Correlation between Coronary Artery Disease with Other Arterial Systems: Similar, Albeit Separate, Underlying Pathophysiologic Mechanisms

Atherosclerosis is a multifactorial systemic disease that affects the entire arterial tree, although some areas are more prone to lipid deposits than others. Moreover, the histopathological composition of the plaques differs, and the clinical manifestations are also different, depending on the location and structure of the atherosclerotic plaque. Some arterial systems are correlated with each other more than in that they simply share a common atherosclerotic risk. The aim of this perspective review is to discuss this heterogeneity of atherosclerotic impairment in different arterial districts and to investigate the current evidence that resulted from studies of the topographical interrelations of atherosclerosis

PCSK9 Biology and Its Role in Atherothrombosis

It is now about 20 years since the first case of a gain-of-function mutation involving the as-yet-unknown actor in cholesterol homeostasis, proprotein convertase subtilisin/kexin type 9 (PCSK9), was described. It was soon clear that this protein would have been of huge scientific and clinical value as a therapeutic strategy for dyslipidemia and atherosclerosis-associated cardiovascular disease (CVD) management. Indeed, PCSK9 is a serine protease belonging to the proprotein convertase family, mainly produced by the liver, and essential for metabolism of LDL particles by inhibiting LDL receptor (LDLR) recirculation to the cell surface with the consequent upregulation of LDLR-dependent LDL-C levels. Beyond its effects on LDL metabolism, several studies revealed the existence of additional roles of PCSK9 in different stages of atherosclerosis, also for its ability to target other members of the LDLR family. PCSK9 from plasma and vascular cells can contribute to the development of atherosclerotic plaque and thrombosis by promoting platelet activation, leukocyte recruitment and clot formation, also through mechanisms not related to systemic lipid changes. These results further supported the value for the potential cardiovascular benefits of therapies based on PCSK9 inhibition. Actually, the passive immunization with anti-PCSK9 antibodies, evolocumab and alirocumab, is shown to be effective in dramatically reducing the LDL-C levels and attenuating CVD. While monoclonal antibodies sequester circulating PCSK9, inclisiran, a small interfering RNA, is a new drug that inhibits PCSK9 synthesis with the important advantage, compared with PCSK9 mAbs, to preserve its pharmacodynamic effects when administrated every 6 months. Here, we will focus on the major understandings related to PCSK9, from its discovery to its role in lipoprotein metabolism, involvement in atherothrombosis and a brief excursus on approved current therapies used to inhibit its action

Genetic polymorphisms, platelet activation and plasma homocysteine concentrations in atherothrombotic stroke

Atherothrombotic stroke arises following rupture of an atheromatous plaque, and occlusion occurs directly due to thrombosis in small arteries, or indirectly by embolisation if a large vessel plaque ruptures. Three risk factors that are claimed to influence these process were investigated. The influence of platelet activation and genetic polymorphisms of platelet membrane glycoproteins on the risk of thrombotic stroke was assessed. Following plaque rupture, platelets have a pivotal role in arterial thrombus formation, and platelet membrane glycoproteins (GP) IIIa (the fibrinogen receptor) and Ib (which binds von Willebrand factor) are crucial in this process. The lb allele of the HPA 1a/1b GPIIIa polymorphism and the 2b allele of the HPA 2a/2b GPIb polymorphism are claimed to be risk factors for stroke and myocardial infarction (MI), but reports are conflicting and consistent functional evidence of enhanced thrombogenicity is lacking. Increased factor VII activity (VIIc) has been claimed to be a risk factor for MI and stroke, but the data are conflicting. VIIc is dependent on both environmental and genetic influences, and recently two polymorphisms of the factor VII gene associated with lower VIIc have been claimed to be protective against MI. A raised plasma homocysteine concentration has been proposed as a cause for atherosclerosis. However the role of homocysteine in stroke aetiology remains controversial, since prospective studies have reported a weaker association than those conducted retrospectively. Furthermore there are few reports of plasma homocysteine concentrations both before and after the event. The following studies were conducted to address these issues: An investigation of the effect of HPA la/lb genotype on platelet fibrinogen binding by whole blood flow cytometry in healthy subjects. The effect of the lb allele on platelet fibrinogen binding was investigated in healthy subjects by whole blood flow cytometry. 35 platelet or plasma donors (34 HPA 1a/1b and one HPA 1b/1b) possessing the lb allele were compared with 35 donors homozygous for the la allele. There was no allele dependent difference in the percentage of platelets binding fibrinogen at baseline (p=0.14, Mann Whitney U test) or following stimulation with ADP (p=0.72, Student's t-test). An paradoxical increase in the density of fibrinogen binding sites was observed in la platelets after ADP stimulation (p=0.05, Mann Whitney U test), 1b platelets tended to exhibit greater activation as assessed by the percentage of platelets expressing P-Selectin, but this did not reach statistical significance (p=0.08, Mann-Whitney U test). These data do not identify a functional mechanism by which the 1b allele might mediate an increased risk of arterial thrombosis. (Abstract shortened by ProQuest.)

