Patient-Specific Haemodynamic Analysis of Virtual Grafting Strategies in Type-B Aortic Dissection: Impact of Compliance Mismatch.

INTRODUCTION: Compliance mismatch between the aortic wall and Dacron Grafts is a clinical problem concerning aortic haemodynamics and morphological degeneration. The aortic stiffness introduced by grafts can lead to an increased left ventricular (LV) afterload. This study quantifies the impact of compliance mismatch by virtually testing different Type-B aortic dissection (TBAD) surgical grafting strategies in patient-specific, compliant computational fluid dynamics (CFD) simulations. MATERIALS AND METHODS: A post-operative case of TBAD was segmented from computed tomography angiography data. Three virtual surgeries were generated using different grafts; two additional cases with compliant grafts were assessed. Compliant CFD simulations were performed using a patient-specific inlet flow rate and three-element Windkessel outlet boundary conditions informed by 2D-Flow MRI data. The wall compliance was calibrated using Cine-MRI images. Pressure, wall shear stress (WSS) indices and energy loss (EL) were computed. RESULTS: Increased aortic stiffness and longer grafts increased aortic pressure and EL. Implementing a compliant graft matching the aortic compliance of the patient reduced the pulse pressure by 11% and EL by 4%. The endothelial cell activation potential (ECAP) differed the most within the aneurysm, where the maximum percentage difference between the reference case and the mid (MDA) and complete (CDA) descending aorta replacements increased by 16% and 20%, respectively. CONCLUSION: This study suggests that by minimising graft length and matching its compliance to the native aorta whilst aligning with surgical requirements, the risk of LV hypertrophy may be reduced. This provides evidence that compliance-matching grafts may enhance patient outcomes.

A systematic review of clinical and biomechanical engineering perspectives on the prediction of restenosis in coronary and peripheral arteries.

Objective: Restenosis is a significant complication of revascularization treatments in coronary and peripheral arteries, sometimes necessitating repeated intervention. Establishing when restenosis will happen is extremely difficult due to the interplay of multiple variables and factors. Standard clinical and Doppler ultrasound scans surveillance follow-ups are the only tools clinicians can rely on to monitor intervention outcomes. However, implementing efficient surveillance programs is hindered by health care system limitations, patients' comorbidities, and compliance. Predictive models classifying patients according to their risk of developing restenosis over a specific period will allow the development of tailored surveillance, prevention programs, and efficient clinical workflows. This review aims to: (1) summarize the state-of-the-art in predictive models for restenosis in coronary and peripheral arteries; (2) compare their performance in terms of predictive power; and (3) provide an outlook for potentially improved predictive models. Methods: We carried out a comprehensive literature review by accessing the PubMed/MEDLINE database according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The search strategy consisted of a combination of keywords and included studies focusing on predictive models of restenosis published between January 1993 and April 2023. One author independently screened titles and abstracts and checked for eligibility. The rest of the authors independently confirmed and discussed in case of any disagreement. The search of published literature identified 22 studies providing two perspectives-clinical and biomechanical engineering-on restenosis and comprising distinct methodologies, predictors, and study designs. We compared predictive models' performance on discrimination and calibration aspects. We reported the performance of models simulating reocclusion progression, evaluated by comparison with clinical images. Results: Clinical perspective studies consider only routinely collected patient information as restenosis predictors. Our review reveals that clinical models adopting traditional statistics (n = 14) exhibit only modest predictive power. The latter improves when machine learning algorithms (n = 4) are employed. The logistic regression models of the biomechanical engineering perspective (n = 2) show enhanced predictive power when hemodynamic descriptors linked to restenosis are fused with a limited set of clinical risk factors. Biomechanical engineering studies simulating restenosis progression (n = 2) are able to capture its evolution but are computationally expensive and lack risk scoring for individual patients at specific follow-ups. Conclusions: Restenosis predictive models, based solely on routine clinical risk factors and using classical statistics, inadequately predict the occurrence of restenosis. Risk stratification models with increased predictive power can be potentially built by adopting machine learning techniques and incorporating critical information regarding vessel hemodynamics arising from biomechanical engineering analyses.

Towards Reduced Order Models via Robust Proper Orthogonal Decomposition to capture personalised aortic haemodynamics.

