Coronary Artery Disease

Punit Goel, MD
Asst Professor in Cardiology, University of
Missouri Hospital & Clinics
Staff Cardiologist, Harry Truman VA Hospital

Epidemiology
Risk factors
Pathogenesis
Spectrum
Prevention

Atherosclerosis is the leading cause of death and disability

in the developed and developing world

Clinical manifestations depend on the particular vascular

bed affected
Coronary vasculature
Cerebral
Peripheral
Renal

angina, MI, sudden death

TIA, stroke
claudication, gangrene
hypertension

Atherothrombotic disease is often a diffuse condition involving

multiple vascular beds
Multi-territory atherothrombosis
3-8% have symptomatic atherosclerosis in all
three territories
23-32% have involvement in two territories

Epidemiology

Risk factors
Pathogenesis

Spectrum
Prevention

Epidemiology
The three major clinical manifestations of atherosclerotic CVD are:
CHD
CVA
PVD

Disease impact:

In 1997, more than 5mn Americans had CVD

Currently one in five American has some form of CVD
Each year 1mn deaths are due to CVD (42% of all deaths!)
One-sixth of CVD deaths are in persons <65 yrs of age
Annually
1.5mn Americans have MI
0.5mn die from CHD
0.5mn have stroke
0.15mn die from stroke

Death rates from CHD has decreased by 40% since 1968

CVD still remains the leading cause of death in developed
nations
CHD & stroke are the 2nd and 3rd leading causes of mortality
even in the developing regions

Economic impact:

Despite age adjusted decline in CVD mortality,

there is paradoxic increase in economic burden due to:
1) aging population causing actual number of CVD
cases to remain stable
2) technologic advances causing more aggressive and
extensive treatment

Epidemiology

Risk factors
Pathogenesis

Spectrum
Prevention

Concept of risk factors for CAD evolved from prospective

epidemiological studies in US and Europe which
demonstrated consistent association among
characteristics observed at one point of time in
apparently healthy individuals and subsequent
incidence of CAD in these patients.

But, presence of a risk factor does not necessarily imply a

direct causal relationship.

ATP III classifies Risk factors for CVD into three

categories:
-Underlying

-Major (traditional)
-Emerging

Underlying risk factors include:

Obesity
Disinclination to exercise

Atherogenic diet

Major (traditional risk factors):

-Age
-Male gender
-Dyslipidemia
High LDL cholesterol
Low HDL cholesterol
-DM
-HTN
-Smoking
-Family history of premature CAD in first degree relative

Emerging risk factors:

-Metabolic syndrome
-Triglyceride
-Lp(a)
-Lp-PLA2
-Fibrinogen
-Homocysteine
-Urine microalbuminuria/creatinine ratio
-Hs CRP
-Impaired fasting glucose (100-125 mg/dl per ADA)
-Markers of subclinical ASCVD
ABI
Exercise testing
EBCT/MRI
Carotid IMT

Dyslipidemia
Better term than hyperlipidemia as it includes the risk
of having low HDL

Serum total cholesterol (TC) is a composite of:

LDL cholesterol- directly related to CVD
HDL cholesterol- inversely related to CVD
VLDL cholesterol- related to CVD in patients with
DM and low HDL
Best single predictor for CVD risk is TC/HDL ratio.
Ideal ratio is <3, intermediate 3-5, high risk >5
This ratio is also the best predictor of treatment benefits

Relationship Between Cholesterol and CHD Risk:

Epidemiologic Trials
Multiple Risk Factor Intervention Trial
(MRFIT) (n=361,662)

Framingham Study (n=5209)

CHD indications per 1000

40
(De aths/100 0)

10-year CHD death rate

50

30
20
10

150
125
100
75
50
25
0

150

200

250

300

Serum cholesterol (mg/dL)

1% reduct ion in total cholest erol
resulte d in a 2 % decreas e in CHD risk

Gotto AM Jr, e t al . Ci rcula ti on. 199 0;81:17 21-1 733 .

Ca ste lli WP. Am J Med. 198 4;76:4-1 2.

204

205-234

235-264

265-294

295

Serum cholesterol (mg/100 mL)

Eac h 1% increas e in total chole sterol leve l is
ass ociated wit h a 2% increase in CHD risk

Hypertension
Potent risk factor for all CVD and dominant risk factor for
stroke.