Carotid plaque stress analysis by fluid structure interaction based on in-vivo MRI: Implications to plaque vulnerability assessment

This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University, 2010.Stroke is one of the leading causes of death in the world, resulting mostly from the sudden rupture of atherosclerotic plaques. From a biomechanical view, plaque rupture can be considered as a mechanical failure caused by extremely high plaque stress. In this PhD project, we are aiming to predict 3D plaque stress based on in-vivo MRI by using fluid structure interaction (FSI) method, and provide information for plaque rupture risk assessment. Fluid structure interaction was implemented with ANSYS 11.0, followed by a parameter study on fibrous cap thickness and lipid core size with realistic carotid plaque geometry. Twenty patients with carotid plaques imaged by in-vivo MRI were provided in the project. A framework of reconstructing 3D plaque geometry from in-vivo multispectral MRI was designed. The followed reproducibility study on plaque geometry reconstruction procedure and its effect on plaque stress analysis filled the gap in the literature on imaging based plaque stress modeling. The results demonstrated that current MRI technology can provide sufficient information for plaque structure characterization; however stress analysis result is highly affected by MRI resolution and quality. The application of FSI stress analysis to 4 patients with different plaque burdens has showed that the whole procedure from plaque geometry reconstruction to FSI stress analysis was applicable. In the study, plaque geometries from three patients with recent transient ischemic attack were reconstructed by repairing ruptured fibrous cap. The well correlated relationship between local stress concentrations and plaque rupture sites indicated that extremely high plaque stress could be a factor responsible for plaque rupture. Based on the 20 reconstructed carotid plaques from two groups (symptomatic and asymptomatic), fully coupled fluid structure interaction was performed. It was found that there is a significant difference between symptomatic and asymptomatic patients in plaque stress levels, indicating plaque stress could be used as one of the factors for plaque vulnerability assessment. A corresponding plaque morphological feature study showed that plaque stress is significantly affected by fibrous cap thickness, lipid core size and fibrous cap surface irregularities (curvedness). A procedure was proposed for predicting plaque stress by using fibrous cap thickness and curvedness, which requires much less computational time, and has the potential for clinical routine application. The effects of residual stress on plaque stress analysis and arterial wall material property characterization by using in-vivo MRI data were also discussed for patient specific modeling. As the further development, histological study of plaque sample has been combined with conventional plaque stress analysis by assigning material properties to each computational element, based on the data from histological analysis. This method could bridge the gap between biochemistry and biomechanical study of atherosclerosis plaques. In conclusion, extreme stress distributions in the plaque region can be predicted by modern numerical methods, and used for plaque rupture risk assessment, which will be helpful in clinical practice. The combination of plaque MR imaging analysis, computational modelling, and clinical study/ validation would advance our understandings of plaque rupture, prediction of future rupture, and establish new procedures for patient diagnose, management, and treatment.Financial Support was obtained from British Heart Foundation, Brunel Institute for Bioengineering and Brunel Graduate School

Résolution du problème inverse en élastographie ultrasonore par une méthode variationnelle

