Pathophysiology and Risk Factors

of Coronary Artery Disease

 Overview
 Cardiovascular Diseases
 Atherogenesis and response to Injury
(Endothelial Dysfunction)
 Manifestations and Diagnosis of CAD
 Treatment of CAD
 Risk Factors Contributing to CAD
– Modifiable vs Non-modifiable
 Cardiovascular Diseases
 Arteriosclerosis – loss of elasticity of the
arteries; thickening and hardening of artery
walls.
 Atherosclerosis – process where fatty material
is deposited along walls of arteries. This
material thickens, hardens, and can eventually
block the artery. Atherosclerosis is just one type
of Arteriosclerosis.
 Our understanding of the development and
progression of atherosclerosis (atherogenesis)
is still incomplete
 Vascular Anatomy
 Endothelium: barrier between blood and
arterial wall
 3 layers in arterial wall:
– Tunica Intima - connective tissue; where lesions
form
– Tunica Media - smooth muscle
 advanced atherosclerosis characterized by proliferation of
smooth muscle cells here
– Tunica Adventitia - connective tissue; highly
vascularized to provide nutrients
 Endothelial Endothelial
Function Dysfunction
 Regulates vasomotion  Inadequate vasodilation
 Regulates thrombosis  Prothrombotic
 Regulates transport of  Altered permeability
substances to and from  Increased secretion of
vascular space
growth factors
 Regulates growth and
 Increased oxidation of
apoptosis of vascular
wall LDL
 Regulates LDL
oxidation
 Atherogenesis
Response to Injury
 Arterial Injury
– Can result from smoke, hypertension, cholesterol,
glycated substances, vasoconstriction, homocysteine
or infectious agents
– Normal endothelial function is not repaired by
inherent mechanisms
 Endothelial Dysfunction and Inflammatory
Response
– Arterial homoeostasis is altered by injury, results in
inflammatory response
– Increased adhesiveness endothelial cells lose
selective permeability
 Atherogenesis
 Platelet aggregation
– Platelets adhere to damaged endothelium and form
small blood clots on vessel wall (mural thrombi)
– Release growth factors and vasoconstrictor
substances
– Can cause obstruction to blood flow
 Atherogenesis
 LDL oxidation
– Excess oxidized LDL particles accumulate in arterial
wall, attracting monocytes and other cells into intima
– Monocytes mature into macrophages and cause
proliferation of smooth muscle cells and promote
uptake of more lipids, particularly LDL
– These cells move from the media to the intima,
becoming foam cells, producing fatty streaks or
lesions
– Continued release of vasoactive substances and
growth factors
 Atherogenesis
 Foam cells
– Release cholesterol into extracellular space
 Fatty streaks
– Earliest visually detectable lesion of atherosclerosis
– As the process continues, smooth muscle cells
accumulate in the intima and form a fibrous plaque
 Response to Injury
 Fibromuscular plaque
– With continued accumulation, lesion progresses in
size and appearance to Fibromuscular plaque with
an Atheroma (cholesterol core)
 Remodeling
– Outward growth of artery & increased lumen size
– Lumen size increases to compensate for
atherosclerotic plaque
– If plaque bulk continues to increase, lumen diameter
is decreased and blood flow obstruction occurs
 Atherogenesis
 Plaque rupture, thrombus formation,
incorporation
– Layered appearance to lesion and increased plaque
progression
– Rupture may result from local stress or chemical
factors and exposes contents or lesion to blood
– Plaques that are most vulnerable to rupture typically
have a large lipid core, thinned fibrous cap, and
outward remodeling of arterial wall
 Advanced Atherosclerotic Plaque
 Progression of Atherosclerosis
Coronary artery at
Type II (Lesion) Type III (Preatheroma)
lesion-prone location

Adaptive Small pools of

thickening Macrophage
foam cells extracellular
(smooth muscle) lipid
Intima
Media

