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Atherosclerosis

Outline

A Distinguish from Arteriosclerosis
    1. atherosclerosis is the presence of focal thickenings (plaques)
        of the innermost layer (intima) of elastic and muscular arteries.

    2.arteriosclerosis is a more generalized term for "hardening of the  arteries" and actually describes three diseases:
        a. atherosclerosis
        b. medial calcific sclerosis (accumulation of calcium in media
            of artery)

        c. arteriolar sclerosis- loss of elasticity in media of artery, thickening
            of walls and narrowing of lumen of small arteries often associated
            with hypertension

B Epidemiology
    1. most frequent cause of death in US and Europe
    2. incidence increases with age
    3. major risk factors
        a. hypertension
        b. hyperlipidemia
        c. smoking

C. Role of LDL (low density lipoprotein)
    a. Lipoproteins (complex of lipid and protein, protein enables lipid
        to be transported in blood)
        1. Chylomicrons - synthesized in wall of small intestine, carry
            mostly triglyceride
        2. VLDL's - synthesized by liver, converted to IDL, then LDL in vasculature,
     contain both triglyceride and cholesterol
        3. LDL's - mainly carry cholesterol
        4. HDL's- "good cholesterol", taken up by receptors in liver, inhibits
            cellular uptake of LDL        

    b. LDL's
        1. influence of dietary cholesterol, unsaturated fats, saturated fats

        2. importance of LDL receptors on cell surface

        3. genetic basis for LDL receptors
            a. homozygous (no genes at all)- 1/250,000, LDL 6X
                higher then normal, heart attacks at age 2

            b. heterozygous (one normal, one mutant gene), LDL
                2x normal, begin to have heart attacks around age 35

D. Atherogenesis
1. fully developed atherosclerotic plaque consists of
       lipid
       collagen and smooth muscle
       calcium
       cellular debris

2.in areas of damage in endothelium, LDL accumulates

3. monocytes from blood enter subendothelial space where they differentiate
    into macrophages and digest LDL, resulting in their conversion to
    FOAM CELLS, leading to formation of a FATTY STREAK.Platelets
    also enter into lesion, secrete platelet derived growth factor which starts
    smooth muscle cells to multiply and move into damaged area

4. smooth muscle cells secrete a connective tissue matrix rich in collagen

5. death of foam cells leads to formation of a core of acellular lipid, =
    RAISED PLAQUE

6. later, them plaque may fissure, causing a thrombus to form =
    COMPLICATED LESION, this is an unstable plaque

E. Role of Macrophages and LDL
1 fatty streaks develop early in life (at necropsy, 45% of infants show
            fatty streaks in ascending and thoracic aorta

        2. in order for macrophages to bind LDL, LDL must be oxidized, hence
            value of anti-oxidants such as Vit C, Vit E and B carotene in preventing
            ischemic heart disease

        3. oxidized LDL's impair nitric oxide mediated vasodilation and may cause
            release of tissue factors from macrophages that predispose to prevent
            breakdown of clots.

    Discussion  

    One of the major complications of atherosclerosis is coronary artery disease (CAD).Angina occurs when heart muscle is unable to be adequately oxygenated to meet its metabolic demand (resulting in anaerobic metabolism and the production of lactic acid as a waste product at the cellular level- lactic acid stimulates nerve endings causing pain). a person with atherosclerosis may suffer angina in the following situations: Exercise increases metabolic demand for oxygen, occluded coronary arteries cannot supply the increased blood flow needed to carry additional oxygen to heart muscle.Since this type of angina always occurs in response to increased demand it is predictable and is called stable angina. In the second situation, a coronary artery, especially if it has a complicated lesion, causes the destabilization of the arterial wall (through production of a variety of factors from platelets, macrophages etc). With destabilization, the artery may spasm, cutting off blood supply in an already occluded vessel. At rest, a spasm can decrease the amount of oxygen getting through sufficiently enough to cause resting heart muscle to have to depend on anaerobic metabolism. Spasm can occur anytime, it is unpredictable. Hence, angina of this nature is called unstable angina and reflects a much more serious condition. If it occurs while sleeping, it can be called nocturnal angina, a variation of nocturnal angina is
called Prinzmetal angina.
Anaerobic metabolism cannot sustain the cell indefinitely. It is a very inefficient way of generating ATP. If it lasts briefly and oxygen is restored in time to the cell, the cell recovers without lasting damage. However, if conditions persist long enough, i.e. if a cell is deprived of adequate oxygen long enough, then ischemia and cell death occurs. Ischemia quickly leads to necrosis. When heart cells die they trigger off an inflammatory process in the surrounding tissue. The whole process of ischemia, necrosis (cell death) and inflammation of surrounding tissue is a myocardial infarction (MI). Dead heart cells cannot be replaced.
   

Clinically  

    Few woman prior to menopause suffer from coronary artery disease. The reason for this is the protective actions of estrogen. Estrogen reduces LDL accumulation, inhibits platelet aggregation, inhibits foam cell formation, decreases collagen and elastin production and, generally, acts as an anti- oxidant. After menopause, when estrogen is diminished, the protective role is also diminished and woman start suffering heart disease at rates that soon exceed those of men
Total cholesterol measurements take into account all circulating cholesterol. Normal range in adults, 40 - 50 yrs of age, is 160 - 245 mg/dl. Total cholesterol is a good screening test. Elevated levels of cholesterol should be followed up with a lipid profile in which HDL and LDL levels are determined .  In adults ages 40 - 50, normal HDL is 33- 60 mg/dl, normal LDL is 100- 185 mg/dl. HDL levels are lower in men then woman (estrogen favors HDL) and is inversely proportional to triglyceride levels. High HDL levels with low LDL is less predictive of cardiovascular risk then vice versa.