Graded relationship between level of BP and outcomes.

SBP rises with age, whereas DBP plateaus in the late middle
life and decreases somewhat then.
Trials for isolated systolic hypertension have shown benefits
for both stroke and CHD

Systolic and diastolic hypertension increase the RR for CVD

by 1.6 times
For combined Systolic and diastolic HTN the RR is 2.0

The risk for CVD is increased even in individuals with

high normal BP (130-39/85-89 mm Hg)

Smoking
This habit increases the risk of vascular outcomes by 2 fold.
Both, regular and filter cigarettes have same adverse effects.
Low tar/low nicotine products have not been shown to reduce
the risk
Unlike other modifiable risk factors, cigarette smoking
can be eliminated entirely
Benefits of quitting smoking are dramatic. Risk in
ex-smokers falls to near non-smoking levels in
2 yrs.

Obesity
It contributes independently to CVD risk and also aggravates
known CVD risk factors.
Measures of obesity include:
BMI
Waist: hip ratio.

Synergy of risk factors:

The CHD death risk in men who smoke, have DBP>90
mm Hg, TC>250 mg/dl, the actual risk is 82/1000 v/s
43/1000 if all the three risk factors are added
Thus there is multiplicative effect of multiple risk
factors acting in concert.
Also control of one risk factor provides substantial
benefit in persons with multiple risk factors

Diabetes Mellitus
Patients with either type I or type II diabetes have increased
risk for CVD
Risk of CHD is increased 2-fold in young men and 3-fold in
young women with type 2 diabetes

Type II diabetics have one or more metabolic abnormalities

(hypertriglyceridemia, low HDL, hypertension)
They may also have normal LDL levels but LDL particles
are dense and small thus being more atherogenic

(Circulation 1998;97:1837)

Metabolic syndrome:
-Abdominal obesity: waist circumference
Men >40 inches
Women >35 inches
-Triglycerides >150 mg/dl
-HDL
Men <40 mg/dl
Women <50 mg/dl
-BP >130/85 mm Hg
-Fasting glucose >100 mg/dl
(presence of 3 or more criteria constitutes metabolic syndrome)

Epidemiology

Risk factors
Pathogenesis

Spectrum
Prevention

Pathogenesis
Atherosclerosis is a progressive disease
The term was first proposed by pathologist Felix Marchand
in 1904
Athero= gruel/porridge, sclerosis=hardening

The process begins in childhood and has clinical manifestations

in late adulthood
Advanced lesions are a result of three processes:
1. Lipid accumulation
2. Accumulation of intimal SMC, macrophages,
T-lymphocytes
3. Formation of connective tissue matrix by proliferated
SMC

Atherosclerotic disease can lead to stenosis and occlusion

as in most muscular arteries or cause ectasia or
aneurysm formation as in elastic vessels (aorta)
Even in a given arterial bed it tends to involve certain
predisposed areas- proximal LAD,
proximal renal arteries,
carotid bifurcation
The process develops over years to decades and progression
is not linear and smooth but discontinuous with
periods of quiescence and rapid evolution.
Manifestations may be varied from asymptomatic to chronic
stable angina/claudication to dramatic acute MI/
stroke/sudden death.

Normal arterial wall has three layers:

intima- limited by internal elastic lamina
media- between internal and external elastic lamina
adventitia

Intima is the site at which the atherosclerotic lesions form

Lesions can form in one of the two ways:

Positive remodelling- intimal thickening associated

with dilatation of the artery,
so the
lumen remains large
Negative remodeling- asymmetrical intimal
thickening with lumen encroachment

Endothelium:
Largest and the most extensive tissue in the body which performs
several functions.
-Barrier between blood and arterial wall
-non-thrombogenic surface by secreting PGI2
-highly active metabolic tissue capable of forming
several vasoactive substances and connective
tissue macromolecules
Endothelial cells have receptor for several molecules:
LDL
Growth factors
Pharmacological agents

Initiation of atherosclerosis
Lipoprotien accumulation and modification
fatty streak formation
lipid oxidation
nonenzymatic glycation

Leukocyte recruitment (T lymphocytes, macro)

foam cell formation
Evolution and complications
SMC involvement

LDL
Binds to receptor on endothelial cell surface
Internalized
Oxidized to oxidized-LDL
Ingested by
Macrophages