Data driven, reduced order modelling has shown promise in tackling the challenges associated with computational and experimental haemodynamic models. In this work, we focus on the use of Reduced Order Models (ROMs) to reconstruct velocity fields in a patient-specific dissected aorta, with the objective being to compare the ROMs obtained from Robust Proper Orthogonal Decomposition (RPOD) to those obtained from the traditional Proper Orthogonal Decomposition (POD). POD and RPOD are applied to in vitro, haemodynamic data acquired by Particle Image Velocimetry and compare the decomposed flows to those derived from Computational Fluid Dynamics (CFD) data for the same geometry and flow conditions. In this work, PIV and CFD results act as surrogates for clinical haemodynamic data e.g. MR, helping to demonstrate the potential use of ROMS in real clinical scenarios. The flow is reconstructed using different numbers of POD modes and the flow features obtained throughout the cardiac cycle are compared to the original Full Order Models (FOMs). Robust Principal Component Analysis (RPCA), the first step of RPOD, has been found to enhance the quality of PIV data, allowing POD to capture most of the kinetic energy of the flow in just two modes similar to the numerical data that are free from measurement noise. The reconstruction errors differ along the cardiac cycle with diastolic flows requiring more modes for accurate reconstruction. In general, modes 1-10 are found sufficient to represent the flow field. The results demonstrate that the coherent structures that characterise this aortic dissection flow are described by the first few POD modes suggesting that it is possible to represent the macroscale behaviour of aortic flow in a low-dimensional space; thus significantly simplifying the problem, and allowing for more computationally efficient flow simulations or machine learning based flow predictions that can pave the way for translation of such models to the clinic.

Experimental evaluation of the patient-specific haemodynamics of an aortic dissection model using particle image velocimetry.

Aortic Dissection (AD) is a complex pathology that affects the aorta. Diagnosis, management and treatment remain a challenge as it is a highly patient-specific pathology and there is still a limited understanding of the fluid-mechanics phenomena underlying clinical outcomes. Although in vitro models can allow the accurate study of AD flow fields in physical phantoms, they are currently scarce and almost exclusively rely on over simplifying assumptions. In this work, we present the first experimental study of a patient-specific case of AD. An anatomically correct phantom was produced and combined with a state-of-the-art in vitro platform, informed by clinical data, employed to accurately reproduce personalised conditions. The complex AD haemodynamics reproduced by the platform was characterised by flow rate and pressure acquisitions as well as Particle Image Velocimetry (PIV) derived velocity fields. Clinically relevant haemodynamic indices, that can be correlated with AD prognosis - such as velocity, shear rate, turbulent kinetic energy distributions - were extracted in two regions of interest in the aortic domain. The acquired data highlighted the complex nature of the flow (e.g. recirculation regions, low shear rate in the false lumen) and was in very good agreement with the available clinical data and the CFD results of a study conducted alongside, demonstrating the accuracy of the findings. These results demonstrate that the described platform constitutes a powerful, unique tool to reproduce in vitro personalised haemodynamic conditions, which can be used to support the evaluation of surgical procedures, medical devices testing and to validate state-of-the-art numerical models.

A Computational Framework for Pre-Interventional Planning of Peripheral Arteriovenous Malformations.

PURPOSE: Peripheral arteriovenous malformations (pAVMs) are congenital lesions characterised by abnormal high-flow, low-resistance vascular connections-the so-called nidus-between arteries and veins. The mainstay treatment typically involves the embolisation of the nidus, however the complexity of pAVMs often leads to uncertain outcomes. This study aims at developing a simple, yet effective computational framework to aid the clinical decision making around the treatment of pAVMs using routinely acquired clinical data. METHODS: A computational model was developed to simulate the pre-, intra-, and post-intervention haemodynamics of a patient-specific pAVM. A porous medium of varying permeability was employed to simulate the sclerosant effect on the nidus haemodynamics. Results were compared against clinical data (digital subtraction angiography, DSA, images) and experimental flow-visualization results in a 3D-printed phantom of the same pAVM. RESULTS: The computational model allowed the simulation of the pAVM haemodynamics and the sclerotherapy-induced changes at different interventional stages. The predicted inlet flow rates closely matched the DSA-derived data, although the post-intervention one was overestimated, probably due to vascular system adaptations not accounted for numerically. The nidus embolization was successfully captured by varying the nidus permeability and increasing its hydraulic resistance from 0.330 to 3970 mmHg s ml-1. The nidus flow rate decreased from 71% of the inlet flow rate pre-intervention to 1%: the flow completely bypassed the nidus post-intervention confirming the success of the procedure. CONCLUSION: The study demonstrates that the haemodynamic effects of the embolisation procedure can be simulated from routinely acquired clinical data via a porous medium with varying permeability as evidenced by the good qualitative agreement between numerical predictions and both in vivo and in vitro data. It provides a fundamental building block towards a computational treatment-planning framework for AVM embolisation.

