigs on a high fat diet were imaged by computed coronary tomography angiography (CCTA) and intravascular ultrasound (IVUS) at 3 (T1, baseline) and 9.4 ± 1.9 (T2) months follow-up. The baseline geometries of imaged coronary arteries (n = 15) were reconstructed, and combined with pig-specific boundary conditions (based on in vivo Doppler blood flow measurements) to perform computational fluid dynamic simulations. Local wall thickness (WT) was measured on IVUS images at T1 and T2, and its temporal changes were assessed. Descriptors of HF and WSS nature were computed for each model, and statistically compared to WT data. RESULTS: HF intensity was strongly positively associated with WSS magnitude (p < 0.001). Overall, coronary segments exposed to high baseline levels of HF intensity exhibited a significantly lower WT growth (p < 0.05), compared to regions with either mid or low HF intensity. CONCLUSIONS: This study confirms the physiological significance of HF in coronary arteries, revealing its protective role against atherosclerotic WT growth and its potential in predicting regions undergoing WT development. These findings support future in vivo measurement of coronary HF as atherosclerotic risk marker, overcoming current limitations of in vivo WSS assessment.

Multidirectional wall shear stress promotes advanced coronary plaque development: comparing five shear stress metrics.

AIMS: Atherosclerotic plaque development has been associated with wall shear stress (WSS). However, the multidirectionality of blood flow, and thus of WSS, is rarely taken into account. The purpose of this study was to comprehensively compare five metrics that describe (multidirectional) WSS behaviour and assess how WSS multidirectionality affects coronary plaque initiation and progression. METHODS AND RESULTS: Adult familial hypercholesterolaemic pigs (n = 10) that were fed a high-fat diet, underwent imaging of the three main coronary arteries at three-time points [3 (T1), 9 (T2), and 10-12 (T3) months]. Three-dimensional geometry of the arterial lumen, in combination with local flow velocity measurements, was used to calculate WSS at T1 and T2. For analysis, arteries were divided into 3 mm/45° sectors (n = 3648). Changes in wall thickness and final plaque composition were assessed with near-infrared spectroscopy-intravascular ultrasound, optical coherence tomography imaging, and histology. Both in pigs with advanced and mild disease, the highest plaque progression rate was exclusively found at low time-averaged WSS (TAWSS) or high multidirectional WSS regions at both T1 and T2. However, the eventually largest plaque growth was located in regions with initial low TAWSS or high multidirectional WSS that, over time, became exposed to high TAWSS or low multidirectional WSS at T2. Besides plaque size, also the presence of vulnerable plaque components at the last time point was related to low and multidirectional WSS. Almost all WSS metrics had good predictive values for the development of plaque (47-50%) and advanced fibrous cap atheroma (FCA) development (59-61%). CONCLUSION: This study demonstrates that low and multidirectional WSS promote both initiation and progression of coronary atherosclerotic plaques. The high-predictive values of the multidirectional WSS metrics for FCA development indicate their potential as an additional clinical marker for the vulnerable disease.

The influence of multidirectional shear stress on plaque progression and composition changes in human coronary arteries.

AIMS: Local wall shear stress (WSS) plays an important role in the onset of atherosclerotic plaque formation; however, it does not fully explain plaque progression and destabilisation. We aimed to investigate for the first time the influence of multidirectional WSS features on plaque progression and plaque composition changes in human coronary arteries. METHODS AND RESULTS: Coronary artery imaging using biplane angiography and virtual histology intravascular ultrasound (VH-IVUS) was performed in twenty patients with coronary artery disease at baseline and after six-month follow-up. Three-dimensional surfaces of the coronary arteries were generated using the coronary imaging and, together with patient-specific flow measurements, different WSS features (multidirectional and conventional time-averaged WSS [TAWSS]) were determined at baseline using computational fluid dynamics (CFD). The changes in plaque component area over the six-month period were determined from VH-IVUS. Changes in plaque composition rather than plaque size were primarily associated with the (multidirectional) WSS at baseline. Interestingly, regions simultaneously exposed to low TAWSS and low multidirectional WSS showed the greatest plaque progression (p<0.001). CONCLUSIONS: In this patient study, several multidirectional WSS features were found to contribute significantly to coronary plaque progression and changes in plaque composition.

