10. Artherosclerosis_Hazen-Martin_NOTES.pdf

Atherosclerois Debra Hazen-Martin, PhD Office: 792-2906 Email: [email protected] Atherosclerosis: A Chronic Inflammatory Disease Outline: I. Review of Vessel Morphology A. Components of the normal vessel wall B. Classification of arteries II. General Vascular Response to Injury A. Endothelial res...

Atherosclerois Debra Hazen-Martin, PhD Office: 792-2906 Email: [email protected] Atherosclerosis: A Chronic Inflammatory Disease Outline: I. Review of Vessel Morphology A. Components of the normal vessel wall B. Classification of arteries II. General Vascular Response to Injury A. Endothelial response B. Smooth muscle response C. Stereotypic intimal thickening III. Diseases of Vessels A. Examples IV. Atherosclerosis A. Atheroma features B. Clinical Implications C. Incidence D. Risk Factors 1. Framingham Heart Study 2. Hypercholesterolemia 3. Inflammation 4. Flow patterns E. Development of disease 1. Fatty streak 2. Endothelial dysfunction and response 3. Inflammatory cells and mediators 4. T-cell activation 5 Smooth muscle proliferation 6. Plaque maturation 7. Loss of stability V. Monckeburg Medial Calcific Sclerosis VI. Arteriolosclerosis and Hypertension A. Hypertension 1. Types and terms B. Vascular injury 1. Hyaline arteriolosclerosis 2. Hyperplastic arteriolosclerosis Suggested Reading: Robbins Basic Pathology by Kumar, Abbas and Aster, Chapter 10 (361-364, 366-376) 1 Atherosclerois Objectives: 1) Describe the components of intimal thickening in vascular injury. 2) List the types of arteriosclerosis. 3) Describe the composition of an atheroma and compare it to the composition of a fatty streak. 4) Describe the modifiable and non-modifiable risk factors for atherosclerosis/cardiovascular disease. 5) Describe the steps and timeframe of atherosclerotic plaque formation. 6) Describe the pathogenesis of atherosclerosis at a cellular level. 7) Provide supporting evidence for why atherosclerosis is considered an inflammatory disease. 8) Describe the implications of C-reactive protein levels in concert with other established risk factors in cardiovascular disease. 9) Differentiate between essential, secondary, benign and malignant hypertension. 10) Describe two forms of arteriolosclerosis and the conditions that contribute to their development. I. Review of Vessel Morphology A. Components of the normal vessel wall You will study diseases that either narrow, obstruct, weaken, and/or damage the vessel wall so it is important to understand the normal structure of the wall before trying to understand the pathogenesis of the diseases. Vessels have 3 layers: the tunica intima, tunica media and tunica adventitia. The intima and media are separated by a fenestrated internal elastic membrane. The media and adventitia are separated by the external elastic membrane. The vascular tissue receives nutrients from blood circulating within the vessel by diffusion and from blood circulating within the vessels of the adventitia. 2 Atherosclerois B. Classification of arteries Arteries are classified by size and composition of the tunica media. You will learn that atherosclerosis affects elastic and muscular arteries while hypertension affects and is regulated by the small arteries and arterioles. Atherosclerosis - Elastic & Muscular arteries Hypertension - Small arteries & arterioles II. General Vascular Response to Injury A. Endothelial response Various forms of injury or stress can lead to loss of the endothelial surface. Adjacent endothelial cells are ready to respond, as in the process of thrombus formation, to facilitate the clot formation. They also are equipped to counter that activity. In the pathogenesis of atherosclerosis the endothelium is remarkably intact, leading investigators to hypothesize that the endothelial cell’s wide array of activities and possible responses to agents lead to dysregulation and altered function in this disease process. B. Smooth muscle response In the diseases we will discuss today, you will see that the normal function of smooth muscle cells make them valuable in responding to injury and attempting repair. They are not passive in the process. 1. Stable cell population 2. Migration 3. ECM 4. Grown factors/Cytokines 5. Vasodilation/Vasoconstriction 3 Atherosclerois C. Stereotypic intimal thickening Smooth muscle cells move into the tunica intima where they proliferate and secrete ECM to increase the overall thickness of the intima and vessel wall. The thickening may be normalized or may be permanent. In cases of chronic stimuli, the thickening can lead to progressive stenosis as in atherosclerosis. The contribution of smooth muscle cells and the resulting production of ECM is thought to resemble that of fibroblasts that move into sites of injury in other areas of the body in order to repair through scar formation. Mec(4) In this PNAS article by Caplice, et.al. (2003) data is shown that suggests that ~ 10% of the smooth muscle cells within the thickened intima of a damaged vessel may be derived from bone marrow stem cell precursors. III. Diseases of Vessels A. Definition and Examples Arteriosclerosis is a genera term that means “hardening of the arteries”. Three vascular disorders cause thickening and inelasticity of arteries of different sizes: 1) Atherosclerosis 2) Monckeberg medial calcific sclerosis 3) Arteriolosclerosis Each disease process has unique characteristics and consequences. 