A novel MRI-based data fusion methodology for efficient, personalised, compliant simulations of aortic haemodynamics.

We present a novel, cost-efficient methodology to simulate aortic haemodynamics in a patient-specific, compliant aorta using an MRI data fusion process. Based on a previously-developed Moving Boundary Method, this technique circumvents the high computational cost and numerous structural modelling assumptions required by traditional Fluid-Structure Interaction techniques. Without the need for Computed Tomography (CT) data, the MRI images required to construct the simulation can be obtained during a single imaging session. Black Blood MR Angiography and 2D Cine-MRI data were used to reconstruct the luminal geometry and calibrate wall movement specifically to each region of the aorta. 4D-Flow MRI and non-invasive pressure measurements informed patient-specific inlet and outlet boundary conditions. Luminal area closely matched 2D Cine-MRI measurements with a mean error of less than 4.6% across the cardiac cycle, while physiological pressure and flow distributions were simulated to within 3.3% of patient-specific targets. Moderate agreement with 4D-Flow MRI velocity data was observed. Despite lower peak velocity, an equivalent rigid-wall simulation predicted a mean Time-Averaged Wall Shear Stress (TAWSS) 13% higher than the compliant simulation. The agreement observed between compliant simulation results and MRI data is testament to the accuracy and efficiency of this MRI-based simulation technique.

Computer assisted Doppler waveform analysis and ultrasound derived turbulence intensity ratios can predict early hyperplasia development in newly created vascular access fistula: Pilot study, methodology and analysis.

OBJECTIVES: Following surgical creation of arterio-venous fistulae (AVF), the desired outward remodeling is often accompanied by the development of neointimal hyperplasia (NIH), which can stymie maturation and may lead to thrombosis and access failure. The aim of this study was to investigate the feasibility of using a non-invasive test, to detect and quantify the turbulent flow patterns believed to be associated with NIH development. DESIGN: This was a prospective, observational study. Ultrasound derived turbulence intensity ratios (USTIR) were calculated from spectral Doppler waveforms, recorded from newly formed AVF, and were compared with haemodynamic and structural changes observed during the initial maturation period. SETTING: Measurements were obtained by accredited Clinical Vascular Scientists, at the Royal Free Hospital, London. PARTICIPANTS: Patients with newly created AVF were invited to participate in the study. A total of 30 patients were initially recruited with 19 participants completing the 10 week study protocol. OUTCOME MEASURES: The primary outcome measure was the development of NIH resulting in a haemodynamically significant lesion.The secondary outcome was successful maturation of the AVF at 10 weeks. RESULTS: Elevated USTIR in the efferent vein 2 weeks post surgery corresponded to the development of NIH formation (P = 0.02). A cut off of 6.39% predicted NIH development with a sensitivity of 87.5% and a specificity of 80%. CONCLUSION: Analysis of Doppler waveforms can successfully identify deleterious flow patterns and predict inward luminal remodelling in maturing AVF. We propose a longitudinal follow up study to assess the viability of this technique as a surveillance tool.

A Combined In Vivo, In Vitro, In Silico Approach for Patient-Specific Haemodynamic Studies of Aortic Dissection.

The optimal treatment of Type-B aortic dissection (AD) is still a subject of debate, with up to 50% of the cases developing late-term complications requiring invasive intervention. A better understanding of the patient-specific haemodynamic features of AD can provide useful insights on disease progression and support clinical management. In this work, a novel in vitro and in silico framework to perform personalised studies of AD, informed by non-invasive clinical data, is presented. A Type-B AD was investigated in silico using computational fluid dynamics (CFD) and in vitro by means of a state-of-the-art mock circulatory loop and particle image velocimetry (PIV). Both models not only reproduced the anatomical features of the patient, but also imposed physiologically-accurate and personalised boundary conditions. Experimental flow rate and pressure waveforms, as well as detailed velocity fields acquired via PIV, are extensively compared against numerical predictions at different locations in the aorta, showing excellent agreement. This work demonstrates how experimental and numerical tools can be developed in synergy to accurately reproduce patient-specific AD blood flow. The combined platform presented herein constitutes a powerful tool for advanced haemodynamic studies for a range of vascular conditions, allowing not only the validation of CFD models, but also clinical decision support, surgical planning as well as medical device innovation.

