AtherosclerosisAtherosclerosisCSBR.Prasad, MD.,

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Some Questions

• What are turbulent and laminar flows?• What are ROS ?• What is HDL cholesterol ?• What is LDL cholesterol ?• Name some markers of inflammation ?• What is glycocalyx ?• What is metabolic syndrome ?

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Clinical Implications of AS

• Myocardial infarction• Stroke• Hypertension• Gangrene

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ARTERIOSCLEROSISARTERIOSCLEROSISSclerosis = HardeningARTERIOSCLEROSIS: Hardening of the Arteries

Three Patterns:1.Atherosclerosis2.Monkeberg’s Medial Calcific Sclerosis3.Diseases of small arteries & arterioles:

Arteriolosclerosis1. HTN &

2. DM

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AtherosclerosisAtherosclerosis

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Epidemiology

• Atherosclerosis-associated ischemic heart disease used to be the most common cause of morbidity in developed nations– However, implementing risk reduction and

improved therapies have reduced the mortality

• Adoption of western style of life style led to increased incidence of IHD in developing countries

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Risk Factors• Risk factors have been identified through a number

of prospective analyses (e.g: The Framingham Heart Study)• Important Risk factors:

– Hyperlipidemia– Hypertension and – Smoking

• These risk factors have roughly multiplicative effect– 2 factors – increase the risk by 4x– 3 factors – increase risk by 7x

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Constitutional Risk Factors

• Genetics / Family history• Age • Gender

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Constitutional Risk Factors

• Genetics: Family history is the most important independent risk factor for atherosclerosis

• Single Mendalian disorders like Familial Hypercholesterolemia – Constitutes only a small percentage

• Polygenic, relating to familial clustering constitute a major chunk

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Constitutional Risk Factors

• Genetics• Age: Formation of atherosclerotic plaque

is typically a progressive process• Hence, complications are seen usually

between ages 40 and 60• Death rates from ischemic heart disease

rise with each decade

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Constitutional Risk Factors• Genetics• Age • Gender: Myocardial infarction and other

complications of atherosclerosis are uncommon in premenopausal women

• After menopause, however, the incidence of atherosclerosis related diseases increases in women and at older ages actually exceeds that of men– ? Estrogen

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Modifiable Major Risk Factors

• Hyperlipidemia• Hypertension• Cigarette smoking• Diabetes• Inflammation

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Modifiable Major Risk FactorsHyperlipidemia: Even in the absence of other risk factors,

hypercholesterolemia is sufficient to initiate AS• High LDL – Increased risk• High HDL – Reduced risk• Diet:

– Saturated FA – rises Cholesterol – Polyunsaturated FA – reduces Cholesterol – Omega-3 fatty acids – beneficial– Artificial hydrogenation of polyunsaturated oils – adversely affect

cholesterol levels• Exercise and moderate consumption of ethanol raise HDL

levels• Obesity and smoking lower HDL• In the past decade statins have been used widely to lower

serum cholesterol levels

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Modifiable Major Risk Factors

• Hyperlipidemia• Hypertension: both systolic and diastolic

levels are important• Hypertensives show 60% increased risk of

cardiovascular events than normotensives• Left ventricular hypertrophy is a surrogate

marker for cardiovascular risk

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Modifiable Major Risk Factors

• Hyperlipidemia• Hypertension• Cigarette smoking: Smoking of one pack

of cigarettes or more daily doubles the death rate from ischemic heart disease

• Smoking cessation reduces that risk substantially

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Modifiable Major Risk Factors

• Hyperlipidemia• Hypertension• Cigarette smoking• Diabetes: induces hypercholesterolemia

– 2x prone for IHD– 100x prone for gangrene– Increased risk for stroke

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Additional Risk Factors

• Inflammation• Hyperhomocystinemia• Metabolic syndrome• Lipoprotein a [Lp(a)] • Factors affecting hemostasis• Other factors

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Additional Risk Factors

Inflammation: • C-reactive protein (HS-CRP): plasma CRP

is a strong, independent marker of risk for myocardial infarction, stroke, peripheral arterial disease and sudden cardiac death

• CRP is also a useful marker for gauging the effects of risk reduction measures

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Additional Risk Factors

• Inflammation• Hyperhomocystinemia: is associated

with premature vascular disease– Congenital– Acquired

• NOTE: Supplemental vitamin ingestion does not affect the incidence of cardiovascular disease

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Additional Risk Factors

• Inflammation• Hyperhomocystinemia• Metabolic syndrome: characterized by insulin

resistance, hypertension, dyslipidemia (elevated LDL and depressed HDL), hypercoagulability and a proinflammatory state– Hypertension, dyslipidemia contribute to IHD– Systemic hypercoagulable and proinflammatory state

contribute to endothelial dysfunction

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Additional Risk Factors

• Inflammation• Hyperhomocystinemia• Metabolic syndrome• Lipoprotein a [Lp(a)]: Lp(a) levels are

associated with coronary and cerebrovascular disease risk, independent of total cholesterol or LDL levels

