ATHEROSCLEROSIS

22. [Path] Pathology of atherosclerosis: Objectives This lecture provides an understanding of atherosclerosis in terms of definition, epidemiology, risk factors, pathogenesis, and clinical significance of atherosclerosis  Learning outcomes At the end of the lecture, student will be able to Explain the terms atherosclerosis, arteriosclerosis and Monckeberg medial calcific sclerosis Discuss the epidemiology, risk factors, pathogenesis, and clinical consequences of atherosclerosis Describe the gross and microscopic morphology of the atherosclerosis

COMPONENTS Intima, Media, Adventitia, M>A or A>M ENDOTHELIUM INTERNAL ELASTIC LAMINA ECM: Elastin ,collagen, mucopolysaccharides Smooth Muscle Connective Tissue Fat

Aorta (elastic artery), artery, vein, capillary: Know all the differentiating histologic features

ARTERIO-SCLEROSIS GENERIC term for ANYTHING which HARDENS arteries Three general patterns Atherosclerosis (99%) Mönckeberg medial calcific sclerosis (1%) Arteriolosclerosis - involving small arteries and arterioles, related to hypertension and/or diabetes Atherosclerosis and arteriosclerosis are often used so interchangeably, it is hardly worth differentiating them anymore, other than to know they are different!

Arteriosclerosis Arteriosclerosis literally means “hardening of the arteries” it is a generic term reflecting arterial wall thickening and loss of elasticity Atherosclerosis (Greek )words for “gruel” and “hardening,” is the most frequent and clinically important pattern

Arteriosclerosis Mönckeberg medial sclerosis is characterized by calcific deposits in muscular arteries in persons typically older than age 50 deposits may undergo metaplastic change into bone lesions do not encroach on the vessel lumen and are usually not clinically significant  

ATHEROSCLEROSIS (classical) Etiology/Risk Factors Pathogenesis Morphology Clinical Expression

ATHEROSCLEROSIS *Natural History *Epidemiology *Risk Factors *Pathogenesis *Other Factors *Effects *Prevention

ATHEROSCLEROSIS Atherosclerosis is characterized by intimal lesions called atheromas that protrude into vessel lumens (Atheroma = Atheromatous plaques = Atherosclerotic plaques)

ATHEROSCLEROSIS An atheromatous plaque consists of a raised lesion with a soft, yellow, grumous core of lipid (mainly cholesterol and cholesterol esters) covered by a firm, white fibrous cap

ATHEROMATOUS PLAQUE

Effects of ATHEROSCLEROSIS Mechanically obstructing blood flow Rupture, leading to thrombosis Weaken the underlying media leading to aneurysm formation

EPIDEMIOLOGY & RISK FACTORS

Epidemiology most developed nations much less prevalent in Central and South America, Africa, and Asia mortality rate for IHD in the United States is among the highest in the world

Epidemiology prevalence and severity of atherosclerosis and IHD among individuals and groups are related to several risk factors Major Risks factors - Non modifiable -Potentially Controllable Lesser or Nonquantitated Risks factors

Risk Factors for Atherosclerosis Major Minor NON-modifiable Modifiable Increasing age Obesity Male gender Physical inactivity Family history Stress ("type A" personality) Genetic abnormalities Postmenopausal estrogen deficiency   High carbohydrate intake Modifiable Hyperlipidemia Alcohol Hypertension Lipoprotein Lp(a) Cigarette smoking Hardened (trans)unsaturated fat intake Diabetes Chlamydia pneumoniae

Major Risks factors Hyperlipidemia Hypertension Cigarette Smoking Diabetes Mellitus

Additional risk factors Inflammation (C-reactive protein) Hyperhomocystinemia Metabolic syndrome Lipoprotein (a) Other factors

HYPERLIPIDEMIA Hypercholesterolemia-is a major risk factor for atherosclerosis even in the absence of other risk factors, hyercholesterolemia is sufficient to stimulate lesion development

HYPERLIPIDEMIA The major component of serum cholesterol associated with increased risk is low-density lipoprotein (LDL) cholesterol ("bad cholesterol") LDL cholesterol has an essential physiologic role delivering cholesterol to peripheral tissues

HYPERLIPIDEMIA high-density lipoprotein (HDL, "good cholesterol") mobilizes cholesterol from developing and existing atheromas and transports it to the liver for excretion in the bile higher levels of HDL correlate with reduced risk

CHOLESTEROL CLEFTS Needle shaped washed out spaces in arteries, are cholesterol clefts, and can be nothing else, and like all other fat, yellow grossly, white microscopically.

HYPERTENSION major risk factor for atherosclerosis both systolic and diastolic levels are important

HYPERTENSION HYPERTENSION causes ATHEROSCLEROSIS. Why? ATHEROSCLEROSIS causes HYPERTENSION. Why?

