Rationale and Objectives: While calcification is a highly prevalent component in atherosclerotic extracranial carotid arteries and is known to impact plaque stability, the link between carotid calcification and ischemic events is yet to be identified. We aimed to investigate the associations of geometric features of carotid calcifications, and their temporal changes, with ischemic events. Materials and Methods: We retrospectively analyzed 128 mildly stenotic carotid arteries (Plaque At Risk study) from 64 patients with recent ischemic event, using multi-detector computed tomography angiography data at baseline and after 2 years. The 3D artery and calcification geometries were reconstructed with a semi-automatic pipeline, and an in-depth calcification morphometric assessment was performed. We examined the distribution of the calcification morphometrics and their temporal changes and investigated their associations with ischemic events at the time of inclusion, using generalized linear mixed models. Results: At baseline, compared to contralateral asymptomatic arteries, symptomatic carotids had more calcification bodies (mean [95%CI]: 1.9 [1.4–2.6] vs. 1.6 [1.2–2.2]). These calcifications were smaller (mean area [95%CI]: 3.7 mm² [2.9–5.1] vs. 4.5 mm² [3.5–5.8]) and narrower (mean width [95%CI]: 2.7 mm [2.3–3.4] vs. 3.1 mm [2.5–3.6]). At 2-year follow-up, adjusting for baseline measurements, these calcifications were smaller (mean width [95%CI]: 2.9 mm [2.5–3.5] vs. 3.3 mm [2.7–3.7]) and longer (mean [95%CI]: 8.6 mm [7.1–10.5] vs. 7.5 mm [6.3–9.5]) compared to asymptomatic side. Conclusion: Symptomatic carotid arteries presented more and smaller calcifications with a tendency to grow more in the longitudinal artery direction, providing insights into the role of carotid calcifications in ischemic events.

Introduction: Ischemic stroke incidence varies significantly with respect to sex and cardiovascular risk factors (CVRFs), a relationship that it is not well understood. Calcification in carotid atherosclerosis is known to impact plaque stability, potentially linked to ischemic stroke. The objective was to assess the in-depth calcification morphometrics within extracranial carotid atherosclerosis, their temporal changes, and associations with sex and CVRFs. Methods: Carotid arteries (n = 144) with confirmed atherosclerosis and mild-to-moderate stenosis from 72 symptomatic patients (Plaque-At-Risk study) with recent ischemic event due to ischemia in the territory of a carotid artery were imaged using multidetector computed tomography angiography (MDCTA) at baseline and after 2 years. The lumen, vessel wall, and calcifications were segmented semiautomatically, and the carotid geometries were 3D reconstructed. A comprehensive morphometric assessment of carotid calcifications was performed on the baseline and followup scans. We investigated distributions of these metrics and their associations with sex and CVRFs using generalized linear mixed models. Results: Our findings suggest that women have larger (4.5 mm2 [95% CI: 3.2-6.2] vs. 3.2 mm2 [95% CI: 2.4-4.2]) calcifications, located closer to the lumen (0.6 mm [95% CI: 0.4-0.8] vs. 0.9 mm [95% CI: 0.7-1.2]) in contrast to men at baseline and follow-up, adjusted for baseline measurements. At the baseline, nonsmokers had larger (5.3 mm2 [95% CI: 3.7-7.5] vs. 3.2 mm2 [95% CI: 2.3-4.4]) and longer (5.7 mm [95% CI: 4.1-7.3] vs. 2.4 mm [95% CI: 1.6-3.6]) calcifications than the current smokers. Diabetic patients had thicker (1.1 mm [95% CI: 0.8-1.3] vs. 0.8 mm [95% CI: 0.7-0.9]) carotid calcifications at baseline. Conclusion: Our in-depth analyses exposed several geometric features of carotid calcifications associated with sex and CVRFs and provided further insight into the pathophysiology of carotid atherosclerosis.

