Universidad Católica Redemptoris Mater (UNICA)Facultad de Ciencias Médicas

Escuela de MedicinaPatología Humana

Atherosclerosis

Teacher: Jhoana CruzStudents:

Marco Bolaños David Markony Meydeling Hernandez

Terms Arteriosclerosis is a general term describing any hardening (and loss of elasticity) of medium or large arteries Arteriolosclerosis is any hardening (and loss ofelasticity) of arterioles (small arteries); Atherosclerosis is a hardening of an artery specifically due to an atheromatous plaque. Atherogenic is used for substances or processes that cause atherosclerosis. Atherogenesis is the developmental process of atheromatous plaques.

INTRODUCTION

Definition: Atherosclerosis (a rteriosclerotic vascular disease) is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol. InGreek, athere means gruel, and sklerosmeans h ard.

EPIDEMIOLOGY- UBIQUITOUS AMONG MOST DEVELOPED NATIONS...’’LIFESTYLE AND DIET DISEASE’’

MAJOR RISKS LESSER OR UNCERTAIN RISKS

Nonmodifiable Obesity

• Increasing age Physical inactivity

• Male gender Stress (type A personality)

• Family History Postmenopausal estrogen def.

• Genetic Abnormalities High Carbohydrate intake

Potentially Controllable Lipoprotein (a)

• Hyperlipidemia Hardened (trans) unsaturated fat intake

• Hypertension Chlamydia pneumoniae infection

• Cigarette smoking

• Diabetes

• C-reactive protein

Age-slowly progressing...take decades-middle age or later. Between ages 40 & 60, incidence of MI in men increases fivefold.Gender-premenopausal women realtively protected.Genetics-multifactorial...familial clustering of risk factor e.g hypertension, diabetes, familial hypercholesterolemiaHyperlipidemia-hypercholesterolemia-LDL ‘bad’ cholesterol. HDL ‘good’ cholesterol mobilizes cholesterol from existing atheromas and transports it to the liver for excretion in the bile.High dietary intake-egg yolks, butter raises plasma cholesterolOmega -3 fatty acids beneficial (fish oils).Raising HDL-exercise, moderate consumption of ethanol ; obesity and smoking lower it.Statins lower cholesterol.Hypertension-Increase risk of IHD by 60%Cigarette Smoking- Years of smoking one pack or more a day increases the death rate from IHD by 200%.Diabetes Mellitus- incidence of MI twice as high. Induces hypercholesterolemia.

Inflammation- marked by C-reactive protein. Assess systemic inflammatory status. CRP cheap and sensitive-acute phase reactant that is synthesized by the liver. Strongly and independently predicts the risk of MI, stroke, peripheral arterial disease, sudden cardiac death. Lowering CRP-smoking cessation, weight loss, exercise, statins.Hyperhomocystinemia- strong relationship between total serum homocysteine levels and coronary artery disease, peripheral vascular disease, stroke and venous thrombosis. Elevated levels- low folate and Vitamin B intake.

PATHOGENESIS

Response-to-injury hypothesis- 4 main stages to atherogenesis:

1. Chronic endothelial injury2. Accumulation of lipoproteins3. Resultant Inflammation & Factor release4. Smooth muscle cell recruitment, proliferation and ECM production

1) CHRONIC ENDOTHELIAL INJURY : Hyperlipidemia Hypertension Smoking Homocysteine Hemodynamic factors Toxins Viruses Immune Reactions

ENDOTHELIAL INJURY

Intimal thickening; in the presence of high-lipid diets, typical atheromas ensue. Early human lesions begin at sites of morphologically intact endothelium. Endothelial dysfunction underlies human atherosclerosis; in the setting of intact but dysfunctional ECs :

1. increased endothelial permeability2. enhanced leukocyte adhesion3. altered gene expression

2) ACCUMULATION OF LIPOPROTEIN:

Dyslipoproteinemia Other underlying disorder that affects the circulating levels of lipids:

1) nephrotic syndrome, alcoholism, hypothyroidism, or diabetes mellitus

2) increased LDL cholesterol levels,3) decreased HDL cholesterol levels, and increased levels of the abnormal Lp(a)