Résumé: La rupture des plaques d’athérosclérose est associée à la majorité des infarctus du myocarde et des syndromes coronariens aigus. La distribution des contraintes mécaniques dans ces plaques d’athérosclérose peut fournir des indices importants sur leur vulnérabilité d’un point de vue mécanique. La mesure de ces contraintes n’est pas encore possible directement in vivo. Toutefois, les images médicales, telles que les images échographiques, peuvent aider à estimer ces contraintes. Les approches d’inversion des images échographiques permettent d’obtenir des indications sur les contraintes mécaniques en milieu clinique. Les approches utilisées actuellement dans ce domaine vasculaire admettent des limites. En effet, les approches classiques d’inversion sont souvent basées sur des hypothèses restrictives sur la contrainte elle-même, telles que le fait qu’elle soit constante dans la région d’intérêt. Les autres approches se font généralement dans un processus itératif. Elles sont basées sur le recalage de données mesurables à partir des images à d’autres données calculées par un modèle d’éléments finis simulant la lésion analysée. Ce modèle est la limite de ces méthodes de recalage à leur application en milieu clinique : il nécessite des connaissances a priori sur chaque plaque analysée. Ce besoin de connaissance a priori complique la transférabilité de ces méthodes de recalage à l’analyse de différents types de plaques. De plus, la formulation des approches d’inversion classiques des images échographiques ne permet généralement pas d’intégrer les effets des caractéristiques mécaniques non linéaires de la lésion artérielle. Dans ce projet, nous démontrons que les effets non linéaires sont importants pour l’analyse de la stabilité mécanique des plaques d’athérosclérose. Ensuite, nous développons une approche d’inversion des images échographiques qui ne nécessite pas d’hypothèses restrictives sur les contraintes, qui est transférable à différents types de plaques artérielles et qui peut s’étendre à des analyses mécaniques non linéaires. Enfin, nous validons notre approche pour plusieurs types de plaques et pour différents types d’images échographiques synthétisées pour des modalités d’imagerie intravasculaire et extravasculaires.----------Abstract: Atherosclerotic plaque rupture is responsible for the majority of myocardial infarctions and acute coronary syndromes. In vivo assessment of the mechanical stress could provide valuable plaque rupture indices for the diagnosis and prognosis of those clinical outcomes. As for now, it is not yet possible to determine the internal distribution of stresses directly in vivo. However, medical imaging modality such as ultrasound imaging could help achieving this goal through processing of image sequences providing the strains of the tissue and its elasticity parameters distribution. The strains and elasticity parameters of an elastic tissue can help to estimate its mechanical stresses. A number of ultrasound images processing methods have been proposed for that purpose. However, often their underlying hypotheses prevent them from being clinically applicable to clinical data. For example, a method may assume a constant stress distribution within a region where therefore the strain map can be interpreted also as an elastic parameter map in this region. Other methods would use an iterative process to best match the measurable data obtained from images to the ones predicted from a finite element model (FEM) of the tissue. But, their implementation generally requires a priori knowledge on each analyzed plaque, as for example its boundary conditions that are not often identifiable from clinical images. This obviously limits the transferability of those methods to the analysis of a broad range of clinical data. Such model-based inversions of ultrasound images do not currently consider non-linear rheological laws of arteries, an important concern for stress analysis. In this project, we first re-examine assessment of plaque vulnerability and demonstrate that non linear mechanical effects are important for the analysis of the stability of the atherosclerotic plaques. We then develop an inversion approach to process ultrasound images, based on the optimization of functionals that minimize the mechanical energy of elastic tissues. Then, we evaluate our approach on several plaque models and several ultrasound imaging modalities: radio-frequency ultrasound data, envelope or B-Mode data, intra-vascular and extra-vascular ones. Due to its generality, this approach can be applied to a broad range of plaque geometry and can be extended to inversions for non linear mechanical cases

Intravascular Ultrasound

Intravascular ultrasound (IVUS) is a cardiovascular imaging technology using a specially designed catheter with a miniaturized ultrasound probe for the assessment of vascular anatomy with detailed visualization of arterial layers. Over the past two decades, this technology has developed into an indispensable tool for research and clinical practice in cardiovascular medicine, offering the opportunity to gather diagnostic information about the process of atherosclerosis in vivo, and to directly observe the effects of various interventions on the plaque and arterial wall. This book aims to give a comprehensive overview of this rapidly evolving technique from basic principles and instrumentation to research and clinical applications with future perspectives

Shear stress and interferon regulatory gactor 5 modulate myeloid cell behaviour in atherosclerosis