CIGARETTES a well-established risk factor

DIABETES Diabetes mellitus induces hypercholesterolemia 100-fold increased risk of atherosclerosis-induced gangrene of the lower extremities

NON-modifiable Age is a dominant influence accumulation of atherosclerotic plaque is typically a progressive process incidence of myocardial infarction in men increases fivefold between ages 40 and 60 Death rates from IHD rise with each decade even into advanced age

NON-modifiable Gender premenopausal women are relatively protected against atherosclerosis After menopause incidence of atherosclerosis-related diseases increases and with greater age eventually exceeds that of men

NON-modifiable Genetics familial predisposition to atherosclerosis and IHD is multifactorial well-defined genetic derangements in lipoprotein metabolism, such as familial hypercholesterolemia that result in excessively high blood lipid levels familial clustering of other risk factors, such as hypertension or diabetes

NON major factors Homocysteinuria/homocysteinemia, related to low B6 and folate intake Coagulation defects Lipoprotein Lp(a), independent of cholesterol. Lp(a) is an altered form of LDL Inadequate exercise, Type “A” personality, obesity (independent of diabetes) Protective effect of moderate alcohol?

PATHOGENESIS Atherosclerosis is a chronic inflammatory response of the arterial wall initiated by injury to the endothelium

PATHOGENESIS Lesion progression occurs through interactions of modified lipoproteins monocyte-derived macrophages T lymphocytes normal cellular constituents of the arterial wall

PATHOGENESIS Chronic endothelial injury Accumulation of lipoproteins in arterial WALL OXIDATION of lipoproteins Monocytes migrate endothelium Platelet adhesion and activation Migration of SMOOTH MUSCLE from media to intima to activate macrophages (foam cells) Proliferation of SMOOTH MUSCLE and ECM Accumulation of lipids in cells and ECM

PATHOGENESIS Endothelial Injury Causes hemodynamic forces, immune complex deposition, irradiation, or chemicals Early lesions begin at sites of morphologically intact endothelium

PATHOGENESIS Non-denuding endothelial dysfunction underlies atherosclerosis in the setting of intact but dysfunctional ECs there is increased endothelial permeability enhanced leukocyte adhesion altered gene expression

PATHOGENESIS Causes of endothelial dysfunction Hemodynamic disturbances Hypercholesterolemia Toxins from cigarette smoke, Homocysteine infectious agents Inflammatory cytokines (e.g., tumor necrosis factor, TNF)

PATHOGENESIS Hypercholesterolemia can directly impair EC function by increasing local production of reactive oxygen species With chronic hyperlipidemia, lipoproteins accumulate within the intima

PATHOGENESIS These lipids are oxidized through the action of oxygen free radicals locally generated by macrophages or Ecs Oxidized LDL is ingested by macrophages through a scavenger receptor resulting in foam-cell formation

PATHOGENESIS Oxidized LDL stimulates the release of growth factors, cytokines, and chemokines by ECs and macrophages that increase monocyte recruitment into lesions cytotoxic to ECs and SMCs and can induce EC dysfunction

PATHOGENESIS Causes of Dyslipoproteinemias mutations that encode defective apoproteins alter the lipoprotein receptors on cells other underlying disorder that affects the circulating levels of lipids (e.g., nephrotic syndrome, alcoholism, hypothyroidism, or diabetes mellitus)

PATHOGENESIS Common lipoprotein abnormalities in the general population include increased LDL cholesterol levels (2) decreased HDL cholesterol levels (3) increased levels of the abnormal Lp(a) Genetic defects in lipoprotein uptake and metabolism that cause hyperlipoproteinemia are associated with accelerated atherosclerosis

PATHOGENESIS Inflammation Inflammatory cells and mediators are involved in the initiation, progression, and the complications of atherosclerotic lesions

PATHOGENESIS Inflammation Dysfunctional arterial ECs express adhesion molecules that encourage leukocyte adhesion Monocytes and T cells adhere to the endothelium, they migrate into the intima under the influence of locally produced chemokines

PATHOGENESIS Monocytes transform into macrophages and avidly engulf lipoproteins, including oxidized LDL progressive accumulation of oxidized LDL drives lesion progression

PATHOGENESIS Activated macrophages cytokine production (e.g., TNF) that further increases leukocyte adhesion and chemokine production that in turn propel mononuclear inflammatory cell recruitment produce reactive oxygen species, aggravating LDL oxidation

PATHOGENESIS T lymphocytes recruited to the intima interact with macrophages and can generate a chronic immune inflammatory state Activated T cells in the growing intimal lesions elaborate inflammatory cytokines, (e.g., interferon-γ), which in turn can stimulate macrophages as well as ECs and SMCsAs