Multiscale, patient-specific computational fluid dynamics models predict formation of neointimal hyperplasia in saphenous vein grafts.

Stenosis due to neointimal hyperplasia (NIH) is among the major causes of peripheral graft failure. Its link to abnormal hemodynamics in the graft is complex, and isolated use of hemodynamic markers is insufficient to fully capture its progression. Here, a computational model of NIH growth is presented, establishing a link between computational fluid dynamics simulations of flow in the lumen and a biochemical model representing NIH growth mechanisms inside the vessel wall. For all three patients analyzed, NIH at proximal and distal anastomoses was simulated by the model, with values of stenosis comparable to the computed tomography scans.

Investigating the physiology of normothermic ex vivo heart perfusion in an isolated slaughterhouse porcine model used for device testing and training.

BACKGROUND: The PhysioHeart™ is a mature acute platform, based isolated slaughterhouse hearts and able to validate cardiac devices and techniques in working mode. Despite perfusion, myocardial edema and time-dependent function degradation are reported. Therefore, monitoring several variables is necessary to identify which of these should be controlled to preserve the heart function. This study presents biochemical, electrophysiological and hemodynamic changes in the PhysioHeart™ to understand the pitfalls of ex vivo slaughterhouse heart hemoperfusion. METHODS: Seven porcine hearts were harvested, arrested and revived using the PhysioHeart™. Cardiac output, SaO2, glucose and pH were maintained at physiological levels. Blood analyses were performed hourly and unipolar epicardial electrograms (UEG), pressures and flows were recorded to assess the physiological performance. RESULTS: Normal cardiac performance was attained in terms of mean cardiac output (5.1 ± 1.7 l/min) and pressures but deteriorated over time. Across the experiments, homeostasis was maintained for 171.4 ± 54 min, osmolarity and blood electrolytes increased significantly between 10 and 80%, heart weight increased by 144 ± 41 g, free fatty acids (- 60%), glucose and lactate diminished, ammonia increased by 273 ± 76% and myocardial necrosis and UEG alterations appeared and aggravated. Progressively deteriorating electrophysiological and hemodynamic functions can be explained by reperfusion injury, waste product intoxication (i.e. hyperammonemia), lack of essential nutrients, ion imbalances and cardiac necrosis as a consequence of hepatological and nephrological plasma clearance absence. CONCLUSIONS: The PhysioHeart™ is an acute model, suitable for cardiac device and therapy assessment, which can precede conventional animal studies. However, observations indicate that ex vivo slaughterhouse hearts resemble cardiac physiology of deteriorating hearts in a multi-organ failure situation and signalize the need for plasma clearance during perfusion to attenuate time-dependent function degradation. The presented study therefore provides an in-dept understanding of the sources and reasons causing the cardiac function loss, as a first step for future effort to prolong cardiac perfusion in the PhysioHeart™. These findings could be also of potential interest for other cardiac platforms.

An in silico study of the influence of vessel wall deformation on neointimal hyperplasia progression in peripheral bypass grafts.

Neointimal hyperplasia (NIH) is a major obstacle to graft patency in the peripheral arteries. A complex interaction of biomechanical factors contribute to NIH development and progression, and although haemodynamic markers such as wall shear stress have been linked to the disease, these have so far been insufficient to fully capture its behaviour. Using a computational model linking computational fluid dynamics (CFD) simulations of blood flow with a biochemical model representing NIH growth mechanisms, we analyse the effect of compliance mismatch, due to the presence of surgical stitches and/or to the change in distensibility between artery and vein graft, on the haemodynamics in the lumen and, subsequently, on NIH progression. The model enabled to simulate NIH at proximal and distal anastomoses of three patient-specific end-to-side saphenous vein grafts under two compliance-mismatch configurations, and a rigid wall case for comparison, obtaining values of stenosis similar to those observed in the computed tomography (CT) scans. The maximum difference in time-averaged wall shear stress between the rigid and compliant models was 3.4 Pa, and differences in estimation of NIH progression were only observed in one patient. The impact of compliance on the haemodynamic-driven development of NIH was small in the patient-specific cases considered.

A modeling and machine learning approach to ECG feature engineering for the detection of ischemia using pseudo-ECG.

