An All-in-One Tool for 2D Atherosclerotic Disease Assessment and 3D Coronary Artery Reconstruction.

Diagnosis of coronary artery disease is mainly based on invasive imaging modalities such as X-ray angiography, intravascular ultrasound (IVUS) and optical coherence tomography (OCT). Computed tomography coronary angiography (CTCA) is also used as a non-invasive imaging alternative. In this work, we present a novel and unique tool for 3D coronary artery reconstruction and plaque characterization using the abovementioned imaging modalities or their combination. In particular, image processing and deep learning algorithms were employed and validated for the lumen and adventitia borders and plaque characterization at the IVUS and OCT frames. Strut detection is also achieved from the OCT images. Quantitative analysis of the X-ray angiography enables the 3D reconstruction of the lumen geometry and arterial centerline extraction. The fusion of the generated centerline with the results of the OCT or IVUS analysis enables hybrid coronary artery 3D reconstruction, including the plaques and the stent geometry. CTCA image processing using a 3D level set approach allows the reconstruction of the coronary arterial tree, the calcified and non-calcified plaques as well as the detection of the stent location. The modules of the tool were evaluated for efficiency with over 90% agreement of the 3D models with the manual annotations, while a usability assessment using external evaluators demonstrated high usability resulting in a mean System Usability Scale (SUS) score equal to 0.89, classifying the tool as "excellent".

A proof-of-concept study for the simulation of blood flow in a post arterial segment for different blood rheology models.

Cardiovascular disease (CVD) and especially atherosclerosis are chronic inflammatory diseases which cause the atherosclerotic plaque growth in the arterial vessels and the blood flow reduction. Stents have revolutionized the treatment of this disease to a great extent by restoring the blood flow in the vessel. The present study investigates the performance of the blood flow after stent implantation in patient-specific coronary artery and demonstrates the effect of using Newtonian vs. non-Newtonian blood fluid models in the distribution of endothelial shear stress. In particular, the Navier-Stokes and continuity equations were employed, and three non-Newtonian fluid models were investigated (Carreau, Carreau-Yasuda and the Casson model). Computational finite elements models were used for the simulation of blood flow. The comparison of the results demonstrates that the Newtonian fluid model underestimates the calculation of Endothelial Shear Stress, while the three non-Newtonian fluids present similar distribution of shear stress. Keywords: Blood flow dynamics, stented artery, non-Newtonian fluid. Clinical Relevance- This work demonstrates that when blood flow modeling is performed at stented arteries and predictive models are developed, the non-Newtonian nature of blood must be considered.

An in silico trials platform for the evaluation of stent design effect in post-implantation outcomes.

Bioresorbable Vascular Scaffolds (BVS), developed to allow drug deliver and mechanical support, followed by complete resorption, have revolutionized atherosclerosis treatment. InSilc is a Cloud platform for in silico clinical trials (ISCT) used in the design, development and evaluation pipeline of stents. The platform integrates beyond the state-of-the-art multi-disciplinary and multiscale models, which predict the scaffold's performance in the short/acute and medium/long term. In this study, a use case scenario of two Bioabsorbable Vascular Stents (BVSs) implanted in the same arterial anatomy is presented, allowing the whole InSilc in silico pipeline to be applied and predict how the different aspects of this intervention affect the success of stenting process.

Machine Learning Coronary Artery Disease Prediction Based on Imaging and Non-Imaging Data.

