Coronary-artery-diseases-Dr-Inass-Zaki (1).pdf

Coronary artery diseases Atherosclerosis Dr. Inass Zaki Lecturer of Pathology Faculty of Medicine, Alexandria university [email protected] ILOs: By the end of this session, the students should be able to: -To understand the risk factors for athero...

Coronary artery diseases Atherosclerosis Dr. Inass Zaki Lecturer of Pathology Faculty of Medicine, Alexandria university [email protected] ILOs: By the end of this session, the students should be able to: -To understand the risk factors for atherosclerosis (environmental & genetic ) - To understand how atherosclerosis is regulated at the molecular and cellular level - To understand the basis of current therapeutic strategies aimed to prevent or reduce atherosclerosis  Loading… What is Atherosclerosis? Atherosclerosis the term atherosclerosis from the Greek "athero", meaning gruel, and "sclerosis", meaning hardening, to describe the fatty substance inside a hardened artery. Atherosclerosis has been a human disease for >3,500 years; it occurred in Egyptian mummies and showed the same pathologicLoading… features that are observed in modern times. Risk factors for Atherosclerosis Advanced age Sex (Male gender) Smoking Dyslipidemia Diabetes Mellitus Hypertension Excess Adiposity and Metabolic Syndrome Psychosocial factors Daily consumption of fruits and vegetables Regular Physical activity Genetic of coronary atherosclerosis ---- Genome Wide Associated Study (GWAS)  9p21 Loading… Basic Atherosclerosis is a chronic inflammatory process triggered by accumulation of mechanism of cholesterol-containing low density lipoprotein (LDL) particles in the arterial Atherosclerosi wall. s  Evolving Concepts of Dyslipidemia, Atherosclerosis, and Cardiovascular Disease Felix Jacob Marchand (22 October 1846 – 4 February 1928) was a German Discovered the significance and role of pathologist cholesterol in atherosclerosis pathogenesis. Nikolay Nikolayevich Anichkov (1885-1964) Russian pathologist 0-Infiltration of apolipoprotein B(apoB)- containing LDL in the arterial wall The turbulent flow at those sites will lead to a local recirculation and consequently increased concentrations of plasma LDL adjacent to the luminal surface. As a result, an increased radial LDL transport will occur into the arterial wall and LDL can be retained by proteoglycans. Disturbed flow creates shear stress/ frictional force onto endothelial cells so proinflammatory transcriptional programs in the cells can be activated Endothelial dysfunction hampers the barrier function of this cell layer, leading to increased influx of cholesterol-containing lipoproteins into the arterial intima 1. Uptake modification Retained LDL can be modified by, for example, oxidation, and serve as an initiating stimulus for inflammatory reactions, by being recognized as a so-called danger-associated-molecular-pattern (DAMP) [ compare pathogen-associated molecular pattern (PAMP)] 1. Endothelial adhesion molecules 2. Leukocyte adhesion and recruitment Specific pattern recognition, such as toll like receptor (TLR) activation by oxidized LDL (oxLDL), stimulates endothelial cells to express adhesion molecules. oxLDL particles induce endothelial cell surface expression of leukocyte adhesion molecules which can bind to their ligands expressed on leukocytes Combinatorial expression of endothelial adhesion molecules and leukocyte integrins and selectins provides a sophisticated regulation of the inflammatory process and determines the type and place for recruitment of a certain type of myeloid or lymphoid cell during atherosclerosis development.  The leukocytes recruited to the developing atherosclerotic lesion produce a number of inflammatory mediators that amplifying the inflammatory reaction through a continued activation of both leukocytes and endothelial cells and by recruiting further immune cells to the forming lesion 1. Monocyte to macrophage differentiation Monocytes (the most numerous white blood cells recruited into atherosclerotic plaques) Once resident in the arterial wall, they differentiate into tissue macrophages under the influence of monocyte-colony stimulating factor (M-CSF) present in forming lesions Classically activated macrophages or M1 macrophages in the atherosclerotic lesion further enrich the proinflammatory milieu, by means of inflammatory proteins and lipid mediators, such as cytokines and leukotrienes, to sustain inflammatory responses and result in tissue damage.  Alternatively activated, or M2, macrophages secrete anti-inflammatory mediators promoting the resolution of inflammation by means of clearance of apoptotic cells (efferocytosis) and dampening of immune responses, hence promoting tissue repair and healing 1. oxLDL uptake and foam cell formation The presence of both retained and modified LDL, together with activated leukocytes, the atherosclerotic lesion is emerging. Oxidized and otherwise modified forms of LDL particles can bind to scavenger receptors expressed on resident macrophages. Uptake of lipoprotein particles will induce the conversion of macrophages into foam cells, pathogenic process that result in the microscopic appearance of lipid-laden macrophages which is characteristic of the atherosclerotic lesion Loading… 1. Antigen presentation Internalization of oxLDL by macrophages and dendritic cells will lead not only to foam cell formation, but also antigen presentation (adaptive immune response) Effector CD4T cells are recruited to the atherosclerotic lesion by leukocyte adhesion molecules and chemotactic factors produced as a consequence of innate immune activation CD4+ T cell are activated/differentiated into helper T cell (Th cells) through antigen presentation. In addition to Th1 cells that promote macrophage activation and inflammation, effector T cell of Treg (regulatory T cell) subtype are present in atherosclerotic lesions and act by inhibiting immune response and inflammation, thus, are considered artheroprotective. Th17 cell subtype promotes fibrosis through action of its cytokine IL-17. Therefore, Th17 activity enhances formation of the lesion’s fibrous cap and plaque stability. 1. Macrophages apoptosis and necrotic core formation Several factors, such as oxidative stress, in the atherosclerotic lesion induce macrophage death through apoptosis. Apoptotic cells are normally cleared by a specific phagocytosis process, efferocytosis, derived from the Greek word ‘to buy’. Efferocytosis is an immune response essential for normal steady state of a tissue and a critical phenomenon in the resolution of inflammation Defective clearance of lipid-laden apoptotic macrophages in the atherosclerotic lesion creates a lipid necrotic core.  Tertiary Lymphoid Organs (TLOs) in the adventitia In addition to the inflammatory circuits taking place in the intima, complex adaptive responses also develop in the adventitia. Inflammatory cell in the adventitia of atherosclerotic lesion include dendritic cells, macrophages, mast cells and lymphocytes. T and B cell activation is present in the adventitia of atherosclerotic vessels, and in advanced stages of atherosclerosis, large lymphoid structures may develop, referred to as adventitial tertiary lymphoid organs. These adventitial tertiary lymphoid organs are sites of antibody production, including antibodies to plasma lipoproteins. Diagnosis Cholesterol  Resources/References Lecture notes Chronic Coronary Artery Disease, A Companion to Braunwald's Heart Disease 1st Edition - January 3, 2017 Robbins & Cotran Pathologic Basis of Disease 10th Edition - May 18, 2020 [email protected]