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Additional Risk Factors

• Inflammation• Hyperhomocystinemia• Metabolic syndrome• Lipoprotein a [Lp(a)] • Factors affecting hemostasis: Platelet-derived

factors, as well as thrombin—through both its procoagulant and proinflammatory effects—are increasingly recognized as major contributors to vascular pathology

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Additional Risk Factors

• Inflammation• Hyperhomocystinemia• Metabolic syndrome• Lipoprotein a [Lp(a)] • Factors affecting hemostasis• Other factors: lack of exercise;

competitive, stressful life style (“type A” personality); and obesity

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Pathogenesis of Atherosclerosis

“Response to Injury” hypothesis:

This model views atherosclerosis as a chronic inflammatory and healing

response of the arterial wall to endothelial injury

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Pathogenesis of AtherosclerosisPathogenesis of Atherosclerosis“Response to Injury” hypothesis

Pathogenesis of Atherosclerosis

• The specific factors contributing to endothelial cell dysfunction in early atherosclerosis are not completely understood

• Etiologic agents may include:– Toxins from cigarette smoke – Elevated Homocysteine levels– Infectious agents– Inflammatory cytokines (eg: TNF)

What causes endothelial injury ?

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Pathogenesis of Atherosclerosis

Two most important causes of endothelial dysfunction are:

• Hemodynamic disturbances and• Hypercholesterolemia

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Figure 11-10 Evolution of arterial wall changes in the response to injury hypothesis:

1, Normal. 2, Endothelial injury with monocyte and platelet adhesion.3, Monocyte and smooth muscle cell migration into the intima, with macrophage activation. 4, Macrophage and smooth muscle cell uptake of modified lipids, with further activation and recruitment of T cells. 5, Intimal smooth muscle cell proliferation with extracellular matrix production, forming a well-developed plaque

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Pathogenesis of Atherosclerosis

• Hemodynamic DisturbancesSome observations:

– Plaques tend to occur at ostia of exiting vessels, branch points

– Laminar flow stimulates the expression of genes which inhibit atherogenesis (Atheroprotective genes)

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Pathogenesis of Atherosclerosis

• Hypercholesterolemia– Dyslipoproteinemias

• increased LDL• decreased HDL• increased levels of lipoprotein (a)

– Maybe due to primary or secondary causes• Nephrotic syndrome• Diabetes mellitus• Hypothyroidism• Alcoholism

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Pathogenesis of AtherosclerosisHypercholesterolemia: is Atherogenic The evidence:1-Cholesterol esters are the dominant lipids in atheromatous plaques2-Genetic defects in lipoprotein uptake and metabolism are

associated with accelerated atherosclerosis3-Other acquired disorders of hypercholesterolemia lead to

premature atherosclerosis4-Epidemiology: Severity of atherosclerosis and total plasma

cholesterol are directly proportional5-Lowering of serum cholesterol has shown to reduce the

atherogenesis and cardiovascular events

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Pathogenesis of AtherosclerosisThe mechanisms by which hyperlipidemia

contributes to atherogenesis include the following:

1-Hyperlipidemia, can directly impair endothelial cell function

• By production of ROS• Mitochondrial damage• Degrading NO

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The mechanisms by which hyperlipidemia contributes to atherogenesis

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Sequence of cellular interactions in atherosclerosis

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Pathogenesis of Atherosclerosis

Inflammation: Chronic inflammation contributes to the initiation and progression of atherosclerotic lesions– Production of IL-1– Macrophage and lymphocyte recruitment and

activation– Liberation of ROS by macrophages– Oxidation of LDL– More inflammation and elaboration of Growth

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Pathogenesis of Atherosclerosis

Infections: Herpes virusCytomegalovirus and Chlamydia pneumoniae

are implicated, More evidence is needed

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Pathogenesis of AtherosclerosisSmooth Muscle Proliferation and Matrix

Synthesis: • Intimal smooth muscle cell proliferation and

extracellular matrix deposition convert a fatty streak into a mature atheroma

• Several growth factors are implicated in smooth muscle cell proliferation– PDGF– FGF– TGF-alfa

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Morphology of a typical AS lesion

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Why VEINS are not involved in

Atherosclerosis?

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Theories of Atherosclerosis

AS is considered as a tumor

Summary Endothelial injury is the primary event Intimal accumulation of lipids esp. LDL Oxidation of LDL –> –> Modified LDL –>–> resulting in ?

