The Biology of Atherosclerotic

Cardiovascular Disease
FYI Venous & Arterial Systems Hey, how
you doin’?
Venous blood
The 4 Chamber Heart
from upper
body
Lung

Mitral valve
Rt. Lt.
atrium atrium
Pulm. Aorta
Artery
Tricuspid
valve Right Left Aortic valve
ventricle ventricle
Venous blood
Pulmonic
from lower
valve
body
 Small Veins & Capillaries
To heart,
neck, arms

Superior
Vena Cava
Pulm. v.
Pulm. a.

Rt. Atrium Aorta

Lungs
Rt.
ventricle
Lt.
ventricle To abd.,
kidneys,
Inferior pelvis, legs
Vena Cava

Small Veins & Capillaries

FYI Anatomy of the Heart
 Blood
Vessels

Adventitia

Media

Intima

Veins & Arteries have 3 layers.

Intima: endothelial cells in contact with the blood. The
internal elastic lamina forms the barrier between the
intima and the underlying “tunica media.”
The media has multiple layers of smooth muscle cells.
The outer layer of connective tissue is the adventitia.
 Veins

• Have thinner walls; less media.

• Have a lower lumen pressure.
• Have valves that direct blood back toward the heart

Artery

Vein
 Magnitude of the Problem

• Despite changes in lifestyle and “statins” to lower

cholesterol, & angioplasty, cardiovascular disease is FYI
the #1 cause of death in the world.
• Atherosclerosis kills 800,000/year in US.
• Worldwide mortality is 12 million/year.
 Atherosclerosis
Atherosclerosis is a disease process that produces blockages
in arteries, mainly large and medium-sized arteries and can
lead to ischemia (inadequate blood flow) of the heart, brain,
or extremities.

When severe, it can produce “infarction,” death of the tissue

being supplied by the blocked artery.
Adventitia Media

Intima
 Lipoproteins Transport Fatty Substances

Since high blood concentrations of cholesterol (especially in

LDL), are a strong risk factor for atherosclerosis, many have
believed that atherosclerosis is simply due to accumulation
of lipids in the arterial wall.

In fact, the pathogenesis of atherosclerosis is more

complicated & interesting than that.
 Response To Injury Theory

Atherosclerosis is initiated by endothelial injury and

dysfunction due to:
• Elevated and modified LDL
• Free radicals caused by cigarette smoking
• Turbulent blood flow
• Hypertension
• Diabetes mellitus (glycation)
• Elevated plasma homocysteine concentrations
• Infectious microorganisms such as herpes
viruses or Chlamydia pneumoniae
 Endothelial Injury Triggers Responses
Earliest phase: injury stimulates inflammatory response:
• Increased adhesiveness of leukocytes
(macrophages, T lymphocytes, and platelets) to
endothelium
• Increased permeability
• Formation of vasoactive molecules, cytokines, and
growth factors.
 Inflammation

With infection or injury, mast cells

release vasodilators that increase
capillary permeability allowing
plasma and leukocytes (white cells
or WBCs) to leave the blood and
enter tissue.
The “Blood-Brain Barrier”:
Cytokines, e.g. TNF & Il-1 induce the The brain has “tight junctions”
production of selectins, chemokines, between endothelial cells making it
and adhesion molecules on the inner hard for cells and large molecules to
surface of the endothelial cells that enter brain tissue.
form the capillaries. Eventually
integrins on the surface of the
leukocyte bind to adhesion molecules
on the inner surface of the endothelial
cells. The leukocytes enter tissues by
flattening out and squeezing between
the endothelial cells.
 LDL In Blood Vessels

In addition to supplying triglycerides to cells

through action of lipoprotein lipase, LDL
particles:
 Can be taken up by endothelial cells by endocytosis
 Can get beneath the endothelial cells due to
increased permeability secondary to inflammatory
changes. Inflammation also increases oxidation of
LDL particles.
 4) Eventually the macrophages
1) Injured endothelium congregate in a central core in the
makes adhesion atherosclerotic plaque. Macrophages
molecules, e.g. vascular can die in this “necrotic core”.
cell adhesion molecule
(VCAM-1) causing white
cells to adhere.

2) Chemokines cause
monocytes to diapedese
into the intima.