4 Atherosclerois IV. Atherosclerosis A. Atheroma features Atherosclerosis involves intimal thickening and specifically development of an atheroma or atherosclerotic plaque. The atheroma has a necrotic core containing cellular debris, lipids (primarily cholesterol), and calcium. The core has a fibrous cap composed on smooth muscle cells and extra-cellular matrix proteins that they have secreted. Neo-vascularization is sometimes seen. B. Clinical Implications The lesions of atherosclerosis (mature plaque) may grow to cause progressive occlusion of the lumen of an artery. In the case of the carotid, cerebral and/or coronary arteries, critical stenosis will lead to loss of blood and oxygen supply to downstream tissues. In many cases the growth is slow and collateral vascular supply will compensate to varying degrees in different organs. More often the atheroma becomes unstable, ruptures and hemorrhages leading to thrombogenesis at the site. The thrombus may more acutely and fully occlude the vessel. 5 Atherosclerois An unstable plaque may also become friable and crumble forming atheroemboli that travel further in the arterial tree to occlude smaller vessels. Although the atheroma is within the tunica intima, the underlying smooth muscle of the tunica media may weaken and allow dissection and/or aneurysms to form. C. Incidence The incidence of atherosclerotic disease is high, accounting for approximately 50% of all deaths in the western world due to downstream ischemic heart disease and cerebral events. The impact/contribution of lifestyle in developed countries is well supported. Increased incidence is noted in populations that adopt more “westernized” diets and lifestyles. 6 Atherosclerois D. Risk Factors 1. Framingham Heart Study Risk factors have been established by several excellent prospective studies of populations including the Framingham Heart Study which have help to identify both modifiable and non-avoidable factors that contribute to the pathogenesis of atherosclerosis related to heart disease. Other risk factors remain under investigation for further confirmation. One of the most interesting things about risk factors identified by the Framingham study, is that multiple risk factors are not simply additive but have a multiplicative effect. So two risk factors quadruple the incidence and 3 risk factors multiply the incidence of cardiac disease due to atherosclerotic events by 7 in both men and women. This data supports the value in elimination of even one risk factor. 2. Hypercholesterolemia is a major risk factor, specifically elevated LDL. Evidence for involvement of LDL is supported by the finding of oxidized LDL within atheromas. Individuals with familial hypercholesterolemia have genetic defects that interrupt LDL receptor synthesis, transport, insertion in the membrane or recycling. Each of the defects can stop uptake of LDL and result in higher circulating LDL. Affected individuals develop accelerated atherosclerosis and ischemic heart disease by 20 years of age. Any factors that raise circulating LDL, lower HDL, or produce abnormal carrier forms (Lpa) will xter(4) influence plaque formation (ex: obesity, diabetes). 7 Atherosclerois 3. Inflammation has been shown to be a major risk factor for the development of disease due to atherosclerosis. In a simple study published in the New England Journal of Medicine 347:1565 (2002) Paul Ridker demonstrated a correlation of C-reactive protein levels with cardiovascular disease and stroke. Twenty percent of cardiovascular events occur in individuals with no known risk factors and 75% of women who have first cardiovascular events have normal levels of LDL. Dr. Ridker identified a population of ~28,000 healthy women and followed their history of myocardial infarct, stroke and death by cardiovascular events for 8 years. Both LDL and C-reactive protein were monitored. C-reactive protein is one of the acute phase proteins synthesized in the liver that is produced downstream of a number of inflammatory events and mediators. It may also be produced within the intima of vessels. It functions to opsonize bacteria, activate complement, and regulate endothelial adhesion and thrombogenic activity. Role(2) Ridker’s study showed that C-reactive protein independently predicted risk of MI, stroke and other cardiovascular events better than LDL alone. When combined with the risk factors developed by the Framingham Heart Study, CRP levels were able to stratify patients within each of the categories of risk. These data clearly support the role of inflammation in atherogenesis. 8 Atherosclerois 4. Flow patterns Dai, et al. have demonstrated that flow patterns at sites of the vascular wall that are prone to atheroma formation are distinct from atheroma-free areas. They have also been able to show that exposure of endothelia cells in culture to these well-defined and variable flow patterns results in distinct proinflammatory phenotypes. This data helps to further the thought that pro-atheroma flow patterns further modulate atheroma development independent of mediators of inflammation. E. Development of disease Overview: The process of forming an atherosclerotic plaque (atheroma) has two parts. Formation of the fatty streak, a non-raised area of the intima, occurs early and involves endothelial injury by agents and conditions known as major risk factors. Endothelial changes then mediate macrophage adhesion and movement to the intima resulting in mediators that facilitate muscle cell recruitment. Both cell types ingest of lipids. Maturation of the lesion into a fibro-fatty atheroma that progressively occludes the lumen involves proliferation of the smooth muscle component, extracellular matrix production by the smooth muscle cells, and lipid accumulation in both macrophages and smooth muscle cells as well as within the necrotic core. The fully mature atheroma will form a fibrous cap. 9 Atherosclerois 1. Fatty streak Fatty steaks develop early in life. It is not clear that all fatty streaks will develop into plaque in all individuals. Understanding the factors and mechanisms that lead to different rates of progression to plaque and clinical consequences in different individuals is the subject of much research. 