Computational modeling of stented coronary arteries

The application of computational fluid dynamics (CFD) and finite element analysis (FEA) has been growing rapidly in the various fields of science and technology. One of the areas of interest is in biomedical engineering. The altered hemodynamics inside the blood vessels plays a key role in the development of the arterial disease called atherosclerosis, which is the major cause of human death worldwide. Atherosclerosis is often treated with the stenting procedure to restore the normal blood flow. A stent is a tubular, flexible structure, usually made of metals, which is driven and expanded in the blocked arteries. Despite the success rate of the stenting procedure, it is often associated with the restenosis (re-narrowing of the artery) process. The presence of non-biological device in the artery causes inflammation or re-growth of atherosclerotic lesions in the treated vessels. Several factors including the design of stents, type of stent expansion, expansion pressure, morphology and composition of vessel wall influence the restenosis process. Therefore, the role of computational studies is crucial in the investigation and optimisation of the factors that influence post-stenting complications. This thesis focuses on the stent-vessel wall interactions followed by the blood flow in the post-stenting stage of stenosed human coronary artery. Hemodynamic and mechanical stresses were analysed in three separate stent-plaque-artery models. Plaque was modeled as a multi-layer (fibrous cap (FC), necrotic core (NC), and fibrosis (F)) and the arterial wall as a single layer domain. CFD/FEA simulations were performed using commercial software packages in several models mimicking the various stages and morphologies of atherosclerosis. The tissue prolapse (TP) of stented vessel wall, the distribution of von Mises stress (VMS) inside various layers of vessel wall, and the wall shear stress (WSS) along the luminal surface of the deformed vessel wall were measured and evaluated. The results revealed the role of the stenosis size, thickness of each layer of atherosclerotic wall, thickness of stent strut, pressure applied for stenosis expansion, and the flow condition in the distribution of stresses. The thicknesses of FC, and NC and the total thickness of plaque are critical in controlling the stresses inside the tissue. A small change in morphology of artery wall can significantly affect the distribution of stresses. In particular, FC is the most sensitive layer to TP and stresses, which could determine plaque’s vulnerability to rupture. The WSS is highly influenced by the deflection of artery, which in turn is dependent on the structural composition of arterial wall layers. Together with the stenosis size, their roles could play a decisive role in controlling the low values of WSS (<0.5 Pa) prone to restenosis. Moreover, the time dependent flow altered the percentage of luminal area with WSS values less than 0.5 Pa at different time instants. The non- Newtonian viscosity model of the blood properties significantly affects the prediction of WSS magnitude. The outcomes of this investigation will help to better understand the roles of the individual layers of atherosclerotic vessels and their risk to provoke restenosis at the post-stenting stage. As a consequence, the implementation of such an approach to assess the post-stented stresses will assist the engineers and clinicians in optimizing the stenting techniques to minimize the occurrence of restenosis.

Cardiac Imaging in the Diagnosis of Coronary Artery Disease: The Value of Quantitative Imaging of Myocardial Perfusion and Deformation

Atherosclerosis is a chronic and progressive disease of the vasculature. Increasing coronary atherosclerosis can lead to obstructive coronary artery disease (CAD) or myocardial infarction. Computed tomography angiography (CTA) allows noninvasive assessment of coronary anatomy and quantitation of atherosclerotic burden. Myocardial blood flow (MBF) can be accurately measured in absolute terms (mL/g/min) by positron emission tomography (PET) with [15O] H O as a radiotracer. We studied the coronary microvascular dysfunction as a risk factor for future coronary calcification in healthy young men by measuring the coronary flow reserve (CFR) which is the ratio between resting and hyperemic MBF. Impaired vasodilator function was not linked with accelerated atherosclerosis 11 years later. Currently, there is a global interest in quantitative PET perfusion imaging. We established optimal thresholds of [15O] H O PET perfusion for diagnosis of CAD (hyperemic MBF of 2.3 mL/g/min and CFR of 2.5) in the first multicenter study of this type (Turku, Amsterdam and Uppsala). In myocardial bridging a segment of the coronary artery travels inside the myocardium and can be seen as intramural course (CTA) or systolic compression (invasive coronary angiography). Myocardial bridging is frequently linked with proximal atherosclerotic plaques. We used quantitative [15O] H O PET perfusion to evaluate the hemodynamic effects of myocardial bridging. Myocardial bridging was not associated with decreased absolute MBF or increased atherosclerotic burden. Speckle tracking allows quantitative echocardiographic imaging of myocardial deformation. Speckle tracking during dobutamine stress echocardiography was feasible and comparable to subjective wall motion analysis in the diagnosis of CAD. In addition, it correctly risk stratified patients with multivessel disease and extensive ischemia.

