Coronary Atherosclerosis- imaging, biology and mechanics

In this thesis, (intravascular) imaging, pathobiology and biomechanical modelling were combined to: 1) describe existing animal models for atherosclerosis and discuss the role biomechanics play in plaque development in these models; 2) further elucidate the involvement of the biomechanical factors wall shear stress and helical flow in the development of coronary atherosclerotic plaques, and to assess the potential of these biomechanical factors and of specific lipoproteins as new biomarkers for atherosclerotic disease development; 3) extend the interpretation of imaging data derived from two commonly used invasive imaging techniques to improve plaque and patient risk-stratification

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

OCT-measured plaque free wall angle is indicative for plaque burden: overcoming the main limitation of OCT?

textabstractThe aim of this study was to investigate the relationship between the plaque free wall (PFW) measured by optical coherence tomography (OCT) and the plaque burden (PB) measured by intravascular ultrasound (IVUS). We hypothesize that measurement of the PFW could help to estimate the PB, thereby overcoming the limited ability of OCT to visualize the external elastic membrane in the presence of plaque. This could enable selection of the optimal stent-landing zone by OCT, which is traditionally defined by IVUS as a region with a PB < 40 %. PB (IVUS) and PFW angle (OCT and IVUS) were measured in 18 matched IVUS and OCT pullbacks acquired in the same coronary artery. We determined the relationship between OCT measured PFW (PFWOCT) and IVUS PB (PBIVUS) by non-linear regression analysis. An ROC-curve analysis was used to determine the optimal cut-off value of PFW angle for the detection of PB < 40 %. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated. There is a significant correlation between PFWOCT and PBIVUS (r2 = 0.59). The optimal cut-off value of the PFWOCT for the prediction of a PBIVUS < 40 % is ≥220° with a PPV of 78 % and an NPV of 84 %. This study shows that PFWOCT can be considered as a surrogate marker for PBIVUS, which is currently a common criterion to select an optimal stent-landing zone

Plaque burden is associated with minimal intimal coverage following drug-eluting stent implantation in an adult familial hypercholesterolemia swine model

Abstract Safety and efficacy of coronary drug-eluting stents (DES) are often preclinically tested using healthy or minimally diseased swine. These generally show significant fibrotic neointima at follow-up, while in patients, incomplete healing is often observed. The aim of this study was to investigate neointima responses to DES in swine with significant coronary atherosclerosis. Adult familial hypercholesterolemic swine (n = 6) received a high fat diet to develop atherosclerosis. Serial OCT was performed before, directly after, and 28 days after DES implantation (n = 14 stents). Lumen, stent and plaque area, uncovered struts, neointima thickness and neointima type were analyzed for each frame and averaged per stent. Histology was performed to show differences in coronary atherosclerosis. A range of plaque size and severity was found, from healthy segments to lipid-rich plaques. Accordingly, neointima responses ranged from uncovered struts, to minimal neointima, to fibrotic neointima. Lower plaque burden resulted in a fibrotic neointima at follow-up, reminiscent of minimally diseased swine coronary models. In contrast, higher plaque burden resulted in minimal neointima and more uncovered struts at follow-up, similarly to patients’ responses. The presence of lipid-rich plaques resulted in more uncovered struts, which underscores the importance of advanced disease when performing safety and efficacy testing of DES

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

In-vitro and in-vivo imaging of coronary artery stents with Heartbeat OCT

To quantify the impact of cardiac motion on stent length measurements with Optical Coherence Tomography (OCT) and to demonstrate in vivo OCT imaging of implanted stents, without motion artefacts. The study consists of: clinical data evaluation, simulations and in vivo tests. A comparison between OCT-measured and nominal stent lengths in 101 clinically acquired pullbacks was carried out, followed by a simulation of the effect of cardiac motion on stent length measurements, experimentally and computationally. Both a commercial system and a custom OCT, capable of completing a pullback between two consecutive ventricular contractions, were employed. A 13 mm long stent was implanted in the left anterior descending branch of two atherosclerotic swine and imaged with both OCT systems. The analysis of the clinical OCT images yielded an average difference of 1.1 ± 1.6 mm, with a maximum difference of 7.8 mm and the simulations replicated the statistics observed in clinical data. Imaging with the custom OCT, yielded an RMS error of 0.14 mm at 60 BPM with the start of the acquisition synchronized to the cardiac cycle. In vivo imaging with conventional OCT yielded a deviation of 1.2 mm, relative to the length measured on ex-vivo micro-CT, while the length measured in the pullback acquired by the custom OCT differed by 0.20 mm. We demonstrated motion artefact-free OCT-imaging of implanted stents, using ECG triggering and a rapid pullback

Variation in Coronary Atherosclerosis Severity Related to a Distinct LDL (Low-Density Lipoprotein) Profile Findings From a Familial Hypercholesterolemia Pig Model

OBJECTIVE: In an adult porcine model of familial hypercholesterolemia (FH), coronary plaque development was characterized. \nTo elucidate the underlying mechanisms of the observed inter-individual variation in disease severity, detailed lipoprotein \nprofiles were determined. \nAPPROACH AND RESULTS: FH pigs (3 years old, homozygous LDLR R84C mutation) received an atherogenic diet for 12 months. \nCoronary atherosclerosis development was monitored using serial invasive imaging and histology. A pronounced difference \nwas observed between mildly diseased pigs which exclusively developed early lesions (maximal plaque burden, 25% [23%\xe2\x80\x93 \n34%]; n=5) and advanced-diseased pigs (n=5) which developed human-like, lumen intruding plaques (maximal plaque burden, \n69% [57%\xe2\x80\x9377%]) with large necrotic cores, intraplaque hemorrhage, and calcifications. Advanced-diseased pigs and mildly \ndiseased pigs displayed no differences in conventional risk factors. Additional plasma lipoprotein profiling by size-exclusion \nchromatography revealed 2 different LDL (low-density lipoprotein) subtypes: regular and larger LDL. Cholesterol, sphingosine1-phosphate, ceramide, and sphingomyelin levels were determined in these LDL-subfractions using standard laboratory \ntechniques and high-pressure liquid chromatography mass-spectrometry analyses, respectively. At 3 months of diet, regular \nLDL of advanced-diseased pigs contained relatively more cholesterol (LDL-C; regular/larger LDL-C ratio 1.7 [1.3\xe2\x80\x931.9] versus \n0.8 [0.6\xe2\x80\x930.9]; P=0.008) than mildly diseased pigs, while larger LDL contained more sphingosine-1-phosphate, ceramides, and \nsphingomyelins. Larger and regular LDL was also found in plasma of 3 patients with homozygous FH with varying LDL-C ratios. \nCONCLUSIONS: In our adult FH pig model, inter-individual differences in atherosclerotic disease severity were directly related to \nthe distribution of cholesterol and sphingolipids over a distinct LDL profile with regular and larger LDL shortly after the diet \nstart. A similar LDL profile was detected in patients with homozygous FH