The prediction of obstructive atherosclerotic disease has significant clinical meaning for the decision making. In this study, a machine learning predictive model based on gradient boosting classifier is presented, aiming to identify the patients of high CAD risk and those of low CAD risk. The machine learning methodology includes five steps: the preprocessing of the input data, the class imbalance handling applying the Easy Ensemble algorithm, the recursive feature elimination technique implementation, the implementation of gradient boosting classifier, and finally the model evaluation, while the fine tuning of the presented model was implemented through a randomized search optimization of the model's hyper-parameters over an internal 3-fold cross-validation. In total, 187 participants with suspicion of CAD previously underwent CTCA during EVINCI and ARTreat clinical studies and were prospectively included to undergo follow-up CTCA. The predictive model was trained using imaging data (geometrical and blood flow based) and non-imaging data. The overall predictive accuracy of the model was 0.81, using both imaging and non-imaging data. The innovative aspect of the proposed study is the combination of imaging-based data with the typical CAD risk factors to provide an integrated CAD risk-predictive model.

Detailed behaviour of endothelial wall shear stress across coronary lesions from non-invasive imaging with coronary computed tomography angiography.

AIMS: Evolving evidence suggests that endothelial wall shear stress (ESS) plays a crucial role in the rupture and progression of coronary plaques by triggering biological signalling pathways. We aimed to investigate the patterns of ESS across coronary lesions from non-invasive imaging with coronary computed tomography angiography (CCTA), and to define plaque-associated ESS values in patients with coronary artery disease (CAD). METHODS AND RESULTS: Symptomatic patients with CAD who underwent a clinically indicated CCTA scan were identified. Separate core laboratories performed blinded analysis of CCTA for anatomical and ESS features of coronary atherosclerosis. ESS was assessed using dedicated software, providing minimal and maximal ESS values for each 3 mm segment. Each coronary lesion was divided into upstream, start, minimal luminal area (MLA), end and downstream segments. Also, ESS ratios were calculated using the upstream segment as a reference. From 122 patients (mean age 64 ± 7 years, 57% men), a total of 237 lesions were analyzed. Minimal and maximal ESS values varied across the lesions with the highest values at the MLA segment [minimal ESS 3.97 Pa (IQR 1.93-8.92 Pa) and maximal ESS 5.64 Pa (IQR 3.13-11.21 Pa), respectively]. Furthermore, minimal and maximal ESS values were positively associated with stenosis severity (P < 0.001), percent atheroma volume (P < 0.001), and lesion length (P ≤ 0.023) at the MLA segment. Using ESS ratios, similar associations were observed for stenosis severity and lesion length. CONCLUSIONS: Detailed behaviour of ESS across coronary lesions can be derived from routine non-invasive CCTA imaging. This may further improve risk stratification.

Error Propagation in the Simulation of Atherosclerotic Plaque Growth and the Prediction of Atherosclerotic Disease Progression.

Assessments of coronary artery disease can be achieved using non-invasive computed tomography coronary angiography (CTCA). CTCA can be further used for the 3D reconstruction of the coronary arteries and the development of computational models. However, image acquisition and arterial reconstruction introduce an error which can be propagated, affecting the computational results and the accuracy of diagnostic and prognostic models. In this work, we investigate the effect of an imaging error, propagated to a diagnostic index calculated using computational modelling of blood flow and then to prognostic models based on plaque growth modelling or binary logistic predictive modelling. The analysis was performed utilizing data from 20 patients collected at two time points with interscan period of six years. The collected data includes clinical and risk factors, biological and biohumoral data, and CTCA imaging. The results demonstrated that the error propagated and may have significantly affected some of the final outcomes. The calculated propagated error seemed to be minor for shear stress, but was major for some variables of the plaque growth model. In parallel, in the current analysis SmartFFR was not considerably affected, with the limitation of only one case located into the gray zone.

An in silico trials platform for the evaluation of effect of the arterial anatomy configuration on stent implantation.

The introduction of Bioresorbable Vascular Scaffolds (BVS) has revolutionized the treatment of atherosclerosis. InSilc is an in silico clinical trial (ISCT) platform in a Cloud-based environment used for the design, development and evaluation of BVS. Advanced multi-disciplinary and multiscale models are integrated in the platform towards predicting the short/acute and medium/long term scaffold performance. In this study, InSilc platform is employed in a use case scenario and demonstrates how the whole in silico pipeline allows the interpretation of the effect of the arterial anatomy configuration on stent implantation.