Early detection of coronary heart disease (CHD) has the potential to prevent the millions of deaths that this disease causes worldwide every year. However, there exist few automatic methods to detect CHD at an early stage. A challenge in the development of these methods is the absence of relevant datasets for their training and validation. Here, the ten Tusscher-Panfilov 2006 model and the O'Hara-Rudy model for human myocytes were used to create two populations of models that were in concordance with data obtained from healthy individuals (control populations) and included inter-subject variability. The effects of ischemia were subsequently included in the control populations to simulate the effects of mild and severe ischemic events on single cells, full ischemic cables of cells and cables of cells with various sizes of ischemic regions. Action potential and pseudo-ECG biomarkers were measured to assess how the evolution of ischemia could be quantified. Finally, two neural network classifiers were trained to identify the different degrees of ischemia using the pseudo-ECG biomarkers. The control populations showed action potential and pseudo-ECG biomarkers within the physiological ranges and the trends in the biomarkers commonly identified in ischemic patients were observed in the ischemic populations. On the one hand, inter-subject variability in the ischemic pseudo-ECGs precluded the detection and classification of early ischemic events using any single biomarker. On the other hand, the neural networks showed sensitivity and positive predictive value above 95%. Additionally, the neural networks revealed that the biomarkers that were relevant for the detection of ischemia were different from those relevant for its classification. This work showed that a computational approach could be used, when data is scarce, to validate proof-of-concept machine learning methods to detect ischemic events.

Patient-specific haemodynamic simulations of complex aortic dissections informed by commonly available clinical datasets.

Patient-specific computational fluid-dynamics (CFD) can assist the clinical decision-making process for Type-B aortic dissection (AD) by providing detailed information on the complex intra-aortic haemodynamics. This study presents a new approach for the implementation of personalised CFD models using non-invasive, and oftentimes minimal, datasets commonly collected for AD monitoring. An innovative way to account for arterial compliance in rigid-wall simulations using a lumped capacitor is introduced, and a parameter estimation strategy for boundary conditions calibration is proposed. The approach was tested on three complex cases of AD, and the results were successfully compared against invasive blood pressure measurements. Haemodynamic results (e.g. intraluminal pressures, flow partition between the lumina, wall shear-stress based indices) provided information that could not be obtained using imaging alone, providing insight into the state of the disease. It was noted that small tears in the distal intimal flap induce disturbed flow in both lumina. Moreover, oscillatory pressures across the intimal flap were often observed in proximity to the tears in the abdominal region, which could indicate a risk of dynamic obstruction of the true lumen. This study shows how combining commonly available clinical data with computational modelling can be a powerful tool to enhance clinical understanding of AD.

Impaired LXRα Phosphorylation Attenuates Progression of Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is a very common indication for liver transplantation. How fat-rich diets promote progression from fatty liver to more damaging inflammatory and fibrotic stages is poorly understood. Here, we show that disrupting phosphorylation at Ser196 (S196A) in the liver X receptor alpha (LXRα, NR1H3) retards NAFLD progression in mice on a high-fat-high-cholesterol diet. Mechanistically, this is explained by key histone acetylation (H3K27) and transcriptional changes in pro-fibrotic and pro-inflammatory genes. Furthermore, S196A-LXRα expression reveals the regulation of novel diet-specific LXRα-responsive genes, including the induction of Ces1f, implicated in the breakdown of hepatic lipids. This involves induced H3K27 acetylation and altered LXR and TBLR1 cofactor occupancy at the Ces1f gene in S196A fatty livers. Overall, impaired Ser196-LXRα phosphorylation acts as a novel nutritional molecular sensor that profoundly alters the hepatic H3K27 acetylome and transcriptome during NAFLD progression placing LXRα phosphorylation as an alternative anti-inflammatory or anti-fibrotic therapeutic target.

A simplified method to account for wall motion in patient-specific blood flow simulations of aortic dissection: Comparison with fluid-structure interaction.

Aortic dissection (AD) is a complex and highly patient-specific vascular condition difficult to treat. Computational fluid dynamics (CFD) can aid the medical management of this pathology, yet its modelling and simulation are challenging. One aspect usually disregarded when modelling AD is the motion of the vessel wall, which has been shown to significantly impact simulation results. Fluid-structure interaction (FSI) methods are difficult to implement and are subject to assumptions regarding the mechanical properties of the vessel wall, which cannot be retrieved non-invasively. This paper presents a simplified 'moving-boundary method' (MBM) to account for the motion of the vessel wall in type-B AD CFD simulations, which can be tuned with non-invasive clinical images (e.g. 2D cine-MRI). The method is firstly validated against the 1D solution of flow through an elastic straight tube; it is then applied to a type-B AD case study and the results are compared to a state-of-the-art, full FSI simulation. Results show that the proposed method can capture the main effects due to the wall motion on the flow field: the average relative difference between flow and pressure waves obtained with the FSI and MBM simulations was less than 1.8% and 1.3%, respectively and the wall shear stress indices were found to have a similar distribution. Moreover, compared to FSI, MBM has the advantage to be less computationally expensive (requiring half of the time of an FSI simulation) and easier to implement, which are important requirements for clinical translation.