Cell wall thickness and tangential and radial cell diameter of fertilized and irrigated Norway spruce

Abstract

Slits in container wall improve root structure and stem straightness of outplanted Scots pine seedlings

Abstract

Intra-specific variation in cell wall constituents of needle age classes of Pinus sylvestris in relation to soil fertility status in Southwest England

Abstract

The p22phox C242T gene polymorphism is associated with a reduced risk of angiographically verified coronary artery disease in a high-risk Finnish Caucasian population. The Finnish Cardiovascular Study.

American Heart Journal Vol. 152, Issue 3, pp 538-542, 2006

Heart rate variability derived from exercise ECG in the detection of coronary artery disease.

Physiol Meas. 2007 Oct;28(10):1189-200. Epub 2007 Sep 18.

Measurement systems in wall production applications

Tässä tutkimuksessa kehitettiin prototyyppi betonielementin dimension mittaus järjestelmästä. Tämä järjestelmä mahdollistaa kolmiulotteisen kappaleen mittauksen. Tutkimuksessa kehitettiin myös stereonäköön perustuva kappaleen mittaus. Prototyyppiä testailin ja tulokset osoittautuivat luotettaviksi. Tutkimuksessa selvitetään ja vertaillaan myös muita lähestymistapoja ja olemassa olevia järjestelmiä kappaleen kolmiuloitteiseen mittaukseen, joita Suomalaiset yhtiöt käyttävät tällä alalla.

Modeling the transport phenomena within arterial wall: porous media approach

The transport of macromolecules, such as low-density lipoprotein (LDL), and their accumulation in the layers of the arterial wall play a critical role in the creation and development of atherosclerosis. Atherosclerosis is a disease of large arteries e.g., the aorta, coronary, carotid, and other proximal arteries that involves a distinctive accumulation of LDL and other lipid-bearing materials in the arterial wall. Over time, plaque hardens and narrows the arteries. The flow of oxygen-rich blood to organs and other parts of the body is reduced. This can lead to serious problems, including heart attack, stroke, or even death. It has been proven that the accumulation of macromolecules in the arterial wall depends not only on the ease with which materials enter the wall, but also on the hindrance to the passage of materials out of the wall posed by underlying layers. Therefore, attention was drawn to the fact that the wall structure of large arteries is different than other vessels which are disease-resistant. Atherosclerosis tends to be localized in regions of curvature and branching in arteries where fluid shear stress (shear rate) and other fluid mechanical characteristics deviate from their normal spatial and temporal distribution patterns in straight vessels. On the other hand, the smooth muscle cells (SMCs) residing in the media layer of the arterial wall respond to mechanical stimuli, such as shear stress. Shear stress may affect SMC proliferation and migration from the media layer to intima. This occurs in atherosclerosis and intimal hyperplasia. The study of blood flow and other body fluids and of heat transport through the arterial wall is one of the advanced applications of porous media in recent years. The arterial wall may be modeled in both macroscopic (as a continuous porous medium) and microscopic scales (as a heterogeneous porous medium). In the present study, the governing equations of mass, heat and momentum transport have been solved for different species and interstitial fluid within the arterial wall by means of computational fluid dynamics (CFD). Simulation models are based on the finite element (FE) and finite volume (FV) methods. The wall structure has been modeled by assuming the wall layers as porous media with different properties. In order to study the heat transport through human tissues, the simulations have been carried out for a non-homogeneous model of porous media. The tissue is composed of blood vessels, cells, and an interstitium. The interstitium consists of interstitial fluid and extracellular fibers. Numerical simulations are performed in a two-dimensional (2D) model to realize the effect of the shape and configuration of the discrete phase on the convective and conductive features of heat transfer, e.g. the interstitium of biological tissues. On the other hand, the governing equations of momentum and mass transport have been solved in the heterogeneous porous media model of the media layer, which has a major role in the transport and accumulation of solutes across the arterial wall. The transport of Adenosine 5´-triphosphate (ATP) is simulated across the media layer as a benchmark to observe how SMCs affect on the species mass transport. In addition, the transport of interstitial fluid has been simulated while the deformation of the media layer (due to high blood pressure) and its constituents such as SMCs are also involved in the model. In this context, the effect of pressure variation on shear stress is investigated over SMCs induced by the interstitial flow both in 2D and three-dimensional (3D) geometries for the media layer. The influence of hypertension (high pressure) on the transport of lowdensity lipoprotein (LDL) through deformable arterial wall layers is also studied. This is due to the pressure-driven convective flow across the arterial wall. The intima and media layers are assumed as homogeneous porous media. The results of the present study reveal that ATP concentration over the surface of SMCs and within the bulk of the media layer is significantly dependent on the distribution of cells. Moreover, the shear stress magnitude and distribution over the SMC surface are affected by transmural pressure and the deformation of the media layer of the aorta wall. This work reflects the fact that the second or even subsequent layers of SMCs may bear shear stresses of the same order of magnitude as the first layer does if cells are arranged in an arbitrary manner. This study has brought new insights into the simulation of the arterial wall, as the previous simplifications have been ignored. The configurations of SMCs used here with elliptic cross sections of SMCs closely resemble the physiological conditions of cells. Moreover, the deformation of SMCs with high transmural pressure which follows the media layer compaction has been studied for the first time. On the other hand, results demonstrate that LDL concentration through the intima and media layers changes significantly as wall layers compress with transmural pressure. It was also noticed that the fraction of leaky junctions across the endothelial cells and the area fraction of fenestral pores over the internal elastic lamina affect the LDL distribution dramatically through the thoracic aorta wall. The simulation techniques introduced in this work can also trigger new ideas for simulating porous media involved in any biomedical, biomechanical, chemical, and environmental engineering applications.