A proof-of-concept study for the prediction of the de-novo atherosclerotic plaque development using finite elements.

The type of the atherosclerotic plaque has significant clinical meaning since plaque vulnerability depends on its type. In this work, we present a computational approach which predicts the development of new plaques in coronary arteries. More specifically, we employ a multi-level model which simulates the blood fluid dynamics, the lipoprotein transport and their accumulation in the arterial wall and the triggering of inflammation using convection-diffusion-reaction equations and in the final level, we estimate the plaque volume which causes the arterial wall thickening. The novelty of this work relies on the conceptual approach that using the information from 94 patients with computed tomography coronary angiography (CTCA) imaging at two time points we identify the correlation of the computational results with the real plaque components detected in CTCA. In the next step, we use these correlations to generate two types of de-novo plaques: calcified and non-calcified. Evaluation of the model's performance is achieved using eleven patients, who present de-novo plaques at the follow-up imaging. The results demonstrate that the computationally generated plaques are associated significantly with the real plaques indicating that the proposed approach could be used for the prediction of specific plaque type formation.

Investigation of Drug Eluting Stents performance in human atherosclerotic artery through in silico modeling.

Atherosclerosis is a chronic inflammatory disease associated with heart attack and stroke. It causes the growth of atherosclerotic plaques inside the arterial vessels, which in turn results to the reduction of the blood flow to the different organs. Drug-Eluting Stents (DES) are mesh-like wires, carrying pharmaceutical coating, designed to dilate and support the arterial vessel, restore blood flow and through the controlled local drug delivery inhibit neo-intimal thickening. In silico modeling is an efficient method of accurately predicting and assessing the performance of the stenting procedure. The present in silico study investigates the performance of two different stents (Bare Metal Stent, Drug-Eluting Stent) in a patient-specific coronary artery and assesses the effect of stent coating, considering that the same procedural approach is followed by the interventional cardiologist. The results demonstrate that even if small differences are obtained in the two models, the incorporation of the stent coatings (in DES) does not significantly affect the outcomes of the stent deployment, the stresses and strains in the scaffold and the arterial tissue. Nevertheless, it is suggested that regarding the DES expansion, higher pressure should be applied at the inner surface of the stent.

SmartFFR, a New Functional Index of Coronary Stenosis: Comparison With Invasive FFR Data.

Aims: In this study, we evaluate the efficacy of SmartFFR, a new functional index of coronary stenosis severity compared with gold standard invasive measurement of fractional flow reserve (FFR). We also assess the influence of the type of simulation employed on smartFFR (i.e. Fluid Structure Interaction vs. rigid wall assumption). Methods and Results: In a dataset of 167 patients undergoing either computed tomography coronary angiography (CTCA) and invasive coronary angiography or only invasive coronary angiography (ICA), as well as invasive FFR measurement, SmartFFR was computed after the 3D reconstruction of the vessels of interest and the subsequent blood flow simulations. 202 vessels were analyzed with a mean total computational time of seven minutes. SmartFFR was used to process all models reconstructed by either method. The mean FFR value of the examined dataset was 0.846 ± 0.089 with 95% CI for the mean of 0.833-0.858, whereas the mean SmartFFR value was 0.853 ± 0.095 with 95% CI for the mean of 0.84-0.866. SmartFFR was significantly correlated with invasive FFR values (RCCTA = 0.86, p CCTA < 0.0001, RICA = 0.84, p ICA < 0.0001, R overall = 0.833, p overall < 0.0001), showing good agreement as depicted by the Bland-Altman method of analysis. The optimal SmartFFR threshold to diagnose ischemia was ≤0.83 for the overall dataset, ≤0.83 for the CTCA-derived dataset and ≤0.81 for the ICA-derived dataset, as defined by a ROC analysis (AUCoverall = 0.956, p < 0.001, AUCICA = 0.975, p < 0.001, AUCCCTA = 0.952, p < 0.001). Conclusion: SmartFFR is a fast and accurate on-site index of hemodynamic significance of coronary stenosis both at single coronary segment and at two or more branches level simultaneously, which can be applied to all CTCA or ICA sequences of acceptable quality.