2. Endothelial dysfunction and response - Endothelial cells are subjected to non-denuding types of injury by various toxic substances, LDL, hemodynamic factors, microbes, etc. An increase in permeability allows entry of LDL into the intima. Here LDL is oxidized and engulfed by resident macrophages. The macrophages take up the lipids by scavenger receptors and also produce free radicals. Free radicals may eliminate NO and therefore inhibit vasodilation resulting in increased shear stress and additional injury of endothelial cells. All of these factors activate the endothelial cells to increase adhesive properties binding platelets. 3. Inflammatory cells and mediators Adhesion molecules also increase binding of circulating monocytes that migrate to the intima and differentiate into macrophages that continue to take up additional lipids forming foam cells. The macrophages via toll-like receptors can also bind pathogen-like molecules. Activated macrophages release cytokines, chemokines and free radicals to facilitate further recruitment of monocytes. 10 Atherosclerois 4. T-cell activation Endothelial VCAM-1 enhances aggregation and recruitment of T-cells. Within the intima they receive presented antigens from macrophages and facilitate a chronic inflammatory response by further activating macrophages. Macrophages secrete IL1 and TNF resulting in secretion of acute phase proteins such as C-reactive protein. All of the above steps occur in the formation of the fatty streak. It is not until the smooth muscle cells enter the intima that the mature plaque is formed. 5. Smooth muscle proliferation and plaque maturation PDGF from activated platelets along with other growth factors will recruit smooth muscle cells from the tunica media. Additionally, circulating bone marrow stem cells will also give rise to smooth muscle cells in the intima. Here they become synthetic, producing collagen and proteoglycans to form the fibrous cap and stabilize the mature plaque. Continued inflammation and lipid uptake will eventually cause death of foam cells that then contribute to the lipid core of debris. 6. Loss of stability The presence of plaque can be uneventful if the structures do not fully occlude vessels. Continued inflammation can result in destabilization, leading to rupture, hemorrhage, and/or thrombus formation.. All of these events occur later in life and lead to clinical consequences. 11 Atherosclerois Investigators believe that nonstable or “vulnerable” plaque has a thinner fibrous cap due to degradation during resolution or continued chronic inflammation and tissue damage. Rupture of plaque occurs in 30% of atherosclerotic plaques. Inflammatory cells secrete proteases that may erode vessels that form adjacent to the plaque. It is interesting that statins stabilize plaque. V. Monckeburg Medial Calcific Sclerosis This condition is seen in individuals of 50 years or more where calcium deposits form in the tunica media of muscular arteries. The deposits do not invade the intimal lining and, at this point, do not seem to be clinically significant. It is likely that the presence of calcium in the tunica media could “stiffen” the arteries. 12 Atherosclerois VI. Arteriolosclerosis and Hypertension A. Hypertension Hypertension (HTN) is elevated blood pressure with a diastolic pressure greater than 90 mmHg or sustained systolic pressure of 140 mmHg. 25% of the population is hypertensive. Prevalence increases with age and is more frequent in African Americans than Caucasians. Blood pressure is determined by cardiac output and peripheral resistance. Cardiac output will rely on blood volume and pumping capacity. Peripheral resistance is determined at the level of the arteriole and it is here that regulation will occur by factors that will either cause vasodilation or constriction. Both circulating mediators and hormones make up the humoral factors regulating vessel diameter and vascular tone. In addition neural stimulation is essential. You will study the factors that regulate blood pressure in the next block. 1. Types and terms 95% of all cases of hypertension do not have a clearly defined cause. This is called essential or idiopathic hypertension. The remaining 5% are secondary to malformation or dysfunction primarily in the renal and endocrine systems. Types of hypertension (by progression) - Most individuals with hypertension are asymptomatic and this is referred to as benign hypertension. 5% of individuals with hypertension will accelerate to malignant hypertension with diastolic pressures >120 mm Hg and systolic pressures >200 mm Hg. If left untreated, these individuals will die of renal failure. B. Vascular injury Long –standing hypertension will result in damage to vessels of all sizes, accelerating atherosclerosis leading to aortic dissection and cerebrovascular events. In addition small arteries and arterioles are affected and the general term for hardening of these arteries in arteriolosclerosis. 13 Atherosclerois 1. Hyaline arteriolosclerosis In this form of arteriolosclerosis one sees a homogeneous, pink hyaline thickening of the arteriolar wall with narrowing of the lumen and loss of the vessel wall detail. The distal organ receives less blood through the narrow lumen. This is seen in the kidneys of hypertensive patients but also in the vessels of elderly normotensive individuals. 2. Hyperplastic arteriolosclerosis This form of arteriolosclerosis is seen in more acute or severe elevations of blood pressure such as that seen in malignant hypertension. The diastolic pressure in these patients is often greater than 120 mmHg. The arteriole wall exhibits an “onion skin” appearance with concentric, laminated thickening of the wall and narrowing of the lumen. The smooth muscle cells of the wall are hypertrophied (increased in size) and hyperplastic (increased in number). The basement membrane is duplicated as well. The vessel wall will actually undergo necrosis. 14