Virtual TEVAR: Overcoming the Roadblocks of In-Silico Tools for Aortic Dissection Treatment.

The use of in silico tools for the interventional planning of complex vascular conditions, such as Aortic Dissections has been often limited by high computational cost, involving long timescales for accurate results to be produced and low numbers of patients, precluding the use of statistical analyses to inform individual-level models. In the paper [Theranostics 2018; 8(20):5758-5771. doi:10.7150/thno.28944], Chen et al. proposed a novel algorithm to compute patient-specific 'virtual TEVAR' that will help clinicians to approach individual treatment and decision-making based on objective and quantifiable metrics and validated on a cohort of 66 patients in real time. This research will significantly impact the field and has the potential to transform the way clinical interventions will be approached in the future.

Computational tools for clinical support: a multi-scale compliant model for haemodynamic simulations in an aortic dissection based on multi-modal imaging data.

Aortic dissection (AD) is a vascular condition with high morbidity and mortality rates. Computational fluid dynamics (CFD) can provide insight into the progression of AD and aid clinical decisions; however, oversimplified modelling assumptions and high computational cost compromise the accuracy of the information and impede clinical translation. To overcome these limitations, a patient-specific CFD multi-scale approach coupled to Windkessel boundary conditions and accounting for wall compliance was developed and used to study a patient with AD. A new moving boundary algorithm was implemented to capture wall displacement and a rich in vivo clinical dataset was used to tune model parameters and for validation. Comparisons between in silico and in vivo data showed that this approach successfully captures flow and pressure waves for the patient-specific AD and is able to predict the pressure in the false lumen (FL), a critical variable for the clinical management of the condition. Results showed regions of low and oscillatory wall shear stress which, together with higher diastolic pressures predicted in the FL, may indicate risk of expansion. This study, at the interface of engineering and medicine, demonstrates a relatively simple and computationally efficient approach to account for arterial deformation and wave propagation phenomena in a three-dimensional model of AD, representing a step forward in the use of CFD as a potential tool for AD management and clinical support.

Understanding the Effect of Statins and Patient Adherence in Atherosclerosis via a Quantitative Systems Pharmacology Model Using a Novel, Hybrid, and Multi-Scale Approach.

Background and Objective: Statins are one of the most prescribed drugs to treat atherosclerosis. They inhibit the hepatic HMG-CoA reductase, causing a reduction of circulating cholesterol and LDL levels. Statins have had undeniable success; however, the benefits of statin therapy crystallize only if patients adhere to the prescribed treatment, which is far away from reality since adherence decreases with time with around half of patients discontinue statin therapy within the first year. The objective of this work is to; firstly, demonstrate a formal in-silico methodology based on a hybrid, multiscale mathematical model used to study the effect of statin treatment on atherosclerosis under different patient scenarios, including cases where the influence of medication adherence is examined and secondly, to propose a flexible simulation framework that allows extensions or simplifications, allowing the possibility to design other complex simulation strategies, both interesting features for software development. Methods: Different mathematical modeling paradigms are used to present the relevant dynamic behavior observed in biological/physiological data and clinical trials. A combination of continuous and discrete event models are coupled to simulate the pharmacokinetics (PK) of statins, their pharmacodynamic (PD) effect on lipoproteins levels (e.g., LDL) and relevant inflammatory pathways whilst simultaneously studying the dynamic effect of flow-related variables on atherosclerosis progression. Results: Different scenarios were tested showing the impact of: (1) patient variability: a virtual population shows differences in plaque growth for different individuals could be as high as 100%; (2) statin effect on atherosclerosis: it is shown how a patient with a 1-year statin treatment will reduce his plaque growth by 2-3% in a 2-year period; (3) medical adherence: we show that a patient missing 10% of the total number of doses could increase the plaque growth by ~1% (after 2 years) compared to the same "regular" patient under a 1-year treatment with statins. Conclusions: The results in this paper describe the effect of pharmacological intervention combined with biological/physiological or behavioral factors in atherosclerosis progression and treatment in specific patients. It also provides an exemplar of basic research that can be practically developed into an application software.