Type IV Type V Type VI

(Atheroma) (Fibroatheroma) (Complicated lesion)

Core of Thrombus
Fibrous fissure &
extracellular thickening
lipid hemtoma

Adapted from Stary in Fuster et al (eds). Atherosclerosis and Coronary Artery Disease 1996.
 Atherogenesis
 Does not occur in a predictable linear pattern
 Some lesions develop slowly and are stable for
long periods of time, others develop quickly
 Partial regression of fatty, soft lesions is
possible with aggressive risk reduction
 Endothelial dysfunction can be reversed
– Exercise, dietary fat intake control, decreasing
stress, maintaining optimal blood pressure and
blood glucose levels
 Manifestations of
Atherosclerosis
 The Heart
– Myocardial Ischemia
– Angina
– Myocardial Infarction
 Brain
 Legs
 Manifestations of
Atherosclerosis
Myocardial Ischemia – ischemic cascade
 LV stiffening & decreased diastolic filling (diastolic
dysfunction)
 Impaired LV systolic emptying
 ECG changes associated with altered repolarization
 Angina Pectoris – transient, referred cardiac pain
resulting from ischemia
 Manifestations of
Atherosclerosis
Angina – Types:
 Silent ischemia: no pain
 Anginal Equivalent: shortness of breath, diaphoresis
etc.
 Typical Angina: occurs with exertion, emotions &
relieved with rest or NTG
 Atypical Angina: similar symptoms, but no exertion
etc
 Stable Angina: reproducible, predictable
 Unstable Angina: new onset, increased freq,
intensity, duration, or occurs at rest
 Manifestation of
Atherosclerosis
 Brain
– Transient ischemic attack (TIA)
– Cerebrovascular accident (stroke)
 Legs
– Intermittent claudication
Diagnosis of Coronary
Artery
Disease
 Interventions and
Treatment of Coronary
Artery Disease
No Cure!!!
Risk Factor Modification

Treat to Target
Risk Factors for Coronary
Artery Disease

Non-modifiable and Modifiable

Non-Modifiable Risk Factors
 Family History
– Twice the risk of MI if one first-degree relative with MI
– Triple the risk of MI if 2+ first-degree relatives with MI
– Risk is strongest if MI occurred at age 55 or less
 Advancing Age
– Risk of CAD Increases as we get older
 Gender
– Men are at risk at an earlier age than women
– Women’s risk of heart disease increases after
menopause and soon equals men’s
 Modifiable Risk Factors
 Tobacco Smoking
 Dyslipidemia
 Hypertension
 Obesity
 Sedentary Lifestyle
 Diabetes
 Emerging Risk Factors
 Tobacco Smoking
 The MOST preventable risk factor
 Smokers have 2 to 5 times the risk of CAD as
nonsmokers
 Risk factor if one is currently smoking, has quit
within the past 6 months, or has exposure to
environmental tobacco smoke
 Tobacco Smoking
 Increase workload to heart
– Increased HR and BP
 Endothelial dysfunction
– Increased vasoconstriction
– Decreased HDL
– Increased LDL and Triglycerides
– Increased LDL oxidation
– Increased platelet aggregation
– Decreased O2 carrying capacity of red blood cells
 Dyslipidemia
 2 main types of lipids:
– Cholesterol
– Triglycerides (TGs)
 Lipids are an essential component of healthy
body functioning, including:
– Structural component of cell walls
– Hormones
– Energy source
 Dyslipidemia
 Much research to support the link between
abnormal serum lipid levels and CAD
 LDL =  risk of CAD
 HDL =  risk of CAD
 TGs =  risk of CAD
 Dyslipidemia
 Abnormal lipid levels are known to be the basis
of the atherosclerotic process
 Endothelial Dysfunction
– Elevated cholesterol levels
Reduce vasodilation
Increase thrombosis
– Elevated triglyceride levels
 Mechanism is unclear
 Lipid Targets for CAD
2009 Canadian Cholesterol Guidelines

Primary Targets:
 LDL-C < 2.0mmol/L (75 mg/dl) or 50% reduction

Can J Cardiol 2009; 25(10): 567-579.