3) In the intima the monocyte becomes a macrophage expressing

receptors that bind and take up lipoprotein particles modified by
oxidation or glycation. This creates “foam cells”, a hallmark of
atheromas. Foam cells secrete inflammatory cytokines that amplify
the inflammatory response, & also reactive oxygen species.
 Arterial
Lumen

Monocyte
differentiated to
a macrophage Foam Cell
VCAM-1

Intima

LDL being taken up

by macrophage
 T Lymphocytes

Lymphocytes also bind to VCAM and enter the intima

following chemoattractants. When the T cell encounters
oxidized LDL, it produces cytokines that influence other cells
and amplify the response.
 The Fatty Streak

A fatty streak consists of lipid-containing foam cells in the

arterial wall just beneath the endothelium. It is the first
obvious lesion during atherogenesis, and can be found in
teenagers.
 Smooth Muscle Cell Migration & Proliferation
Fatty streaks can slowly evolve into “plaques” or “atheroma”
via migration & multiplication of smooth muscle cells stimulated
by growth factors from leukocytes.
 Monocyte Adhesion Fatty streak
& Diapedesis

Intima LDL
Foam Cells

Macrophage
Cytokine

Cytokine Proliferation Smooth muscle

T-cell cell migration

Smooth muscle cells

Media
 Ischemic Symptoms

Over time, the arterial lumen narrowed, impeding blood flow &
leading to ischemic symptoms (e.g. angina pectoris), which
would be more pronounced with increased demand (e.g.
exercise). Ischemia implies that blood flow is inadequate to
supply tissue demands. If severe enough infarction results.
In early atherogenesis, A Newer View of Infarction
recruitment of inflammatory
cells & accumulation of
lipids cause the artery to
enlarge outward.

Stable

Vulnerable
 Rupture of the Fibrin Cap

With continued lipid abnormalities & inflammation, the lipid core grows, and
activated leukocytes secrete proteinases that degrade the extracellular
matrix and weaken the fibrin cap. Several things can happen to the
plaque:
 Erosion
 Rupture of the fibrin cap
 Rupture of microvessels

• This activates platelets in blood and triggers coagulation (thrombosis or

blood clotting). The thrombus (clot) may dissolve due to endogenous or
therapeutic thrombolysis. If not, the thrombus occludes the vessel, and
an acute myocardial infarction (MI) results. In either event, release of
thrombin and platelet-derived growth factor during blood coagulation
stimulate smooth muscle migration and proliferation, causing even more
constriction of the artery and more ischemia, especially during
increased cardiac demand.
 Plaque Stability
Older, advanced plaques may be less susceptible to rupture and renewed
thrombosis because they have thicker fibrin caps. Also, lipid lowering can
enhance plaque stability by reducing lipid content & inflammation.
 Thus, older plaques cause constriction and ischemic symptoms
during increased demand (e.g., angina or heart attack during snow
shoveling).
 Newer plaques with thin fibrin caps are less stable and may account
for acute myocardial infarctions that sometimes occur with little
provocation.

Plaque rupture
So How Does Aspirin Work?
Aspirin Relieves Pain & Reduces Inflammation by
Inhibiting Synthesis of Prostaglandins

Prostaglandins
+ PGI2 Vascular dilation;
PPL A2
PGE2
Cyclooxygenase Pain, inflammation
X PGF2a
Arachidonic Thromboxane Platelet aggregation,
acid Aspirin clotting
Coronary Angiography
Myocardial Infarction
Acute Myocardial Infarction
Occluded Femoral Artery
Aorta
Common iliac a.
External iliac a.
Common femoral a.

Deep femoral a.

Superficial femoral a.

Popliteal a.

Symptoms:
• Claudication
• Rest pain
• Atrophy; ulcer
Vein graft bypass
from femoral artery
to the tibial artery
Cerebrovascular Disease (Stroke)

Hemorrhagic

Occlusive
 Specialization In The Brain

Strokes result in death of discrete brain areas. Sequelae of a

stroke will depend on size and location of the affected area.
 Buerger’s Disease

Acute inflammation and thrombosis

(clotting) of arteries and veins —
affected hands and feet.
Classic patient is a 20–40 year old male
& a heavy cigarette smoker.

