Atherosclerosis

Cardiovascular Disease (CVD)

• Main type of CVD is Atherosclerosis (AS)
• Endothelial dysfunction is one of earliest
changes in AS
• Mechanical, chemical, inflammatory mediators
can trigger endothelial dysfunction:
– High blood pressure
– Smoking (free radicals that oxidatively damage
endothelium)
– Elevated homocysteine
– Inflammatory stimuli
– Hyperlipidemia
A Healthy Endothelium
produces:
 PGI2
 NO

Maintaining an
anti-coagulant,
anti-thrombotic
surface
A Dysfunctional Endothelium
has decreased:
 PGI2
 NO

Increased:
pro-inflammatory
molecules:
MCP-1
TNF
VCAM-1
Shifting to a
pro-coagulant, pro-
thrombotic surface
 Pro-Inflammatory Molecules
• Chemokines = monocyte chemoattractant protein 1
(MCP-1)
• Inflammatory cytokines = tumor necrosis factor 
(TNF)
• Adhesion molecules = intercellular adhesion molecule
1 (ICAM-1), vascular cell adhesion molecule 1
(VCAM-1)
• Over expression of all these inflammatory mediators is
commonly seen in atherosclerotic lesions.
 Endothelial Dysfunction
( endothelial activation, impaired endothelial-dependent
vasodilation)

•  endothelial synthesis of PGI2 (prostacylcin), & NO

(nitric oxide)
– PGI2 = vasodilator, platelet adhesion/aggregation
– NO = vasodilator, platelet & WBC (monocyte) adhesion

•  Adhesion of monocytes onto endothelium -->

transmigration into subendothelial space (artery
wall) --> change to macrophages

• Endothelial dysfunction --> increased flux of LDL into

artery wall
 Oxidation of LDL (oxLDL)
• Oxidation = process by which free radicals (oxidants) attack and
damage target molecules / tissues
• Targets of free radical attack:
– DNA - carbohydrates
– Proteins - PUFA’s>>> MUFA’s>>>>> SFA’s

• LDL can be oxidatively damaged: PUFA’s are oxidized and

trigger oxidation of apoB100 protein --> oxLDL

• OxLDL is engulfed by macrophages in subendothelial space

 Role of LDL in atherosclerosis
• Damage to endothelium (hypertension, smoking etc).
• LDLs penetrate vascular wall, deposit in the intima and with time are damaged by
oxidation.
• Oxidised LDLs attract the attention of macrophages which ingest the LDL.
• Macrophages become overloaded with lipid and become “foam” cells which die and
release pools of lipid in the vessel wall (plaques).
• A complex processes mediated by cytokines and growth factors causes smooth muscle
cells to form a collagenous cap over the lipid (mature atherosclerotic plaque).
• Cap grows and can constrict the vessel (causing angina for example).
• Macrophages can degrade the cap while T cells can inhibit collagen synthesis – the cap
can rupture to expose collagen and lipids
• This leads to aggregation of platelets and blood clot formation.
• If the coronary artery is blocked by a clot – heart attack.
• Blocking of arteries in the brain causes stroke.
• Antioxidants (vitamin E and C) may protect LDL from oxidation and so protect against
heart attack and stroke.
 Atherosclerotic Plaque
• Continued endothelial dysfunction (inflammatory response)
• Accumulation of oxLDL in macrophages (= foam cells)
• Migration and accumulation of:
– smooth muscle cells,
– additional WBC’s (macrophages, T-lymphocytes)
– Calcific deposits
– Change in extracellular proteins, fibrous tissue formation

• High risk =  VLDL (TG)  LDL  HDL

 LDL membrane receptor
• Found in clathrin coated pits (endocytosis)

• After endocytosis the receptor is recycled whilst the LDL (or CMR) is degraded to
releasing lipid cargo. Cholesterol uptake down regulates the cells own production
of cholesterol and down regulates LDL receptor synthesis .

• Mutations in LDL receptors causes increased plasma LDL levels (i.e. increased
cholesterol levels). This accelerates progress of atherosclerosis (Familial
hyperlipedimias).

• The cholesterol in LDL is often called “bad cholesterol”.