Background and aims: Local biomechanical factors are known to influence atherosclerosis in extracranial carotid arteries. While the role of some flow-driven biomechanical factors has been investigated, the influence of pressure-driven mechanical wall stress (MWS) has received limited attention. In this study, the association of the pressure-driven and flow-driven biomechanical factors with carotid atherosclerosis was examined. Methods: Carotid arteries (n = 150) with mild-to-moderate stenosis from 75 symptomatic patients (Plaque-At-Risk study) were imaged using multi-detector computed tomography angiography (MDCTA) at the time of inclusion and after 2 years. Structural changes in carotid wall and calcifications were quantified from MDCTA data while the local baseline biomechanical factors in the carotids were determined using fluid-structure interaction (FSI) computational models. The associations of the local pressure-driven and flow-driven biomechanical factors with the carotid wall and calcification changes were studied using Generalized Linear Mixed models. Results: Over two years, plaque sectors, with calcified and non-calcified sectors combined, exhibited minimal change in wall thickness, likely due to medical treatment. High MWS was associated (p < 0.001) with a reduction in plaque thickness. In calcified plaque sectors, high MWS and low oscillatory shear index (OSI) were associated (p < 0.001) with greater calcification thickness increase. The distance between the lumen and calcification decreased over time, especially in the sectors exposed to high time-averaged wall shear stress (TAWSS) and high MWS. Conclusions: Our results suggest that the pressure-driven local MWS and flow-driven OSI and TAWSS significantly correlate with the development of calcified and non-calcified plaques in carotid arteries. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01208025.

Background and objective: Although the association of wall shear stress (WSS) with coronary artery disease has been well studied, that of mechanical wall stress (MWS) is mainly overlooked. In this study, we performed in-silico artery-specific modeling to investigate the involvement of both MWS and WSS in coronary artery disease. Methods: Fifteen coronary arteries from five adult familial hypercholesterolemic pigs were imaged by coronary computed tomography angiography, intravascular ultrasound, and optical coherence tomography at three time points (3, 9, and 12 months). Local WSS and MWS in 3 mm/45° sectors were determined using artery-specific computational models. The relationship of WSS and MWS with wall thickness change (ΔWT) over time was statistically analyzed using Generalized Linear Mixed models. Results: A positive ΔWT was measured in all sectors, where plaque sectors presented a greater ΔWT rate compared to plaque-free sectors. In plaque-free sectors, low WSS was associated with a higher ΔWT rate (p < 0.001). In plaque sectors, high MWS was associated with a higher ΔWT rate (p < 0.05), where ΔWT rate was, although slightly, even greater in the plaque sectors with lipid-rich necrotic core (p < 0.05). Conclusions: Our results from in-silico coronary-specific models suggest that WSS and MWS may play a dominant role at different stages of coronary artery disease. WSS may be more critical in the early stages of plaque formation while MWS might have greater significance in the progression of existing plaques.

BACKGROUND: Kidney disease is the most important predictor of death in patients with a Fontan circulation, yet its clinical and hemodynamic correlates have not been well established. METHODS AND RESULTS: A total of 53 ambulatory patients with a Fontan circulation (median age, 16.2 years, 52.8% male patients) underwent advanced cardiovascular magnetic resonance assessment, including 4-dimensional flow imaging and computational fluid dynamics. Estimated glomerular filtration rate (eGFR) <90 mL/min per 1.73 m2 was observed in 20.8% and albumin-to-creatinine ratio >3 mg/mmol in 39.6%. The average eGFR decline rate was -1.83 mL/min per 1.73 m2 per year (95% CI, -2.67 to -0.99; P<0.001). Lower eGFR was associated with older age, larger body surface area at examination, longer time since Fontan procedure, and lower systemic ventricular ejection fraction. Higher albumin-to-creatinine ratio was associated with absence of fenestration at the Fontan operation, and older age and lower systemic ventricular ejection fraction at the assessment. Lower cross-sectional area of the Fontan conduit indexed to flow (r=0.32, P=0.038), higher inferior vena cava-conduit velocity mismatch factor (r=-0.35, P=0.022), higher kinetic energy indexed to flow in the total cavopulmonary connection (r=-0.59, P=0.005), and higher total cavopulmonary connection resistance (r=-0.42, P=0.005 at rest; r=-0.43, P=0.004 during exercise) were all associated with lower eGFR but not with albuminuria. CONCLUSIONS: Kidney dysfunction and albuminuria are common among clinically well adolescents and young adults with a Fontan circulation. Advanced cardiovascular magnetic resonance-derived metrics indicative of declining Fontan hemodynamics are associated with eGFR and might serve as targets to improve kidney health. Albuminuria might be driven by other factors that need further investigation.