Nocturnal Transcutaneous Carbon Dioxide and Early Changes in Atherosclerosis in Pre- and Postmenopausal Women

The risk of cardiovascular diseases and sleep-disordered breathing increases after menopause. This cross-sectional study focuses on overnight transcutaneous carbon dioxide (TcCO₂) measurements and their power to predict changes in the early markers of cardiovascular and metabolic diseases. The endothelial function of the brachial artery, the intima-media thickness of the carotid artery, blood pressure, glycosylated hemoglobin A1C and plasma levels of cholesterols and triglycerides were used as markers of cardiovascular and metabolic diseases. The study subjects consisted of healthy premenopausal women of 46 years of age and postmenopausal women of 56 years of age. From wakefulness to sleep, the TcCO₂ levels increased more in postmenopausal women than in premenopausal women. In estrogen-users the increase in TcCO₂ levels was even more pronounced than in other postmenopausal women. From the dynamic behaviour of the nocturnal TcCO₂ signal, several important features were detected. These TcCO₂ features had a remarkable role in the prediction of endothelial dysfunction and thickening of the carotid wall in healthy premenopausal women. In addition, these TcCO₂ features were linked with blood pressure, lipid profile and glucose balance in postmenopausal women. The nocturnal TcCO₂ profile seems to contain significant information, which is associated with early changes in cardiovascular diseases in middle-aged women. TcCO₂ might not only measure the tissue carbon dioxide levels, but the TcCO₂ signal variation may also reflect peripheral vasodynamic events caused by increased sympathetic activity during sleep.

Imaging of the Vulnerable Atherosclerotic Plaque. Pre-Clinical Evaluation of PET Tracers for Vascular Inflammation

Atherosclerosis is a vascular inflammatory disease causing coronary artery disease, myocardial infarct and stroke, the leading causes of death in Finland and in many other countries. The development of atherosclerotic plaques starts already in childhood and is an ongoing process throughout life. Rupture of a plaque and the following occlusion of the vessel is the main reason for myocardial infarct and stroke, but despite extensive research, the prediction of rupture remains a major clinical problem. Inflammation is considered a key factor in the vulnerability of plaques to rupture. Measuring the inflammation in plaques non-invasively is one potential approach for identification of vulnerable plaques. The aim of this study was to evaluate tracers for positron emission tomography (PET) imaging of vascular inflammation. The studies were performed with a mouse model of atherosclerosis by using ex vivo biodistribution, autoradiography and in vivo PET and computed tomography (CT). Several tracers for inflammation activity were tested and compared with the morphology of the plaques. Inflammation in the atherosclerotic plaques was evaluated as expression of active macrophages. Systematic analysis revealed that the uptake of 18F-FDG and 11C-choline, tracers for metabolic activity in inflammatory cells, was more prominent in the atherosclerotic plaques than in the surrounding healthy vessel wall. The tracer for αvβ3 integrin, 18Fgalacto- RGD, was also found to have high potential for imaging inflammation in the plaques. While 11C-PK11195, a tracer targeted to receptors in active macrophages, was shown to accumulate in active plaques, the target-to-background ratio was not found to be ideal for in vivo imaging purposes. In conclusion, tracers for the imaging of inflammation in atherosclerotic plaques can be tested in experimental pre-clinical settings to select potential imaging agents for further clinical testing. 18F-FDG, 18F-galacto-RGD and 11C-choline choline have good properties, and further studies to clarify their applicability for atherosclerosis imaging in humans are warranted.