 Role of LDL in atherosclerosis
• Damage to endothelium (hypertension, smoking etc).
• LDLs penetrate vascular wall, deposit in the intima and with time are damaged by
oxidation.
• Oxidised LDLs attract the attention of macrophages which ingest the LDL.
• Macrophages become overloaded with lipid and become “foam” cells which die and
release pools of lipid in the vessel wall (plaques).
• A complex processes mediated by cytokines and growth factors causes smooth
muscle cells to form a collagenous cap over the lipid (mature atherosclerotic plaque).
• Cap grows and can constrict the vessel (causing angina for example).
• Macrophages can degrade the cap while T cells can inhibit collagen synthesis – the
cap can rupture to expose collagen and lipids
• This leads to aggregation of platelets and blood clot formation.
• If the coronary artery is blocked by a clot – heart attack.
• Blocking of arteries in the brain causes stroke.
• Antioxidants (vitamin E and C) may protect LDL from oxidation and so protect
against heart attack and stroke.
 Antioxidant Defense Systems
• 1. Prevent oxidation from being initiated

• 2. Halt oxidation once it has begun

• 3. Repair oxidative damage

 Antioxidant Mechanisms
• Antioxidant vitamins (vitamins C, E, carotenoids)

• Flavanoids and other phytochemicals

• Antioxidant enzyme systems

– Minerals required: Mn, Cu, Zn, Se
 Factors Associated with CVD

• Genetic Variables
– Being male
– Being post-menopausal female
– Family history of heart disease before the age of 55
(some are associated with genetic defects in LDL
receptors)
 Factors Associated with CVD

• Dietary
1. Elevated levels of LDL
--More LDL around to potentially oxidize and accumulate in artery wall
2. Low levels of HDL
--HDL carries cholesterol from artery walls back to the liver
3. Low levels of antioxidant vitamins
--Vit. E, Vit. C, Beta-carotene
4. Low levels of other dietary antioxidants
--Phenolics, flavanoids, red wine, grape juice, vegetables, fruits
 Factors Associated with CVD

• High blood pressure

• Damages the artery wall allowing LDL to enter the wall
more readily
Cigarette Smoking
• Cigarette smoke products are oxidants and can oxidize LDL
• Cigarette smoking compromises the body’s antioxidant
vitamin status, especially Vit. C
• Damages the artery wall
Activity Level
• Exercise is the most effective means of raising HDL levels
Obesity
 Homocysteine Levels
• Normal byproduct of certain metabolic pathways
• Normally metabolized to other products
• Elevated levels cause damage to artery walls =
increased the oxidation of LDL
• Elevated homocysteine levels are significantly
correlated with increased risk to heart disease.
• Vitamins B6, B12, and Folic acid normalize homocysteine
levels.
 Diet

Methionine (a.a.)

Enzymes
B12, Folate

Homocysteine SAM
Enzyme 1. Norepinephrine
B6 2. Guanidinoacetate
3. Serotonin
4. Serine
cysteine CH3
1. Epinephrine
SAH 2. Creatine
3. Melatonin
sulfate 4. Choline
 Dietary/Lifestyle Prevention/Intervention of Heart
Disease
Maintain Platelet Decrease LDL Increase HDL Increase
Endothelial Activity Antioxidants
Function
 High Blood -3 PUFAs  Saturated Fat  MUFA/ PUFA MUFA/
Pressure  -6 PUFA  -6 PUFA

 Homocysteine  Phytochemicals  Cholesterol  -3 PUFAs (fish) Vegetables

B6, B12, Folic Acid

Phytochemicals Aspirin  -3 oils (fish)  Exercise Fruits

Stop smoking  Fiber Stop smoking Stop smoking

 Trans Fats Body weight if

overweight

 Fiber
 Know Your Lipid Profile

Fasting Blood Level Ideal, Healthy Level

Total Cholesterol < 200 mg/dl

LDL-Cholesterol < 100 mg/dl

HDL-Cholesterol ≥ 60 mg/dl

Triglycerides < 150 mg/dl

 Know Your Diabetes, Metabolic Risk

Fasting Healthy Pre-Diabetes Diabetes

(Metabolic Syndrome)

Blood Glucose < 110 mg/dl 110-125 mg/dl ≥ 126 mg/dl

2 hr GTT < 140 mg/dl 140-200 mg/dl > 200 mg/dl

Typically
Triglyceride < 150 mg/dl > 150 mg/dl
elevated

M < 40 mg/dl
HDL ≥ 60 mg/dl Typically low
F < 50 mg/dl
 The Metabolic Syndrome
Abdominal Obesity
Men > 40 inch waist
Women > 35 inch waist

Triglycerides ≥ 150 mg/dL

HDL cholesterol
Men < 40 mg/dL
Women < 50 mg/dL
Blood Pressure ≥ 130/ 85 mm Hg
Fasting Blood Glucose 110-125 mg/dL
 Know Your Blood Pressure

Diastolic
Category Systolic (mm/Hg)
(mm/Hg)

Normal 120 or less 80 or less

High Normal 130-139 85-89

High Blood
140 or more 90 or more
Pressure
Strive for blood pressure of 120/80 or less