Rupture of “vulnerable” atherosclerotic plaques and subsequent thrombosis cause acute cardiovascular events, and can develop upon exposure of the arterial wall to low shear stress. Myeloid cells - the main inflammatory cells within atherosclerotic plaques - are heterogeneous; ranging from “classical” pro-inflammatory M1 macrophages to “alternative” M2 macrophages and various subsets of dendritic cells. The activation of Toll-like receptors and downstream Interferon Regulatory Factors (IRFs) is involved in atherosclerosis. IRF5 polarises macrophages towards the M1 phenotype and modulates cytokine production by dendritic cells. I utilised two murine models of atherosclerosis: the hypercholesterolaemic ApoE-/- (Apolipoprotein E knockout) mouse strain, and a perivascular cast modifying shear stress patterns in the carotid artery. Firstly, I found the majority of macrophages in early and intermediate lesions of the aortic root and advanced oscillatory shear stress-modulated lesions express heme oxygenase-1 (HO-1). The representation of the M1 macrophage marker iNOS (inducible nitric oxide synthase) and IRF5 is more prevalent in low shear stress-modulated plaques, which resemble a vulnerable plaque, while M2 macrophage markers are elevated in oscillatory shear stress-modulated plaques resembling stable plaques. Secondly, I studied the effect of IRF5 deletion on the development of atherosclerosis by comparing the severity of atherosclerosis in ApoE-/- mice with ApoE-/-IRF5-/- mice. Atherosclerotic lesions in the aortic root of ApoE-/-IRF5-/- mice are reduced in size, and in all vascular regions they have smaller necrotic cores (a marker of plaque vulnerability), due to a reduction in efferocytosis, and an increase in atheroprotective macrophages. Lesions in ApoE-/-IRF5-/- mice also have a depleted content of cells expressing CD11c; therefore IRF5 is detrimental in atherosclerosis by skewing myeloid cell differentiation towards dendritic cells possibly via GM-CSF. My study provides a novel link between inflammatory signalling, efferocytosis and necrotic core formation.Open Acces

TRANSLATIONAL APPROACHES TO UNDERSTANDING THE ROLE OF CYTOCHROME P450-DERIVED EPOXYEICOSATRIENOIC ACIDS IN CORONARY ARTERY DISEASE

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality in the United States (US). Most notably, coronary artery disease (CAD) including its clinical complications (acute myocardial infarction [AMI] and heart failure) is the primary source of this public health burden. This burden highlights the need for new therapies that target biological pathways integral to the pathophysiology of CAD and its consequences. However, a more thorough understanding of the mechanisms underlying the pathophysiology is necessary to facilitate the development of new therapeutic strategies. Epoxyeicosatrienoic acids (EETs) are cytochrome P450 (CYP)-derived metabolites of arachidonic acid that are hydrolyzed by soluble epoxide hydrolase (sEH) into the less biologically active dihydroxyeicosatrienoic acids (DHETs). EETs yield potent cardiovascular protective effects in preclinical models of atherosclerosis, ischemia reperfusion (IR) injury, and post-AMI ventricular remodeling, suggesting that increasing EET levels may be a viable therapeutic strategy for CAD, AMI, and post-AMI maladaptive ventricular remodeling. Key questions, however, remain to be addressed prior to translation of therapeutic EET-promoting strategies into successful clinical trials. The overall aim of this dissertation is to advance our understanding of the role of the EET metabolic pathway across the full spectrum of CAD and post-AMI consequences as a means to determine the biological and therapeutic importance of EETs in the progression of this disease cascade. We used both pre-clinical and human studies to complete the specific aims of this work. We found that obstructive CAD is significantly and independently associated with lower circulating EET levels. In addition, we observed that a functionally relevant polymorphism linked with enhanced EET hydrolysis was potentially associated with mortality in a population of AMI patients. Moreover, we showed that mice with cardiomyocyte-specific overexpression of human sEH exhibited enhanced IR-induced myocardial collagen deposition. Overall, we demonstrated that the EET metabolic pathway may play a role in the pathophysiology of CAD and its associated complications including the development of coronary atherosclerosis, post-AMI early ventricular remodeling, and post-AMI mortality. These findings set the stage for future studies that investigate the therapeutic utility of modulating EETs in CAD patients.Doctor of Philosoph