CT and PET/CT Hybrid Imaging of Coronary Artery Disease

Coronary artery disease (CAD) is a chronic process that evolves over decades and may culminate in myocardial infarction (MI). While invasive coronary angiography (ICA) is still considered the gold standard of imaging CAD, non-invasive assessment of both the vascular anatomy and myocardial perfusion has become an intriguing alternative. In particular, computed tomography (CT) and positron emission tomography (PET) form an attractive combination for such studies. Increased radiation dose is, however, a concern. Our aim in the current thesis was to test novel CT and PET techniques alone and in hybrid setting in the detection and assessment of CAD in clinical patients. Along with diagnostic accuracy, methods for the reduction of the radiation dose was an important target. The study investigating the coronary arteries of patients with atrial fibrillation (AF) showed that CAD may be an important etiology of AF because a high prevalence of CAD was demonstrated within AF patients. In patients with suspected CAD, we demonstrated that a sequential, prospectively ECG-triggered CT technique was applicable to nearly 9/10 clinical patients and the radiation dose was over 60% lower than with spiral CT. To detect the functional significance of obstructive CAD, a novel software for perfusion quantification, CarimasTM, showed high reproducibility with 15O-labelled water in PET, supporting feasibility and good clinical accuracy. In a larger cohort of 107 patients with moderate 30-70% pre-test probability of CAD, hybrid PET/CT was shown to be a powerful diagnostic method in the assessment of CAD with diagnostic accuracy comparable to that of invasive angiography and fractional flow reserve (FFR) measurements. A hybrid study may be performed with a reasonable radiation dose in a vast majority of the cases, improving the performance of stand-alone PET and CT angiography, particularly when the absolute quantification of the perfusion is employed. These results can be applied into clinical practice and will be useful for daily clinical diagnosis of CAD.

Lipotoxicity in Obesity and Coronary Artery Disease. Studies by PET, CT and MR

Lipotoxicity is a condition in which fatty acids (FAs) are not efficiently stored in adipose tissue and overflow to non-adipose tissue, causing organ damages. A defect of adipose tissue FA storage capability can be the primary culprit in the insulin resistance condition that characterizes many of the severe metabolic diseases that affect people nowadays. Obesity, in this regard, constitutes the gateway and risk factor of the major killers of modern society, such as cardiovascular disease and cancer. A deep understanding of the pathogenetic mechanisms that underlie obesity and the insulin resistance syndrome is a challenge for modern medicine. In the last twenty years of scientific research, FA metabolism and dysregulations have been the object of numerous studies. Development of more targeted and quantitative methodologies is required on one hand, to investigate and dissect organ metabolism, on the other hand to test the efficacy and mechanisms of action of novel drugs. The combination of functional and anatomical imaging is an answer to this need, since it provides more understanding and more information than we have ever had. The first purpose of this study was to investigate abnormalities of substrate organ metabolism, with special reference to the FA metabolism in obese drug-naïve subjects at an early stage of disease. Secondly, trimetazidine (TMZ), a metabolic drug supposed to inhibit FA oxidation (FAO), has been for the first time evaluated in obese subjects to test a whole body and organ metabolism improvement based on the hypothesis that FAO is increased at an early stage of the disease. A third objective was to investigate the relationship between ectopic fat accumulation surrounding heart and coronaries, and impaired myocardial perfusion in patients with risk of coronary artery disease (CAD). In the current study a new methodology has been developed with PET imaging with 11C-palmitate and compartmental modelling for the non-invasive in vivo study of liver FA metabolism, and a similar approach has been used to study FA metabolism in the skeletal muscle, the adipose tissue and the heart. The results of the different substudies point in the same direction. Obesity, at the an early stage, is associated with an impairment in the esterification of FAs in adipose tissue and skeletal muscle, which is accompanied by the upregulation in skeletal muscle, liver and heart FAO. The inability to store fat may initiate a cascade of events leading to FA oversupply to lean tissue, overload of the oxidative pathway, and accumulation of toxic lipid species and triglycerides, and it was paralleled by a proportional growth in insulin resistance. In subjects with CAD, the accumulation of ectopic fat inside the pericardium is associated with impaired myocardial perfusion, presumably via a paracrine/vasocrine effect. At the beginning of the disease, TMZ is not detrimental to health; on the contrary at the single organ level (heart, skeletal muscle and liver) it seems beneficial, while no relevant effects were found on adipose tissue function. Taken altogether these findings suggest that adipose tissue storage capability should be preserved, if it is not possible to prevent excessive fat intake in the first place.