Normal

Buerger’s
 Total Cholesterol (mg/deciliter)
• Desirable: <200
• Borderline High: 200-239
• High: 240+
LDL Total Fractionated into
Lipoprotein Carriers HDL
• Chylomicrons
• VLDL (very low density)
• LDL (low density)
• IDL (intermediate density)
• HDL (high density)
 The French Paradox

The diet of the French is relatively high in fat (cream, rich

sauces, desserts, cheese), but their incidence of heart disease
is low compared with the rest of Europe. Also, the French
consume more wine than any other population in Europe.
• Wine contains water, alcohol, and several dozen other
compounds (e.g., ascorbic acid, sulfur dioxide, carbon
dioxide, tartaric acid, and flavonoids).
• Flavonoids: antioxidants found in edible plants; they reduce
oxidation of LDL and may reduce atherosclerosis.
• Moderate intake of alcohol, mostly in the form of wine,
seems to protect against coronary heart disease although,
some studies have not found any difference between beer,
wine, and spirits. Proving benefit of one over others may be
confounded by the influence of differences in education, diet,
and life style.
LDL
Oxidized LDL

LDL may be modified by oxidation

(loosing electrons) & glycation (attaching
sugars in diabetes). Oxidized LDL is
found in plaques in humans. LDL trapped
in an artery undergoes oxidation and is
taken up by macrophages. Internalization
leads to formation of lipid peroxides (free
radicals) and formation of foam cells.
 LDL
Antioxidants

Vitamins E & C: anti-oxidants

• In animals with hypercholesterolemia, antioxidants
reduce the size of lesions, and they reduce fatty streaks
in nonhuman primates.
• Antioxidants increase the resistance of human LDL to
oxidation in vitro in proportion to the vitamin E content of
the plasma.
• Dietary intake of vitamin E intake from fruits &
vegetables correlates inversely with the incidence of
myocardial infarction.
• BUT, clinical trials have not demonstrated reduced MI in
subjects taken vitamin supplements of C and E.
 Homocysteine & Folic Acid

Homocysteine is toxic to endothelium and is prothrombotic.

Inherited defects in enzymes that metabolize homocysteine
cause severe atherosclerosis in childhood, with 1st
myocardial infarction by age 20.

Many people without inherited defects have slightly elevated

plasma homocysteine levels, and they have an increased
risk of atherosclerosis. Folic acid normalizes their
homocysteine concentrations. Trials are under way to
determine whether this prevents progression or
atherosclerosis.

American Heart Association has not yet said that high

homocysteine levels are a major risk, & they don't
recommend widespread use of folic acid & B vitamins to
reduce the risk of heart disease and stroke.
 Hypertension
(High Blood Pressure)

Hypertension promotes inflammation and

increases formation of reactive oxygen species.

These reduce formation of nitric oxide by the

endothelium, increase leukocyte adhesion, and
increase peripheral resistance.
 Smoking & Atherosclerosis

Smoking increases risk of atherosclerosis, myocardial

infarction, peripheral vascular disease, and stroke.

 Components of tobacco smoke, or their

metabolites, generate reactive oxygen
species and reduce antioxidants, contributing
to endothelial dysfunction.
 Smoking also increases platelet aggregation
and the plasma concentrations of fibrinogen
which both contribute to the occlusion of
arteries.
 Infection & Atherosclerosis

Herpes viruses (Cytomegalovirus) and Chlamydia

pneumoniae have been found in atheromatous plaques, &
increased antibodies to these agents are associated with
increased risk of new infarction in patients who have had
myocardial infarction.
Periodontal disease is associated with increased risk of
atherosclerosis, even after adjusting for other risk factors.
Mouth organisms e.g. Porphyromonas gingivalis &
Streptococcus sanguis have been found in plaques., and P.
gingivalis infection accelerated atherosclerosis in a mouse
model.
Injection of CMV, Chlamydia, or P. gingivalis experimentally
does not induce atherosclerosis, but they do accelerate
atherosclerosis in animal models.
 Role of Infection Is Unclear

Some believe that total “pathogen burden” i.e., the

cumulative exposure to multiple atherogenic
infectious agents might enhance risk.
 Atherosclerosis is an inflammatory disease. The triggers
of inflammation are incompletely understood but may be
infectious as well as noninfectious.
 Circulating inflammatory markers (e.g., C-reactive
protein) are associated with increased risk.