Autoimmunity Recruitment of T-cells & MØ ROS and Cytokine liberation More cytokines & growth factors Recruitment of Smooth muscle cells and MØ More lipid accumulation in extracellularly and in MØ Atheromatous plaque formation

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Atherosclerosis - MorphologyAtherosclerosis - Morphology

CSBR.Prasad, MD.,

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Atherosclerosis - MorphologyAtherosclerosis - Morphology

• Fatty streaks• Atherosclerotic Plaque

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AS – Morphology – AS – Morphology – Fatty streaks

• Multiple minute flat yellow spots or elongated 1 cm long or longer streaks

• Distribution: Similar to AS plaques• Composition: Lipid-filled foamy MØ• No significant alteration in the blood flow• Seen even in infants and adolescents• It may / may not progress to AS plaque

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AS – Morphology – AS – Morphology – Fatty streaks

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AS – Morphology – AS – Morphology – Atherosclerotic Plaque

• Colour of plaque:– White-yellow patches– Red – Brown: When ulcerated and superimposed by thrombus

• Involvement of the artery: Patchy• Location: Eccentric (not circumferential)• Size: Vary. May coalesce to form large masses• Lesions at various stages often coexist• Narrows the lumen of the artery

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AS – Morphology – AS – Morphology – Atherosclerotic Plaque

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AS – Morphology – AS – Morphology – Atherosclerotic Plaque

Vessels affected (some facts)• Lower abdominal aorta: Typically involved to a

greater degree than the thoracic aorta• Vessels that are usually spared are: vessels of upper

extremities, the mesenteric and renal arteries, except at their ostia

• Severity of disease in one arterial distribution does not always predict its severity in another

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AS – Morphology – AS – Morphology – Atherosclerotic Plaque

Atherosclerotic plaques have three principal components:1. CELLS: Smooth muscle cells, macrophages, and T

cells2. MATRIX: Extracellular matrix, including collagen,

elastic fibers, and proteoglycans3. LIPID: Intracellular and extracellular lipidThese components occur in varying proportions and configurations

in different lesions

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AS – Morphology – AS – Morphology – Atherosclerotic Plaque

Typical plaque:• Superficial fibrous cap: composed of smooth muscle cells

and relatively dense collagen• The “shoulder” (sides of the cap): MØ, T-cells, smooth

muscle cells• Necrotic core: containing lipid, debris from dead cells, foam

cells, fibrin, organized thrombus, and other plasma proteins• The periphery: of the lesions demonstrate

neovascularization

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AS – Morphology – AS – Morphology – Typical Atherosclerotic Plaque

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AS – Morphology –AS – Morphology – Atherosclerotic Plaque

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AS – Morphology – AS – Morphology – Atherosclerotic Plaque

Atherosclerotic plaques are susceptible to the following clinically important pathologic changes:

• Rupture, ulceration, or erosion• Hemorrhage into a plaque• Atheroembolism• Aneurysm formation

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The natural history, morphologic features, main pathogenic events, and clinical complications of atherosclerosis

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AS – Morphology –AS – Morphology – Atherosclerotic Plaque

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Consequences of Atherosclerotic Disease

• Major targets vessels: Large elastic arteries, large and medium-sized muscular arteries

• Major arteries affected resulting in Symptoms: Arteries supplying the heart, brain, kidneys, and lower extremities

• The major consequences of atherosclerosis:– Myocardial infarction– Cerebral infarction– Aortic aneurysms and – Peripheral vascular disease

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Mechanisms:Mechanisms:AS lesions that are responsible for the

clinicopathologic manifestations

1. Atherosclerotic Stenosis2. Acute Plaque Change3. Thrombosis4. Vasoconstriction

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1-Atherosclerotic Stenosis1-Atherosclerotic Stenosis• At early stages of stenosis, outward remodeling

of the vessel media tends to preserve the size • Eventually the expanding atheroma impinges

on the lumen causing ischemia– Critical stenosis

• Coronaries: 70% chest pain may develop with exertion – stable angina

Note: The effects of vascular occlusion ultimately depend on arterial supply and the metabolic demand of the affected tissue

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Vulnerable and Stable AS plaque

Stable plaques tend to have a dense fibrous cap, minimal lipid accumulation and little inflammation, whereas “vulnerable” unstable plaques have thin

caps, large lipid cores, and relatively dense inflammatory infiltrates.Mar-2015-CSBRP

2-Acute Plaque Change2-Acute Plaque Change

Plaque changes fall into three general categories:

• Rupture/fissuring, exposing highly thrombogenic plaque constituents

• Erosion/ulceration, exposing the thrombogenic subendothelial basement membrane to blood

• Hemorrhage into the atheroma, expanding its volume

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3-Thrombosis3-Thrombosis

• Thrombosis leads to total occlusion• Mural thrombi in an artery can also

embolize

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4-Vasoconstriction4-VasoconstrictionVasoconstriction compromises lumen size and can

potentiate plaque disruption:• Vasoconstriction at sites of atheroma may be

stimulated by 1. Circulating adrenergic agonists2. Locally released platelet contents3. Endothelial cell dysfunction with imbalance between

nitric oxide & endothelin and 4. Mediators released from perivascular inflammatory cells

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AS – Morphology – AS – Morphology – Atherosclerotic Plaque

Vessels affected (In descending order):– Lower abdominal aorta– Coronary arteries– Popliteal arteries– Internal carotid arteries– Circle of Willis

Common

Less frequent

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AS – Morphology – AS – Morphology – Typical Atherosclerotic Plaque

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