IVUS Longitudinal and Axial Registration for Atherosclerosis Progression Evaluation.

Intravascular ultrasound (IVUS) imaging offers accurate cross-sectional vessel information. To this end, registering temporal IVUS pullbacks acquired at two time points can assist the clinicians to accurately assess pathophysiological changes in the vessels, disease progression and the effect of the treatment intervention. In this paper, we present a novel two-stage registration framework for aligning pairs of longitudinal and axial IVUS pullbacks. Initially, we use a Dynamic Time Warping (DTW)-based algorithm to align the pullbacks in a temporal fashion. Subsequently, an intensity-based registration method, that utilizes a variant of the Harmony Search optimizer to register each matched pair of the pullbacks by maximizing their Mutual Information, is applied. The presented method is fully automated and only required two single global image-based measurements, unlike other methods that require extraction of morphology-based features. The data used includes 42 synthetically generated pullback pairs, achieving an alignment error of 0.1853 frames per pullback, a rotation error 0.93° and a translation error of 0.0161 mm. In addition, it was also tested on 11 baseline and follow-up, and 10 baseline and post-stent deployment real IVUS pullback pairs from two clinical centres, achieving an alignment error of 4.3±3.9 for the longitudinal registration, and a distance and a rotational error of 0.56±0.323 mm and 12.4°±10.5°, respectively, for the axial registration. Although the performance of the proposed method does not match that of the state-of-the-art, our method relies on computationally lighter steps for its computations, which is crucial in real-time applications. On the other hand, the proposed method performs even or better that the state-of-the-art when considering the axial registration. The results indicate that the proposed method can support clinical decision making and diagnosis based on sequential imaging examinations.

A Novel Approach to Generate a Virtual Population of Human Coronary Arteries for In Silico Clinical Trials of Stent Design.

Goal: To develop a cardiovascular virtual population using statistical modeling and computational biomechanics. Methods: A clinical data augmentation algorithm is implemented to efficiently generate virtual clinical data using a real clinical dataset. An atherosclerotic plaque growth model is employed to 3D reconstructed coronary arterial segments to generate virtual coronary arterial geometries (geometrical data). Last, the combination of the virtual clinical and geometrical data is achieved using a methodology that allows for the generation of a realistic virtual population which can be used in in silico clinical trials. Results: The results show good agreement between real and virtual clinical data presenting a mean gof 0.1 ± 0.08. 400 virtual coronary arteries were generated, while the final virtual population includes 10,000 patients. Conclusions: The virtual arterial geometries are efficiently matched to the generated clinical data, both increasing and complementing the variability of the virtual population.

Validation study of a novel method for the 3D reconstruction of coronary bifurcations.

Quantitative Coronary Angiography (QCA) is an important tool in the study of coronary artery disease. Validation of this technique is crucial for their ongoing development and refinement although it is difficult due to several factors such as potential sources of error. The present work aims to a further validation of a new semi-automated method for three-dimensional (3D) reconstruction of coronary bifurcations arteries based on X-Ray Coronary Angiographies (CA). In a dataset of 40 patients (79 angiographic views), we used the aforementioned method to reconstruct them in 3D space. The validation was based on the comparison of these 3D models with the true silhouette of 2D models annotated by an expert using specific metrics. The obtained results indicate a good accuracy for the most parameters (≥ 90 %). Comparison with similar works shows that our new method is a promising tool for the 3D reconstruction of coronary bifurcations and for application in everyday clinical use.