It may be that infection, combined with other factors,

contributes to atherosclerosis in some patients, but
there is no direct evidence that infectious agents cause
atherosclerosis, and there is the potential for
confounding by socioeconomic factors.
 Dysfunction of Endothelial Cells
May Play a Central Role

Endothelial dysfunction (perhaps from inflammation) may

lead to:

 Increased coagulation of blood

 Leaky blood vessels
 Increased vascular tone or constriction causing
hypertension
 Secretion of growth factors that stimulate blood-vessel
walls to hypertrophy, narrowing the lumen.
 Glucose
Insulin
Bloodstream

Insulin
Receptor
GLUT-4
IRS-1 IRS-1
Muscle Cell

PI-3
kinase

Metabolism or Storage
Insulin facilitates entry of glucose into muscle and fat cells by
increasing insertion of GLUT-4 transporters into cell membranes.

Glucose
Insulin
Bloodstream

Insulin
Receptor Muscle Cell
GLUT-4 sugar
transporters
 Type I Diabetes Mellitus: Autoimmune damage to insulin
producing cells in the pancreas leads to loss of insulin.

Insulin Glucose

Bloodstream

Insulin X
Receptor Muscle Cell
GLUT-4 sugar
transporters
If untreated, high levels of blood sugar begin to “spill” into
urine. Fat is broken down for energy.
Results: Weight loss, hunger, X-S urination, ketoacidosis.
 Type II Diabetes Mellitus: There is adequate insulin, but
interaction between insulin & receptor is abnormal.

Insulin Glucose

Bloodstream

Insulin X
Receptor Muscle Cell
GLUT-4 sugar
transporters
 Exercise somehow promotes interaction of insulin with its
receptors and facilitates insertion of GLUT-4 transporters.

Glucose
Insulin
Bloodstream

Insulin Muscle Cell

Receptor

GLUT-4 sugar
transporters
 Type 1 and 2 Diabetes = Endothelial Dysfunction

Lipid abnormalities due to impaired activity of lipoprotein

lipase & increased secretion of VLDL from liver).
 Increased triglycerides.
 Decreased HDL cholesterol.
 Concentrations of LDL cholesterol are normal, but
the LDL particles are smaller and denser than
normal and circulate longer.
PLUS

• Glycosylation of lipoproteins (attachment of

sugar molecules to the surface of lipoproteins) &
other proteins.
• Oxidation of LDL by reactive oxygen species.
 Normal Microvasculature
(Blood Vessels)
Normal

An ophthalmoscope can be used to view small

blood vessels on the surface of the retina.
Microvascular Complications of Diabetes

New vessel formation

Hemorrhages and edema
A larger bleed
 Consequences for Diabetics

• 4x greater risk of heart disease & stroke

• 70% of diabetics will die from vascular
disease (CAD, stroke, peripheral
vascular disease)
• Blindness
• Renal failure
• Amputations
• Cataracts
 Prevention of Complications
Control blood glucose, lipids, BP, & other risk factors (smoking,
inactivity, obesity). Take low-dose aspirin.

Blood glucose Details FYI

• HbA1c (the long-term average glucose level) <6.5 %
• Reduce postprandial hyperglycemia.
BP: Systolic BP<130 mmHg; Diastolic BP<85 mmHg.
Blood lipids
• HDL-cholesterol >40 mg/dl
• Triglycerides <170 mg/dl
• LDL-cholesterol <100 mg/dl (statins if necessary)
• Total/HDL-cholesterol ratio <4.0
• Total cholesterol <200 mg/dl
If these targets can be sustained, the risk of
cardiovascular disease is low, but relatively few
patients are being controlled this carefully.
 Different Types of
Triglycerides (Fats & Oils)

Solid at room temperature:

Coconut butter is a fat with mostly saturated fatty acids.
Lard is animal fat, which is rich in saturated fatty acids.

Liquid at room temperature:

Olive oil is a fat with a high amount of oleic acid
(monounsaturated).
Corn oil is a fat with a high amount of polyunsaturated fatty
acids (2 double bonds).
Fish oils are fats with unusually long fatty acids (20 or 22
carbon atoms) with 5 or 6 double bonds.
 “Partially Hydrogenated” &
“Trans” Fatty Acids
Saturated fatty acids (e.g.
stearic acid) have straight
carbon chains. (MP=72o)

