Atherosclerosis pdf - D. Tahsin

atherosclerosis

At the End of This Lecture You

should Be Able to

• Appreciate the significance of atherosclerosis

as the major cause of death worldwide

• Describe the gross and microscopic

morphology of atherosclerotic plaques

• Appreciate the significance of plaque

morphology in determining its future behavior

• Understand the risk factors and causes of

atherosclerosis

• How would atherosclerosis present you
• How to estimate the likelihood of developing

atherosclerosis

• How to prevent atherosclerosis
• How to treat atherosclerosis

Athereosclerosis

• The major cause of morbidity & mortality

worldwide

• Progressive inflammatory disorder of the

arterial wall

• Focal deposition of lipid-rich material
• Initially clinically silent

Athereosclerosis

• Later on: they become large enough to obstruct

the lumen of the blood vessel

• Endothelial ulceration leads to acute

thrombosis

• Embolization of lipid material leads to distal

arterial occlusion

Manifestations of atherosclerosis

• Largely clinically silent
• Coronary artery disease: angina pectoris,

myocardial infarction, arrhythmias, sudden
death, etc.

• Cerebrovascular disease: stroke, TIA
• Peripheral vascular diseae.
• Renal artery stenosis
• Often these manifestations co-exist

PATHOGENESIS

Normal endothelial function

• The blood vessel wall is not a simple tubing

system that merely transports blood

• Rather, the endothelial lining of the blood

vessels is the largest endocrine system in the
body

Normal Endothelial Function

• Normal function is to maintain blood in a fluid

state

• When the endothelial function is impaired, it

starts to release factors that enhance
inflammation and platelet-fibrin activation

Normal endothelial Function

Factors normally released by the endothelium

include:

• Prostacyclin (PG I2)
• Nitric oxide
• Tissue plasminogen activator (t-PA)

In Atherosclerosis

• In patients with hypercholesterolemia, LDL

infiltrates the artery and

is retained in the intima

In Atherosclerosis

• LDL undergoes oxidative and

enzymatic modifications

(oxidized LDL)

In Atherosclerosis

• Oxidized LDL stimulates the endothelium to

release adhesion molecules:

– Thromboxane A2
– Endothelin
– Plasminogen activator

inhibitor (PAI-1)

In Atherosclerosis

• Monocytes are recruited through the activated

endothelium to differentiate into macrophages

Pathogenesis of atherosclerosis

• The recruited macrophages engulf the oxidized

LDL to become foam cells

Pathogenesis of atherosclerosis

• Also, the recruited macrophages release

cytokines which promote inflammation
including:

– Interlukin 1(IL-1)
– Tumor necrosis factor (TNF)
– Interferon γ
– Matrix metalloproteinase

Pathogenesis of atherosclerosis

Cytokines released from

macrophages and lymphocytes

lead to recruitment of

smooth muscle cells

from the media

Pathogenesis of atherosclerosis

• These smooth muscle cells no longer function

as contractile cells but as repair cells

Pathogenesis of atherosclerosis

• The end result of an atherosclertic plaque

depends on the destructive effect of
macrophages and the reparative role of smooth
muscle cells

Pathogenesis of atherosclerosis

• A stable plaque contains small lipid core and

dense cap composed of smooth muscles and
collagen

Pathogenesis of atherosclerosis

• An unstable plaque has a thin fibrous cap

which can be digested by enzymes released by
macrophages.