The evidence implicating hypercholesterolemia in atherogenesis includes the following observations:

i. The dominant lipids in atheromatous plaques are cholesterol and cholesterol esters.ii. Genetic defects in lipoprotein uptake and metabolism that cause hyperlipoproteinemia are associated

with accelerated atherosclerosis. Thus, homozygous familial hypercholesterolemia, caused by defective LDL receptors and inadequate hepatic LDL uptake, can lead to myocardial infarction before the age of

20 years. Similarly, accelerated atherosclerosis occurs in animal models with engineered deficiencies in apolipoproteins or LDL receptors.

iii. Other genetic or acquired disorders (e.g., diabetes mellitus, hypothyroidism) that cause hypercholesterolemia lead to premature atherosclerosis.

iv. Epidemiologic studies demonstrate a significant correlation between the severity of atherosclerosis and the levels of total plasma cholesterol or LDL.

v. Lowering serum cholesterol by diet or drugs slows the rate of progression of atherosclerosis, causes regression of some plaques, and reduces the risk of cardiovascular events.

HYPERLIPIDEMIA-MAJOR RISK FACTORThe mechanisms :Chronic hyperlipidemia, particularly hypercholesterolemia - increases local production of reactive oxygen species-accelerate nitric oxide decay- local shear stress.Lipoproteins accumulate within the intima- 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. In addition, oxidized LDL stimulates the release of growth factors, cytokines, and chemokines by ECs and macrophages that increase monocyte recruitment into lesions. Finally, oxidized LDL is cytotoxic to ECs and SMCs- EC dysfunction.

Hyperlipidemia-more specifically, hypercholesterolemia- is a major risk factor for atherosclerosis; even in the absence of other risk factors, hypercholesterolemia is sufficient to stimulate lesion development. 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. In contrast, high-density lipoprotein (HDL, "good cholesterol") mobilizes cholesterol from developing and existing atheromas and transports it to the liver for excretion in the bile. Consequently, higher levels of HDL correlate with reduced risk.Understandably, dietary and pharmacologic approaches that lower LDL or total serum cholesterol, and/or raise serum HDL are all of considerable interest. High dietary intake of cholesterol and saturated fats (present in egg yolks, animal fats, and butter, for example) raises plasma cholesterol levels. Conversely, diets low in cholesterol and/or with higher ratios of polyunsaturated fats lower plasma cholesterol levels. Omega-3 fatty acids (abundant in fish oils) are beneficial, whereas (trans)unsaturated fats produced by artificial hydrogenation of polyunsaturated oils (used in baked goods and margarine) adversely affect cholesterol profiles. Exercise and moderate consumption of ethanol both raise HDL levels, whereas obesity and smoking lower it. Statins are a class of drugs that lower circulating cholesterol levels by inhibiting hydroxymethylglutaryl coenzyme A reductase, the rate-limiting enzyme in hepatic cholesterol biosynthesis.

3) MACROPHAGE AS THE INFLAMMATORY MEDIATOR:

Monocyte adhesion to the endothelium, followed by migration into the intima and transformation into macrophages and foam cells.

Monocyte recruitment and differentiation into macrophages (and ultimately into foam cells) is theoretically protective, since these cells remove potentially harmful lipid particles. Over time, however, progressive accumulation of oxidized LDL drives lesion progression

Normal vessels do not bind inflammatory cells-dysfunctional arterial ECs express adhesion molecules; vascular cell adhesion molecule 1 (VCAM-1) in particular binds monocytes and T cells-migrate into the intima under the influence of locally produced chemokines.

Monocytes transform into macrophages and avidly engulf lipoproteins, including oxidized LDL. Thus, macrophage activation (via oxidized LDL or T cells) results in cytokine production (e.g., TNF) that further increases leukocyte adhesion and chemokine production that in turn propel mononuclear inflammatory cell recruitment.

INFLAMMATION: Dysfunctional arterial ECs express VCAM-1- binds monocytes and T cells-migrate- chemokines. Monocytes transform into macrophages and avidly engulf lipoproteins, including oxidized LDL. –

Activated- cytokine production (e.g., TNF)-propel mononuclear inflammatory cell recruitment. T lymphocytes recruited to the intima- elaborate inflammatory cytokines, (e.g., interferon-γ), which in

turn can stimulate macrophages as well as ECs and SMCs. Activated leukocytes and vascular wall cells release growth factors that promote SMC proliferation and

ECM synthesis.

4) SMC PROLIFERATION AND ECM PRODUCTION:

Intimal SMC proliferation and ECM deposition convert a fatty streak to a mature atheroma.