Background and aims: Atherosclerotic plaque onset and progression are known to be affected by local biomechanical factors. While the role of wall shear stress (WSS) has been studied, the impact of another biomechanical factor, namely mechanical wall stress (MWS), remains poorly understood. In this study, we investigated the association of MWS, independently and combined with WSS, towards atherosclerosis in coronary arteries. Methods: Thirty-four human coronary arteries were analyzed using near-infrared spectroscopy intravascular ultrasound (NIRS-IVUS) and optical coherence tomography (OCT) at baseline and after 12 months. Baseline WSS and MWS were calculated using computational models, and wall thickness (ΔWT) and lipid-rich necrotic core size (ΔLRNC) change were measured in non-calcified coronary segments. The arteries were further divided into 1.5 mm/45° sectors and categorized as plaque-free or plaque sectors. For each category, associations between biomechanical factors (WSS & MWS) and changes in coronary wall (ΔWT & ΔLRNC) were studied using linear mixed models. Results: In plaque-free sectors, higher MWS (p < 0.001) was associated with greater vessel wall growth. Plaque sectors demonstrated wall thickness reduction over time, likely due to medical therapy, where higher levels of WSS and WMS, individually and combined, (p < 0.05) were associated with a greater reduction. Sectors with low MWS combined with high WSS demonstrated the highest LRNC increase (p < 0.01). Conclusions: In this study, we investigated the association of the (largely-overlooked) biomechanical factor MWS with coronary atherosclerosis, individually and combined with WSS. Our results demonstrated that both MWS and WSS significantly correlate with atherosclerotic plaque initiation and development.

Background: Optimal timing of pulmonary valve replacement (PVR) in Tetralogy of Fallot (TOF) patients remains challenging. Ventricular wall stress is considered to be an early marker of right ventricular (RV) dysfunction.

Objectives: To investigate the association of RV wall stresses and their change over time with functional parameters in TOF patients.

Methods: Ten TOF patients after surgical repair with moderate/severe pulmonary regurgitation were included. At two timepoints (median follow-up time 7.2 years), patient-specific computational biventricular models for wall stress assessment were created using CMR short-axis cine images and echocardiography-based RV pressures. RV ejection fraction (RVEF), NT-proBNP and cardiopulmonary exercise tests were used as outcome measures reflecting RV function. Associations between regional RV diastolic wall stress and RV function were investigated using linear mixed models.

Results: Increased wall stress correlated with lower RV mass (rrm = −0.70, p = 0.017) and lower RV mass-to-volume (rrm = −0.80, p = 0.003) using repeated measures. Wall stress decreased significantly over time, especially in patients with a stable RVEF (p < 0.001). Higher wall stress was independently associated with lower RVEF, adjusted for left ventricular ejection fraction, RV end-diastolic volume and time since initial surgery (decrease of 1.27% RVEF per kPa increase in wall stress, p = 0.029) using repeated measurements. No association was found between wall stress, NT-proBNP, and exercise capacity.

Conclusions: Using a computational method to calculate wall stress locally in geometrically complex ventricles, we demonstrated that lower wall stress might be important to maintain ventricular function. RV wall stress assessment can be used in serial follow-up, and is potentially an early marker of impending RV dysfunction.

The role of wall shear stress (WSS) in atherosclerotic plaque development is evident, but the relation between WSS and plaque composition in advanced atherosclerosis, potentially resulting in plaque destabilization, is a topic of discussion. Using our previously developed image registration pipeline, we investigated the relation between two WSS metrics, time-averaged WSS (TAWSS) and the oscillatory shear index (OSI), and the local histologically determined plaque composition in a set of advanced human carotid plaques. Our dataset of 11 carotid endarterectomy samples yielded 87 histological cross-sections, which yielded 511 radial bins for analysis. Both TAWSS and OSI values were subdivided into patient-specific low, mid, and high tertiles. This cross-sectional study shows that necrotic core (NC) size and macrophage area are significantly larger in areas exposed to high TAWSS or low OSI. Local TAWSS and OSI tertile values were generally inversely related, as described in the literature, but other combinations were also found. Investigating the relation between plaque vulnerability features and different combinations of TAWSS and OSI tertile values revealed a significantly larger cap thickness in areas exposed to both low TAWSS and low OSI. In conclusion, our study confirmed previous findings, correlating high TAWSS to larger macrophage areas and necrotic core sizes. In addition, our study demonstrated new relations, correlating low OSI to larger macrophage areas, and a combination of low TAWSS and low OSI to larger cap thickness.