“trans”
(across) “cis”
HHHHH H HHHH Most naturally occurring
O | | | | | | | | | | unsaturated fatty acids, e.g.
C-C-C-C-C-C-C=C-C-C-C-C-H oleic acid have “cis” double
O | | | | | | | | | | bonds, with hydrogen atoms
| attached on the same side of
HHH HH H HH HH
H the chain. This causes a bend
Trans fatty acids have double bonds with that prevents tight packing.
(MP=13 o)
hydrogens attached on opposite sides of the
chain, so the chain is fairly straight, like a
saturated fatty acid and packs tighter. (MP=44o).
 Trans Fatty Acids

Found mainly in partially hydrogenated fats such as

margarines. American Heart Association (AHA) &
American Society of Clinical Nutrition/American Institute
of Nutrition (ASCN/AIN) recommend reducing total and
saturated fats in the diet and trans fatty acids to reduce
heart disease and certain types of cancer.

The health effects of trans fatty acids remain uncertain,

although their consumption is associated with elevated
levels of serum cholesterol and triglycerides, which are
associated with increased risk of cardiovascular disease.
 The Metabolic Syndrome
(Syndrome X, insulin resistance syndrome, dysmetabolic syndrome)

A collection of risk factors that increase risk of heart disease,

stroke, & diabetes seen in >20% of Americans.

Diagnosed if you have three or more of the following:

• Waistline of 40” or more for men; 35”or more for women
• Blood pressure >130/85 mm Hg or are on medications
• Serum triglyceride level > 150 mg/dl
• Fasting blood glucose (sugar) level > 100 mg/dl or are on
glucose lowering medications
• HDL < less than 40 mg/dl (men) or < 50 mg/dl (women)
 The Jupiter Study
“Increased levels of the inflammatory biomarker high-sensitivity C-
reactive protein predict cardiovascular events. Since statins lower
levels of high-sensitivity C-reactive protein as well as cholesterol, we
hypothesized that people with elevated high-sensitivity C-reactive
protein levels but without hyperlipidemia might benefit from statin
treatment.
We randomly assigned 17,802 apparently healthy men and women with
low-density lipoprotein (LDL) cholesterol levels of less than 130 mg
per deciliter (3.4 mmol per liter) and high-sensitivity C-reactive protein
levels of 2.0 mg per liter or higher to rosuvastatin, 20 mg daily, or
placebo and followed them for the occurrence of the combined
primary end point of myocardial infarction, stroke, arterial
revascularization, hospitalization for unstable angina, or death from
cardiovascular causes.”
 Results

“Rosuvastatin reduced LDL cholesterol levels by 50% and high-

sensitivity C-reactive protein levels by 37%. The rates of the primary
end point were 0.77 and 1.36 per 100 person-years of follow-up in
the rosuvastatin and placebo groups, respectively (hazard ratio for
rosuvastatin, 0.56; 95% confidence interval [CI], 0.46 to 0.69;
P<0.00001), with corresponding rates of 0.17 and 0.37 for
myocardial infarction (hazard ratio, 0.46; 95% CI, 0.30 to 0.70;
P=0.0002), 0.18 and 0.34 for stroke (hazard ratio, 0.52; 95% CI,
0.34 to 0.79; P=0.002), 0.41 and 0.77 for revascularization or
unstable angina (hazard ratio, 0.53; 95% CI, 0.40 to 0.70;
P<0.00001), 0.45 and 0.85 for the combined end point of myocardial
infarction, stroke, or death from cardiovascular causes (hazard ratio,
0.53; 95% CI, 0.40 to 0.69; P<0.00001), and 1.00 and 1.25 for death
from any cause (hazard ratio, 0.80; 95% CI, 0.67 to 0.97; P=0.02).
Consistent effects were observed in all subgroups evaluated. The
rosuvastatin group did not have a significant increase in myopathy
or cancer but did have a higher incidence of physician-reported
diabetes.”
 Editorial - The Jupiter Study

“The relative risk reductions achieved with the use of statin

therapy in JUPITER were clearly significant. However,
absolute differences in risk are more clinically important than
relative reductions in risk in deciding whether to recommend
drug therapy, since the absolute benefits of treatment must
be large enough to justify the associated risks and costs.”

“The proportion of participants with hard cardiac events in

JUPITER was reduced from 1.8% (157 of 8901 subjects)
in the placebo group to 0.9% (83 of the 8901 subjects) in
the rosuvastatin group; thus, 120 participants were
treated for 1.9 years to prevent one event.”