Prediction of the development of coronary atherosclerotic plaques using computational modeling in 3D reconstructed coronary arteries.

In this work we present a novel method for the prediction and generation of atherosclerotic plaques. This is performed in a two-step approach, by employing first a multilevel computational plaque growth model and second a correlation between the model's results and the 3D reconstructed follow-up plaques. In particular, computer tomography coronary angiography (CTCA) data and blood tests were collected from patients at two time points. Using the baseline data, the plaque growth is simulated using a multi-level computational model which includes: i) modeling of the blood flow dynamics, ii) modeling of low and high density lipoproteins and monocytes' infiltration in the arterial wall, and the species reactions during the atherosclerotic process, and iii) modeling of the arterial wall thickening. The correlation between the followup plaques and the simulated plaque density distribution resulted to the extraction of a threshold of the plaque density, that can be used to identify plaque areas.Clinical Relevance- The methodology presented in this work is a first step to the prediction of the plaque shape and location of patients with atherosclerosis and could be used as an additional tool for patient-specific risk stratification.

Site specific prediction of PCI stenting based on imaging and biomechanics data using gradient boosting tree ensembles.

Cardiovascular diseases are nowadays considered as the main cause of morbidity and mortality worldwide. Coronary Artery Disease (CAD), the most typical form of cardiovascular disease is diagnosed by a variety of imaging modalities, both invasive and non-invasive, which involve either risk implications or high cost. Therefore, several attempts have been undertaken to early diagnose and predict either the high CAD risk patients or the cardiovascular events, implementing machine learning techniques. The purpose of this study is to present a classification scheme for the prediction of Percutaneous Coronary Intervention (PCI) stenting placement, using image-based data. The proposed classification model is a gradient boosting classifier, incorporated into a class imbalance handling technique, the Easy ensemble scheme and aims to classify coronary segments into high CAD risk and low CAD risk, based on their PCI placement. Through this study, we investigate the importance of image based features, concluding that the combination of the coronary degree of stenosis and the fractional flow reserve achieves accuracy 78%.

Simulation of atherosclerotic plaque growth using computational biomechanics and patient-specific data.

Atherosclerosis is the one of the major causes of mortality worldwide, urging the need for prevention strategies. In this work, a novel computational model is developed, which is used for simulation of plaque growth to 94 realistic 3D reconstructed coronary arteries. This model considers several factors of the atherosclerotic process even mechanical factors such as the effect of endothelial shear stress, responsible for the initiation of atherosclerosis, and biological factors such as the accumulation of low and high density lipoproteins (LDL and HDL), monocytes, macrophages, cytokines, nitric oxide and formation of foams cells or proliferation of contractile and synthetic smooth muscle cells (SMCs). The model is validated using the serial imaging of CTCA comparing the simulated geometries with the real follow-up arteries. Additionally, we examine the predictive capability of the model to identify regions prone of disease progression. The results presented good correlation between the simulated lumen area (P < 0.0001), plaque area (P < 0.0001) and plaque burden (P < 0.0001) with the realistic ones. Finally, disease progression is achieved with 80% accuracy with many of the computational results being independent predictors.

A three-dimensional quantification of calcified and non-calcified plaques in coronary arteries based on computed tomography coronary angiography images: Comparison with expert's annotations and virtual histology intravascular ultrasound.