Optical imaging techniques that provide free space, label free imaging are powerful tools in obtaining structural and biochemical information in biological samples. To date, most of the optical imaging technologies create images with a specific contrast and require multimodality integration to add additional contrast. In this study, we demonstrate spectroscopic Thermo-elastic Optical Coherence Tomography (TE-OCT) as a potential tool in tissue identification. TE-OCT creates images based on two different forms of contrast: optical reflectance and thermo-elastic deformation. TE-OCT uses short laser pulses to induce thermo-elastic tissue deformation and measures the resulting surface displacement using phase-sensitive OCT. In this work we characterized the relation between thermo-elastic displacement and optical absorption, excitation, fluence and illumination area. The experimental results were validated with a 2-dimensional analytical model. Using spectroscopic TE-OCT, the thermo-elastic spectra of elastic phantoms and tissue components in coronary arteries were extracted. Specific tissue components, particularly lipid, an important biomarker for identifying atherosclerotic lesions, can be identified in the TE-OCT spectral response. As a label-free, free-space, dual-contrast, all-optical imaging technique, spectroscopic TE-OCT holds promise for biomedical research and clinical pathology diagnosis.

Coronary calcification represents a challenge in the treatment of coronary artery disease by stent placement. It negatively affects stent expansion and has been related to future adverse cardiac events. Intravascular ultrasound (IVUS) is known for its high sensitivity in detecting coronary calcification. At present, automated quantification of calcium as detected by IVUS is not available. For this reason, we developed and validated an optimized framework for accurate automated detection and quantification of calcified plaque in coronary atherosclerosis as seen by IVUS. Calcified lesions were detected by training a supported vector classifier per IVUS A-line on manually annotated IVUS images, followed by post-processing using regional information. We applied our framework to 35 IVUS pullbacks from each of the three commonly used IVUS systems. Cross-validation accuracy for each system was >0.9, and the testing accuracy was 0.87, 0.89 and 0.89 for the three systems. Using the detection result, we propose an IVUS calcium score, based on the fraction of calcium-positive A-lines in a pullback segment, to quantify the extent of calcified plaque. The high accuracy of the proposed classifier suggests that it may provide a robust and accurate tool to assess the presence and amount of coronary calcification and, thus, may play a role in image-guided coronary interventions.

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, r² = 0.91 and r² = 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.

Background and aims In a large stroke-free population, we sought to identify cardiovascular risk factors and carotid plaque components associated with carotid plaque burden, lumen volume and stenosis. Methods The carotid arteries of 1562 stroke-free participants from The Rotterdam Study were imaged on a 1.5-Tesla MRI scanner. Inner and outer wall of the carotid arteries were automatically segmented and lumen volume (mm³), wall volume (outer wall–inner wall) and plaque burden (wall volume/outer wall volume) (%) were quantified. Plaque components were visually determined and luminal stenosis was assessed. We analyzed associations of cardiovascular risk factors and carotid plaque components with plaque burden and lumen volumes using regression analysis. Results We investigated 2821 carotid plaques and found that women had larger plaque burden (50.7 ± 7.8% vs. 49.2 ± 7.7%, p <0.0001) and smaller lumen volumes (933 ± 286 mm³ vs. 1078 ± 334 mm³, p <0.0001) than men. In women, age, HDL-cholesterol and systolic blood pressure, and in men, total cholesterol, non-HDL cholesterol and statin use were independently associated with higher plaque burden and lumen volume. Furthermore, smoking and diabetes were associated with lumen volume in men (respectively p = 0.04 and p = 0.002). Intraplaque hemorrhage (IPH) and lipid were related to a larger plaque burden (OR 1.30 [1.05–1.60] and OR 1.28[1.06–1.55]). Finally, within the highest quartile of plaque burden, IPH was strongly associated with luminal stenosis independent of age, sex, plaque burden and composition (Beta = 15.2; [11.8–18.6]). Conclusions Several cardiovascular risk factors and plaque components, in particular IPH, are associated with higher plaque burden. Carotid IPH is strongly associated with an increased luminal stenosis.