 Lipid Targets for CAD
2009 Canadian Cholesterol Guidelines
Secondary Targets: (once LDL cholesterol is at goal)
 Total Cholestrol to High-Density Lipoprotein (HDL)
cholesterol ratio less than 4.0
 Non HDL cholesterol < 3.5 mmol/L
 Triglycerides < 1.7 mmol/L
 Apolipoprotein B to apolipoprotein AI ratio < 0.8
 High-sensitivity C-reactive protein (CPR) < 2 mg/L

Can J Cardiol 2009; 25(10): 567-579.

 Hypertension
 Primary risk factor for CAD
 Hypertension is associated with three to four times
increased risk for CAD, MI and CVA & PVD
 Hypertension as a precursor or consequence of
endothelial dysfunction?
– Vasoconstriction (increases SBP)
– Vascular wall injury
Increased platelet aggregation
– myocardium
 increased wall stress
 increased myocardial O demand
2
 Blood Pressure Targets
ACSM Guidelines
Optimal 120 / <80*
Normal 120-129 / 80-84*
High Normal 130-139 / 85-89*
Hypertension >140 / >90*

*All units in mmHg

 Obesity
 The risk for CVD is greater in person’s with
central (android) obesity than those with
peripheral (gynoid) obesity
 Obesity is often associated with …
– Diabetes
– Hypertension
– Dyslipidemia
– Inactivity
 Obesity
 Body Mass Index (BMI)
 Measured in Kg/m2

 ACSM BMI Targets

Underweight <18.5
Normal 18.5-24.9
Overweight 25.0-29.9
Obese >30
 Obesity
 Waist Circumference
 ACSM Waist Circumference Targets
Men < 102 cm
Women < 88 cm
 Sedentary Lifestyle
 Lower fitness level is associated with increased
risk of CAD in men and women
 The relative risk of CAD associated with
physical inactivity is comparable to that
observed for cigarette smoking,
hypercholesterolemia and hypertension
 Persons who are physically inactive after a
heart attack have significantly high mortality
rates than active individuals
 Sedentary Lifestyle
Physical activity reduces the risk of CAD through:
 Improved balance between myocardial O2 supply and
demand
 Decreased platelet aggregation
 Decreased susceptibility to malignant ventricular
arrhythmias
 Improved endothelial tone
 Beneficial effect on other CAD risk factors (ie. diabetes,
dyslipidemia, hypertension, obesity, stress)
 Diabetes
 People with diabetes have 2 to 7 times
increased risk of developing CAD than people
without diabetes
 Mechanism of atherosclerosis is unclear
– Endothelial damage
 Increased platelet aggregation
 Insulin promotes synthesis of lipids and uptake of lipids by
smooth muscle
 Excess sugar in vessels damages the lining
making it vulnerable to plaques and clots
 Stress
 Psychosocial factors associated with CAD risk:
– Type A personality
– Hostility/Anger
– Depression/Anxiety
 3 to 4 times increased risk of death in first year
following MI
 Stress (Canadian)
Influence CAD risk via 2 main mechanisms:
 Catacholamine release
– increased BP
– increased HR
– vasoconstriction
– increased O2 demand
 Decreased adherence to lifestyle
modification recommendations
 Atherogenic Diet
 Diets high in fruits, vegetables, whole grains
and unsaturated fatty acids have lower risk for
CAD
 This influence goes beyond what is explained
by other risk factors that may be related to diet.
 Emerging Risk Factors
 Nontraditional factors that are associated with
increased risk of CVD, but a causal link has not yet
been proved with certainty
– Poor oral health – Adhesion
– Dietary trans fat intake molecules
– Homocysteine – Cytokines
– Lipoprotein A – Fibrogen
– Infectious agents – High sensitive C-
reactive protein