Pathophysiology and Risk Factors
of Coronary Artery Disease
Cardiac Wellness
Institute of Calgary
Updated May 2010
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
Function
Endothelial
Dysfunction
 Regulates
vasomotion
 Inadequate
 Regulates
thrombosis
 Prothrombotic
 Regulates
transport of
substances to and from
vascular space
 Regulates
growth and
apoptosis of vascular
wall
 Regulates
oxidation
LDL
 Altered
vasodilation
permeability
 Increased
secretion of
growth factors
 Increased
LDL
oxidation of
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
lesion-prone location
Adaptive
thickening
(smooth muscle)
Type II (Lesion)
Type III (Preatheroma)
Small pools of
extracellular
lipid
Macrophage
foam cells
Intima
Media
Type IV
(Atheroma)
Core of
extracellular
lipid
Type V
(Fibroatheroma)
Type VI
(Complicated lesion)
Fibrous
thickening
Adapted from Stary in Fuster et al (eds). Atherosclerosis and Coronary Artery Disease 1996.
Thrombus
fissure &
hemtoma
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
Manifestations of
Atherosclerosis
Myocardial Infarction

Diagnosis: 2 of 3 criteria:
1) Chest pain > 30 minutes
2) ECG – Q waves / ST segment elevation/ T wave
inversion
3) Cardiac enzymes:
 Creatine phosphokinase (CK) Normal = 0-195
 Troponin T – Normal < 0.03
Manifestations of
Atherosclerosis
Myocardial Infarction
 Signs
& Symptoms:
– Angina, GI upset, Dyspnea, Diaphoresis, Syncope
 Treatment:
– Relieve symptoms (nitroglycerin, painkillers)
– Reperfusion
Manifestations of
Atherosclerosis
Myocardial Infarction

STEMI vs. NSTEMI:
– ST Elevation MI – ST elevation of 1 mm or more in
contiguous leads or new LBBB
– Non-ST Elevation MI – ST depression or T wave
inversion lasting greater than or equal to 24 hours
Manifestation of
Atherosclerosis

Brain
– Transient ischemic attack (TIA)
– Cerebrovascular accident (stroke)

Legs
– Intermittent claudication
Diagnosis of Coronary
Artery
Disease
Graded Exercise Test (GXT)
Used to assess...

Ischemia
– ST segment changes
– Arrhythmia

Functional Capacity
– MET’s

Efficacy of medical or surgical
intervention
Myocardial Perfusion Imaging
(Thallium scan)
Used to assess...
 Ischemia
 Ventricular
Function
– Ejection Fraction
 Myocardial
Viability
– Reversible vs non-reversible
Echocardiography
Used to assess...

Myocardial Structures
– MR, TR, AR

Ventricular Function
– EF
– Wall motion abnormalities

Effusions

Thrombus

Ischemia
Cardiac Angiography
Used to assess...

Coronary arteries

Pressures within cardiac chambers

Valve function

Ventricular function
Interventions and
Treatment of Coronary
Artery Disease
No Cure!!!
Risk Factor Modification
Treat to Target
Medical Management
Balancing the Supply and Demand Equation
Lower the Demand


Beta Blockers

Decrease contractility

Decrease heart rate



Decrease preload

Increase diastole
Nitrates
Decrease preload
Calcium Channel
Blockers

Beta Blockers

Nitrates


Increase the Supply
Increase collateral
circulation
Calcium Channel
Blockers

Decrease vascular
resistance
Percutaneous Coronary
Intervention (PCI)
Indications for Angioplasty (+/- stenting)

Electively for chronic stable angina

Urgently for unstable angina

Emergently for myocardial infarction

1 or 2 vessel disease

NEVER for left main disease
Coronary Artery Bypass Graft
Surgery (CABG)
Indications

Left main disease > 50 %

Proximal 3 vessel disease

Multivessel disease with left ventricular
dysfunction

Lifestyle limiting angina unresponsive to
medical therapy or PCI
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
– Increased HR and BP
 Endothelial
heart
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 or 50% reduction
 Alternate:
Apolipoprotein B < 0.80 g/L
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 O2 demand
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
Blood Pressure Targets
2010 Canadian Hypertension Guidelines

Non-Diabetics
<140/90 mmHg

Diabetics or persons with chronic kidney
disease
<130/80 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
Diabetes
Careful control of blood sugar levels reduces the
risk of developing the complications of diabetes
Targets for diabetic control
ACSM
Canadian
FBG <200 mg/dL
FBG 4-7 mmol/L
2 hr pc BS <200mg/dL
2 hr pc BS 5-11 mmol/L
HgbA1C <0.07
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 molecules
– Dietary trans fat intake
– Cytokines
– Homocysteine
– Fibrogen
– Lipoprotein A
– High sensitive C-
– Infectious agents
reactive protein