PATHOGENESIS A consequence of the chronic inflammatory state activated leukocytes and vascular wall cells release growth factors that promote SMC proliferation and ECM synthesis

PATHOGENESIS Infection may drive the local inflammatory process that underlies atherosclerosis (hypothesis has yet to be conclusively proven) Herpesvirus, cytomegalovirus, and Chlamydia pneumoniae have all been detected in atherosclerotic plaques but not in normal arteries increased antibody titers to C. pneumoniae in patients with more severe atherosclerosis

PATHOGENESIS Smooth Muscle Proliferation Intimal smooth muscle cell proliferation and ECM deposition convert a fatty streak (the earliest lesion) into a mature atheroma contribute to the progressive growth of atherosclerotic lesions ( intimal smooth muscle cells may be recruited from circulating precursors and they have a proliferative and synthetic phenotype distinct from the underlying medial smooth muscle cells)

PATHOGENESIS Growth factors (PDGF, FGF, TGF-α) Smooth Muscle Proliferation & ECM synthesis Growth factors (PDGF, FGF, TGF-α) The recruited smooth muscle cells synthesize ECM (notably collagen) that stabilizes atherosclerotic plaques Activated inflammatory cells in atheromas can cause intimal smooth muscle cell apoptosis, and also increase ECM catabolism resulting in unstable plaques

The intimal plaque may progressively encroach on the vessel lumen compress and cause degeneration of the underlying media disruption of the fibrous cap can lead to thrombosis and acute vascular occlusion

A very well constructed graphic understanding of the pathogenesis of atherosclerosis. Please be expected to not only KNOW these five items, but their correct ORDER too.

Main FOUR STARS of PATHOGENESIS 1) Endothelial Injury 2) Inflammation 3) Lipids 4) Smooth Muscle Cells, SMCs

MORPHOLOGIC CONCEPTS Intimal Thickening Lipid Accumulation Streak Atheroma Smooth Muscle Hyperplasia and Migration Fibrosis Calcification Aneurysm Thrombosis

Morphology Most extensively involved vessels are lower abdominal aorta coronary arteries popliteal arteries internal carotid arteries vessels of the circle of Willis

Morphology Fatty Streaks composed of histologically lipid-filled foam cells but are not significantly raised Gross Multiple minute yellow, flat spots that can coalesce into elongated streaks, 1 cm long or longer

Morphology Atherosclerotic Plaque Grossly appear white to yellow superimposed thrombus over ulcerated plaques is red-brown Plaques vary from 0.3 to 1.5 cm in diameter but can coalesce to form larger masses patchy, usually involving only a portion of any given arterial wall

Morphology Atherosclerotic plaques have three principal components: cells, including smooth muscle cells, macrophages, and T cells ECM, including collagen, elastic fibers, and proteoglycans intracellular and extracellular lipid (These components occur in varying proportions and configurations in different lesions)

Morphology A superficial fibrous cap composed of smooth muscle cells and relatively dense collagen Beneath and to the side of the cap (the “shoulder”) is a more cellular area containing macrophages, T cells, and smooth muscle cells Deep to the fibrous cap is a necrotic core, containing lipid (primarily cholesterol and cholesterol esters)

clinically important changes Rupture, ulceration, or erosion & thrombosis calcification Hemorrhage into a plaque Atheroembolism Aneurysm formation

MILD ADVANCED

fibrous cap (F) central necrotic (largely lipid) core (C) lumen (L Histologic features of atheromatous plaque in the coronary artery

*NATURAL HISTORY

1) FATTY STREAK (non-palpable) 2) ATHEROMA (plaque) (palpable) 3) THROMBUS (non-functional, symptomatic) Atherosclerosis is a LIFELONG, even childhood, process. This chart is worth knowing.

Commonly affecting sites

CONSEQUENCES OF ATHEROSCLEROTIC DISEASE Myocardial infarction (heart attack) cerebral infarction (stroke) aortic aneurysms peripheral vascular disease (gangrene of the legs)

Atherosclerosis affecting coronary artery

Atherosclerosis affecting cerebral artery

Myocardial infarction

Stroke 4/28/2017 7:35 AM

Aneurysm

CONSEQUENCES OF ATHEROSCLEROTIC DISEASE Atherosclerotic Stenosis chronic occlusion - significantly limits flow [mesenteric occlusion and bowel ischemia, chronic IHD, ischemic encephalopathy, and intermittent claudication (diminished extremity perfusion)] acute plaque rupture -dangerous complication

CONSEQUENCES OF ATHEROSCLEROTIC DISEASE Acute Plaque Change Rupture/fissuring, exposing highly thrombogenic plaque constituents Erosion/ulceration, exposing the thrombogenic subendothelial basement membrane to blood Hemorrhage into the atheroma expanding its volume Plaque erosion or rupture is typically promptly followed by partial or complete vascular thrombosis