The detection, quantification and characterization of coronary atherosclerotic plaques has a major effect on the diagnosis and treatment of coronary artery disease (CAD). Different studies have reported and evaluated the noninvasive ability of Computed Tomography Coronary Angiography (CTCA) to identify coronary plaque features. The identification of calcified plaques (CP) and non-calcified plaques (NCP) using CTCA has been extensively studied in cardiovascular research. However, NCP detection remains a challenging problem in CTCA imaging, due to the similar intensity values of NCP compared to the perivascular tissue, which surrounds the vasculature. In this work, we present a novel methodology for the identification of the plaque burden of the coronary artery and the volumetric quantification of CP and NCP utilizing CTCA images and we compare the findings with virtual histology intravascular ultrasound (VH-IVUS) and manual expert's annotations. Bland-Altman analyses were employed to assess the agreement between the presented methodology and VH-IVUS. The assessment of the plaque volume, the lesion length and the plaque area in 18 coronary lesions indicated excellent correlation with VH-IVUS. More specifically, for the CP lesions the correlation of plaque volume, lesion length and plaque area was 0.93, 0.84 and 0.85, respectively, whereas the correlation of plaque volume, lesion length and plaque area for the NCP lesions was 0.92, 0.95 and 0.81, respectively. In addition to this, the segmentation of the lumen, CP and NCP in 1350 CTCA slices indicated that the mean value of DICE coefficient is 0.72, 0.7 and 0.62, whereas the mean HD value is 1.95, 1.74 and 1.95, for the lumen, CP and NCP, respectively.

The effect of error propagation in the 3D reconstruction of coronary segments using CTCA images on crucial hemodynamic parameters.

The development of 3D reconstruction methods of the coronary vasculature has gained substantial ground during the past years. The accurate 3D reconstruction is of utmost importance because the propagation of errors caused by either equipment calibration errors, human errors or other error sources can seriously affect the computation of critical hemodynamic parameters such as Endothelial Shear Stress, intracoronary pressures etc. In this work, we present a study on how the 3D reconstruction error can affect the subsequent blood flow simulations in 3D coronary arterial models. Eight arterial segments were reconstructed, creating the control models and were then modified in order to create an underestimated and an overestimated model of the same segment using a 5% error. Cross-sectional ESS values, as well as, smartFFR values were calculated to examine the effect of the reconstruction error. As it was expected, the underestimated models presented with higher ESS values and lower smartFFR values, whereas the overestimated models presented with lower ESS values and higher smartFFR values, respectively.

A computational multi-level atherosclerotic plaque growth model for coronary arteries.

In this work, we present a novel computational approach for the prediction of atherosclerotic plaque growth. In particular, patient-specific coronary computed tomography angiography (CCTA) data were collected from 60 patients at two time points. Additionally, blood samples were collected for biochemical analysis. The CCTA data were used for 3D reconstruction of the coronary arteries, which were then used for computational modeling of plaque growth. The model of plaque growth is based on a multi-level approach: i) the blood flow is modeled in the lumen and the arterial wall, ii) the low and high density lipoprotein and monocytes transport is included, and iii) the major atherosclerotic processes are modeled including the foam cells formation, the proliferation of smooth muscle cells and the formation of atherosclerotic plaque. Validation of the model was performed using the follow-up CCTA. The results show a correlation of the simulated follow-up arterial wall area to be correlated with the corresponding realistic follow-up with r2=0.49, P<; 0.0001.

Site specific prediction of atherosclerotic plaque progression using computational biomechanics and machine learning.

Atheromatic plaque progression is considered as a typical pathological condition of arteries and although atherosclerosis is considered as a systemic inflammatory disorder, atheromatic plaque is not uniformly distributed in the arterial tree. Except for the systematic atherosclerosis risk factors, biomechanical forces, LDL concentration and artery geometry contribute to the atherogenesis and atherosclerotic plaque evolution. In this study, we calculate biomechanical forces acting within the artery and we develop a machine learning model for the prediction of atheromatic plaque progression. 1018 coronary sites of 3 mm, derived by 40 individuals, are utilized to develop the model and after the implementation of 4 different tree based prediction schemes, we achieve a prediction accuracy of 0.84. The best accuracy was achieved by the implementation of a tree-based classifier, the Random Forest classifier, after a ranking feature selection methodology. The novel aspect of the proposed methodology is the implementation of machine learning models in order to address the cardiovascular data modeling, aiming to predict the occurrence of an outcome and not to investigate the association of input features.