The Atheroprotective Nature of Helical Flow in Coronary Arteries.

Arterial hemodynamics is markedly characterized by the presence of helical flow patterns. Previous observations suggest that arterial helical blood flow is of physiological significance, and that its quantitative analysis holds promise for clinical applications. In particular, it has been reported that distinguishable helical flow patterns are potentially atheroprotective in the carotid bifurcation as they suppress flow disturbances. In this context, there is a knowledge gap about the physiological significance of helical flow in coronary arteries, a prominent site of atherosclerotic plaque formation. This study aimed at the quantitative assessment of helical blood flow in coronary arteries, and to investigate its possible associations with vascular geometry and with atherogenic wall shear stress (WSS) phenotypes in a representative sample of 30 swine coronary arteries. This study demonstrates that in coronary arteries: (1) the hemodynamics is characterized by counter-rotating bi-helical flow structures; (2) unfavorable conditions of WSS are strongly and inversely associated with helicity intensity (r = - 0.91; p < 0.001), suggesting an atheroprotective role for helical flow in the coronary tree; (3) vascular torsion dictates helical flow features (r = 0.64; p < 0.001). The findings of this work support future studies on the role of helical flow in atherogenesis in coronary arteries.

Model-based cap thickness and peak cap stress prediction for carotid MRI.

A rupture-prone carotid plaque can potentially be identified by calculating the peak cap stress (PCS). For these calculations, plaque geometry from MRI is often used. Unfortunately, MRI is hampered by a low resolution, leading to an overestimation of cap thickness and an underestimation of PCS. We developed a model to reconstruct the cap based on plaque geometry to better predict cap thickness and PCS. We used histological stained plaques from 34 patients. These plaques were segmented and served as the ground truth. Sections of these plaques contained 93 necrotic cores with a cap thickness <0.62mm which were used to generate a geometry-based model. The histological data was used to simulate in vivo MRI images, which were manually delineated by three experienced MRI readers. Caps below the MRI resolution (n=31) were (digitally removed and) reconstructed according to the geometry-based model. Cap thickness and PCS were determined for the ground truth, readers, and reconstructed geometries. Cap thickness was 0.07mm for the ground truth, 0.23mm for the readers, and 0.12mm for the reconstructed geometries. The model predicts cap thickness significantly better than the readers. PCS was 464kPa for the ground truth, 262kPa for the readers and 384kPa for the reconstructed geometries. The model did not predict the PCS significantly better than the readers. The geometry-based model provided a significant improvement for cap thickness estimation and can potentially help in rupture-risk prediction, solely based on cap thickness. Estimation of PCS estimation did not improve, probably due to the complex shape of the plaques.

Peak cap stress calculations in coronary atherosclerotic plaques with an incomplete necrotic core geometry.