Intimal SMC-proliferative, synthetic phenotype Growth factors:

PDGF (platelets, macrophages, ECs, and SMCs) FGF TGF α.

SMCs synthesize ECM (notably collagen), which stabilizes atherosclerotic plaques.

Inflammatory cells in atheromas can cause intimal SMC apoptosis, and they also increase ECM catabolism, resulting in unstable plaques

Hypothetical sequence of cellular interactions in atherosclerosis.

Hyperlipidemia and other risk factors are thought to cause endothelial injury, resulting in adhesion of platelets and monocytes and release of growth factors, including platelet-derived growth factor (PDGF), which lead to SMC migration and proliferation. Foam cells of atheromatous plaques are derived from both macrophages and SMCs-from macrophages via the very-low-density lipoprotein (VLDL) receptor and low-density lipoprotein (LDL) modifications recognized by scavenger receptors (e.g., oxidized LDL), and from SMCs by less certain mechanisms. Extracellular lipid is derived from insudation from the vessel lumen, particularly in the presence of hypercholesterolemia, and also from degenerating foam cells. Cholesterol accumulation in the plaque reflects an imbalance between influx and efflux, and high-density lipoprotein (HDL) probably helps clear cholesterol from these accumulations. SMCs migrate to the intima, proliferate, and produce ECM, including collagen and proteoglycans.

COMPLICATIONS:

1. MI2. Rupture, Ulceration, or Erosion- thrombus formation-downstream ischaemia3. Aneurysm-pressure or ischaemic atrophy of the underlying media, with loss of elastic tissue-

weakness4. Arrthymias- due to scar formation5. Mural thrombus 6. Atheroembolism- microemboli7. Cerebral infarct8. Renal infarcts9. Death

If the fibrous cap separating a soft atheroma from the bloodstream within the artery ruptures, tissue fragments are exposed and released. These tissue fragments are very clot-promoting, containing collagen and tissue factor; they activate platelets and activate the system of coagulation. The result is the formation of a thrombus (blood clot) overlying the atheroma, which obstructs blood flow acutely. With the obstruction of blood flow, downstream tissues are starved of oxygen and nutrients. If this is the myocardium (heart muscle), angina (cardiac chest pain) or myocardial infarction (heart attack) develops.Signs and Symptoms:Many times, people with atherosclerosis don't have any symptoms until an artery is 40% clogged with plaque. Symptoms vary depending upon which arteries are affected.Coronary Artery DiseaseSymptoms of coronary artery disease are usually brought on by physical exercise, sexual activity, exposure to cold weather, anger, or stress. The most common symptoms include:

• Chest pain (generally a heavy, squeezing, or crushing sensation with possible burning or stabbing pains)

• Abdominal, neck, back, jaw, or shoulder/arm pain• Weakness• Perspiration and Shortness of breath.

Cerebrovascular DiseaseCerebrovascular disease can cause transient ischemic attack (a sudden loss of brain function with complete recovery within 24 hours) and stroke. Symptoms may include:

• Weakness or paralysis on one side of the body• Trouble speaking or understanding speech• Loss of vision in one eye• Muscle weakness• Sudden trouble walking• Dizziness• Loss of balance or coordination• Sudden severe headache

Peripheral Artery DiseasePeripheral artery disease affects the arteries that supply the arms and legs with oxygen rich blood. Symptoms may include:

• Pain, aching, cramps, numbness or sense of fatigue in the leg muscles (intermittent claudication)

• "Bruits" (blowing sounds your doctor can hear with a stethoscope that indicate turbulence in blood flow)

• Hair loss• Thickened nails• Smooth, shiny skin surface• Skin that is cold to the touch• Gangrene

Natural history, main pathogenic events & Clinical complications:

Fatty streaks are composed of lipid-filled foam cells but are not significantly raised and thus do not cause any disturbance in blood flow. They begin as multiple minute yellow, flat spots that can coalesce into elongated streaks, 1 cm long or longer. Fatty streaks can appear in the aortas of infants younger than 1 year and are present in virtually all children older than 10 years, regardless of geography, race, sex, or environment. Coronary fatty streaks begin to form in adolescence, at the same anatomic sites that later tend to develop plaques. The relationship of fatty streaks to atherosclerotic plaques is uncertain; although they may evolve into precursors of plaques, not all fatty streaks are destined to become advanced atherosclerotic lesions.