Application of Computational Fluid Dynamics in Modeling Blood Flow in Human Thoracic Aorta

The aim of this study was to simulate blood flow in thoracic human aorta and understand the role of flow dynamics in the initialization and localization of atherosclerotic plaque in human thoracic aorta. The blood flow dynamics in idealized and realistic models of human thoracic aorta were numerically simulated in three idealized and two realistic thoracic aorta models. The idealized models of thoracic aorta were reconstructed with measurements available from literature, and the realistic models of thoracic aorta were constructed by image processing Computed Tomographic (CT) images. The CT images were made available by South Karelia Central Hospital in Lappeenranta. The reconstruction of thoracic aorta consisted of operations, such as contrast adjustment, image segmentations, and 3D surface rendering. Additional design operations were performed to make the aorta model compatible for the numerical method based computer code. The image processing and design operations were performed with specialized medical image processing software. Pulsatile pressure and velocity boundary conditions were deployed as inlet boundary conditions. The blood flow was assumed homogeneous and incompressible. The blood was assumed to be a Newtonian fluid. The simulations with idealized models of thoracic aorta were carried out with Finite Element Method based computer code, while the simulations with realistic models of thoracic aorta were carried out with Finite Volume Method based computer code. Simulations were carried out for four cardiac cycles. The distribution of flow, pressure and Wall Shear Stress (WSS) observed during the fourth cardiac cycle were extensively analyzed. The aim of carrying out the simulations with idealized model was to get an estimate of flow dynamics in a realistic aorta model. The motive behind the choice of three aorta models with distinct features was to understand the dependence of flow dynamics on aorta anatomy. Highly disturbed and nonuniform distribution of velocity and WSS was observed in aortic arch, near brachiocephalic, left common artery, and left subclavian artery. On the other hand, the WSS profiles at the roots of branches show significant differences with geometry variation of aorta and branches. The comparison of instantaneous WSS profiles revealed that the model with straight branching arteries had relatively lower WSS compared to that in the aorta model with curved branches. In addition to this, significant differences were observed in the spatial and temporal profiles of WSS, flow, and pressure. The study with idealized model was extended to study blood flow in thoracic aorta under the effects of hypertension and hypotension. One of the idealized aorta models was modified along with the boundary conditions to mimic the thoracic aorta under the effects of hypertension and hypotension. The results of simulations with realistic models extracted from CT scans demonstrated more realistic flow dynamics than that in the idealized models. During systole, the velocity in ascending aorta was skewed towards the outer wall of aortic arch. The flow develops secondary flow patterns as it moves downstream towards aortic arch. Unlike idealized models, the distribution of flow was nonplanar and heavily guided by the artery anatomy. Flow cavitation was observed in the aorta model which was imaged giving longer branches. This could not be properly observed in the model with imaging containing a shorter length for aortic branches. The flow circulation was also observed in the inner wall of the aortic arch. However, during the diastole, the flow profiles were almost flat and regular due the acceleration of flow at the inlet. The flow profiles were weakly turbulent during the flow reversal. The complex flow patterns caused a non-uniform distribution of WSS. High WSS was distributed at the junction of branches and aortic arch. Low WSS was distributed at the proximal part of the junction, while intermedium WSS was distributed in the distal part of the junction. The pulsatile nature of the inflow caused oscillating WSS at the branch entry region and inner curvature of aortic arch. Based on the WSS distribution in the realistic model, one of the aorta models was altered to induce artificial atherosclerotic plaque at the branch entry region and inner curvature of aortic arch. Atherosclerotic plaque causing 50% blockage of lumen was introduced in brachiocephalic artery, common carotid artery, left subclavian artery, and aortic arch. The aim of this part of the study was first to study the effect of stenosis on flow and WSS distribution, understand the effect of shape of atherosclerotic plaque on flow and WSS distribution, and finally to investigate the effect of lumen blockage severity on flow and WSS distributions. The results revealed that the distribution of WSS is significantly affected by plaque with mere 50% stenosis. The asymmetric shape of stenosis causes higher WSS in branching arteries than in the cases with symmetric plaque. The flow dynamics within thoracic aorta models has been extensively studied and reported here. The effects of pressure and arterial anatomy on the flow dynamic were investigated. The distribution of complex flow and WSS is correlated with the localization of atherosclerosis. With the available results we can conclude that the thoracic aorta, with complex anatomy is the most vulnerable artery for the localization and development of atherosclerosis. The flow dynamics and arterial anatomy play a role in the localization of atherosclerosis. The patient specific image based models can be used to diagnose the locations in the aorta vulnerable to the development of arterial diseases such as atherosclerosis.