BACKGROUND: Stress calculations in atherosclerotic coronary vulnerable plaques can aid in predicting coronary cap rupture. In vivo plaque geometry and composition of coronary arteries can merely be obtained via intravascular imaging. Only optical driven imaging techniques have sufficient resolution to visualize the fibrous cap, but due to limited penetration depth deeper components such as the backside of the necrotic core (NC) are generally not visible. The goal of this study was to investigate whether peak cap stresses can be approximated by reconstructing the backside of the NC. METHODS: Manual segmentations of coronary histological cross-sections served as a geometrical ground truth and were obtained from seven patients resulting in 73 NCs. Next, the backside was removed and reconstructed according to an estimation of the relative necrotic core thickness (rNCt). The rNCt was estimated at three locations along the NC angle and based on either group averaged parameters or plaque specific parameters. Stress calculations were performed in both the ground truth geometry and the reconstructed geometries and compared. RESULTS: Good geometrical agreement was found between the ground truth NC and the reconstructed NCs, based on group averaged rNCt estimation and plaque specific rNCt estimation, measuring the NC area difference (25.1 % IQR 14.0-41.3 % and 17.9 % IQR 9.81-32.7 %) and similarity index (0.85 IQR 0.77-0.90 and 0.88 IQR 0.79-0.91). The peak cap stresses obtained with both reconstruction methods showed a high correlation with respect to the ground truth, r(2) = 0.91 and r(2) = 0.95, respectively. For high stress plaques, the peak cap stress difference with respect to the ground truth significantly improved for the NC reconstruction based plaque specific features (6 %) compared to the reconstruction group averaged based (16 %). CONCLUSIONS: In conclusion, good geometry and stress agreement was observed between the ground truth NC geometry and the reconstructed geometries. Although group averaged rNCt estimation seemed to be sufficient for the NC reconstruction and stress calculations, including plaque specific data further improved stress predictions, especially for higher stresses.

Atherosclerosis at arterial bifurcations: evidence for the role of haemodynamics and geometry.

Atherosclerotic plaques are found at distinct locations in the arterial system, despite the exposure to systemic risk factors of the entire vascular tree. From the study of arterial bifurcation regions, emerges ample evidence that haemodynamics are involved in the local onset and progression of the atherosclerotic disease. This observed co-localisation of disturbed flow regions and lesion prevalence at geometrically predisposed districts such as arterial bifurcations has led to the formulation of a 'haemodynamic hypothesis', that in this review is grounded to the most current research concerning localising factors of vascular disease. In particular, this review focuses on carotid and coronary bifurcations because of their primary relevance to stroke and heart attack. We highlight reported relationships between atherosclerotic plaque location, progression and composition, and fluid forces at vessel's wall, in particular shear stress and its 'easier-to-measure' surrogates, i.e. vascular geometric attributes (because geometry shapes the flow) and intravascular flow features (because they mediate disturbed shear stress), in order to give more insight in plaque initiation and destabilisation. Analogous to Virchow's triad for thrombosis, atherosclerosis must be thought of as subject to a triad of, and especially interactions among, haemodynamic forces, systemic risk factors, and the biological response of the wall.

Feasibility of wall stress analysis of abdominal aortic aneurysms using three-dimensional ultrasound.

OBJECTIVE: Abdominal aortic aneurysms (AAAs) are local dilations that can lead to a fatal hemorrhage when ruptured. Wall stress analysis of AAAs is a novel tool that has proven high potential to improve risk stratification. Currently, wall stress analysis of AAAs is based on computed tomography (CT) and magnetic resonance imaging; however, three-dimensional (3D) ultrasound (US) has great advantages over CT and magnetic resonance imaging in terms of costs, speed, and lack of radiation. In this study, the feasibility of 3D US as input for wall stress analysis is investigated. Second, 3D US-based wall stress analysis was compared with CT-based results. METHODS: The 3D US and CT data were acquired in 12 patients (diameter, 35-90 mm). US data were segmented manually and compared with automatically acquired CT geometries by calculating the similarity index and Hausdorff distance. Wall stresses were simulated at P = 140 mm Hg and compared between both modalities. RESULTS: The similarity index of US vs CT was 0.75 to 0.91 (n = 12), with a median Hausdorff distance ranging from 4.8 to 13.9 mm, with the higher values found at the proximal and distal sides of the AAA. Wall stresses were in accordance with literature, and a good agreement was found between US- and CT-based median stresses and interquartile stresses, which was confirmed by Bland-Altman and regression analysis (n = 8). Wall stresses based on US were typically higher (+23%), caused by geometric irregularities due to the registration of several 3D volumes and manual segmentation. In future work, an automated US registration and segmentation approach is the essential point of improvement before pursuing large-scale patient studies. CONCLUSIONS: This study is a first step toward US-based wall stress analysis, which would be the modality of choice to monitor wall stress development over time because no ionizing radiation and contrast material are involved.