Pathogenesis of atherosclerosis

• Exposure of the subendothelial tissue to the

flowing blood leads to thrombosis and vessel
occlusion

Pathogenesis of atherosclerosis

• The pathological effects of the plaque do not

depend only on its size but also on the relative
constituents of the plaque:

• A plaque with thin fibrous cap may rupture &

cause sudden occlusion of the artery by
superimposed thrombosis even if it was of
small volume

Risk Factors for Atherosclerosis

• The effects of risk factors are multiplicative,

not additive

Risk Factors for Atherosclerosis

• Hereditary (genetic) factor: multifactorial

(polygenic) inheritance:

• Age and gender:

– Age is the most powerful independent risk factor
– Gender: premenopausal ♀< risk than age-matched

♂

– The beneficial effect of ♀sex disappears rapidly

after menopause

– HRT has no role to prevent CAD

Risk Factors for Atherosclerosis

• Family history:

– Positive family history: when IHD occurs in first

degree relatives

– Family history is considered positive if

atherosclerosis occurs in ♂ relatives < 55 years or
♀relatives < 65 years

• Smoking

Risk Factors for Atherosclerosis

• Hypertension :

– Related both to systolic, diastolic and pulse

pressure

– Antihypertensive therapy has been shown to

reduce the incidence of coronary mortality, stroke,
& heart failure

Risk Factors for Atherosclerosis

• Hypercholeserolemia:

– Most important is total cholesterol:HDL ratio
– Lowering total cholesterol & LDL cholesterol

reduces the risk of cardiovascular events (death,
MI, stroke, & the need for revascularization)

Risk Factors for Atherosclerosis

• Diabetes Mellitus:

– Often associated with diffuse disease
– Insulin resistance: Normal plasma glucose despite

increased insulin levels

• Usually associated with obesity

Risk Factors for Atherosclerosis

• The metabolic syndrome: (syndrome X)

– Obesity
– Impaired fasting glucose: FBS 110-125 mg/dl
– Glucose intolerance: PPBS 140-200 mg/dl
– Hypertension
– Dyslipidemia: high total cholesterol: HDL

RATIO

Risk Factors for Atherosclerosis

• Physical inactivity:

– Regular exercise reduces risk for atherosclerosis:

• Lowers body weight
• Elevates HDL cholesterol
• Reduces BP
• Enhances Collaterals
• Reduces blood clotting

Risk Factors for Atherosclerosis

• Obesity

– Truncal (central)

• Alcohol?

– Moderate amount of alcohol has a protective role
– Heavy alcohol intake is associated with HT

Risk Factors for Atherosclerosis

• DIETARY FACTORS

– Diets deficient in fruit, vegetables, and

polyunsaturated fatty acids

• PERSONALITY?

– No evidence that emotional stress is a major risk

factor for IHD

PRIMARY PREVENTION

PREVENTING THE OCCURRENCE OF THE

DISEASE

• Population-based strategy
• Targeted therapy

PRIMARY PREVENTION

• Population-based strategy:

– Diet

• Avoiding saturated fat and cholesterol
• Increasing intake of fibers
• Low-fat dairy products

– Smoking cessation
– Exercise

• 20-30 min/day, twice or thrice a week

– Maintaining ideal body weight

PRIMARY PREVENTION

Targeted therapy
• Identify and treat high-risk individuals

– Calculating the composite risk profile using special

algorithms and charts

• The expected benefits of therapy should be

balanced against the expenses, inconvenience,
and potential side effects of the drugs

Primary Prevention

• Using the risk profile charts

SECONDARY PREVENTION

PREVENTING THE RECURRENCE OF THE

DISEASE: drug therapy

•

HMG Co-A reductase inhibitors: the
“statins”

•

Aspirin

•

ACE inhibitors

SECONDARY PREVENTION

HMG Co-A reductase inhibitors: “statins”

(simvastatin, atorvastatin, fluvastatin, lovastatin,

rosuvastatin, etc)

– Given to All patients with established

atherosclerosis

– reduce the incidence of major coronary events &

stroke

– Should be administered at night

SECONDARY PREVENTION

ACE inhibitors

• e.g. captopril, enalapril, lisinopril, ramipril
• Shown to improve survival in established

atherosclerosis, even without heart failure or
LV dysfunction

Recent Drug: PCSK9

• Inactivation of the enzyme Preprotein

convertase subtilisin-Kexin type 9

• This leads to reduced degradation of LDL

receptors on the surface of the hepatocytes

• Increased expression of LDL receptors leading

to increased rate of clearance of LDL from the
circulation