Foam Cell

Increased adherence
and migration of T-cells,
monocytes from the lumen
into the wall

Smooth muscle cell

Accumulation of SMC in the intima is the sine qua non for

atherosclerosis. It proliferates in the intima to form
intermediate and advanced lesions of atherosclerosis
Smooth muscle cell can exist as contractile phenotype or
synthetic phenotype.
It is the principal contributor to the reparative and
fibroproliferative process in the development of
atherosclerosis
For the lesions to form, the SMC migrates from the
media to intima

Vulnerable plaques
Thin fibrous cap
Large lipid core
High macrophage content
Stable plaques
Thick cap
Dense extracellular matrix
Less lipid rich core

Epidemiology

Risk factors
Pathogenesis

Spectrum
Prevention

Spectrum of coronary artery disease

Silent ischemia
Chronic stable angina
Acute coronary syndromes
Unstable angina
NSTEMI
STEMI

10/00

medslides.com

Clinical presentation of CHD depends on age and gender

Women:
Angina is most common first CHD event
followed by MI
Men:
MI is the most common first event followed by
angina. Sudden cardiac death is not uncommon

Acute myocardial infarction (AMI)

One of the most common diagnosis in hospitalized
patients in industrialized nations
Mortality of acute MI is 30% and one-half of these
deaths occur before hospitalization
Mortality after admission has decreased by 30% in last
2 decades

1 in 25 pts (4%) who survive till hospital discharge die

within one year

Improvement in Mortality
35

30-Day Mortality (%)

30
25
20

30%
Bed
rest
13%-15%

15

Defibrillation
Defibrillation

10

Hemodyna
Hemodynamic
mic
monitoring
monitoring

5
0

b-Block
b-Blockade
ade

Pre-CCU Era

PTCA, per cutaneo us transluminal co ronary angiopl asty.

CCU Era

5.0%- 6.5%
Aspirin,
Aspirin, PTCA,
PTCA,
Lysis
Lysis

Reperfusion Era

Pathophysiology
AMI results when thrombus (occlusive/nonocclusive)
develops at the site of ruptured plaque
Vulnerable plaque
Rupture
Coagulation cascade
activation

platelet adhesion,
activation,aggregation

Fibrin and platelet clot

Coronary occlusion
MI

Spectrum
Spectrum of
of Acute
Acute Coronary
Coronary Syndromes:
Syndromes: Hematologic
Hematologic
Findings
Findings in
in Q-Wave
Q-Wave AMI
AMI
Stable angina

Unstable NonQ-wave Q-wave

angina
AMI
AMI

Angiographic thrombus

0%-1%

75%

>90%

Increased FPA/TAT

0%-5%

60%-80%

80%-90%

Activated platelets

0%-5%

70%-80%

80%-90%

Acute coronary occlusion

0%-1%

10%-25%

>90%

Mortality

1%-2%

3%-8%

6%-15%

Antman EM. In: Braunwald E, ed. Heart Disease: A Textbook in Cardiovascular Medicine , 5th ed. Philadelphia, Pa: WB Saunders; 1997.

Amount of myocardial damage depends upon:

-territory supplied by the occluded vessel
-collateral circulation
-duration of occlusion
-partial/total occlusion
-oxygen demand of jeopardized myocardium

Presentation:
Chest pain- most common, similar to anginal pain but
more severe and prolonged
described as severe, crushing/squeezing/pressure
worst pain ever

Chest pain may be absent in pts with DM or in elderly

Atypical presentations:
confusion, syncope, profound wkness, arrhythmia

Differential diagnosis:
Pericarditis
Pulmonary embolism
Pneumothorax
Aortic dissection
Esophageal spasm

Examination:
Anxiety, pallor, restlessness
Substernal chest pain with diaphoresis is strongly suggestive
of AMI
Those with anterior MI may have sympathetic overactivity
whereas those with inferior MI may have parasympathetic overactivity
S3/S4
Transient systolic murmur due to dysfunction of mitral
apparatus leading to mitral regurgitation

Laboratory findings:
EKG specific but insensitive tool for diagnosis of myocardial
ischemia
Total occlusion of infarct related artery leads to ST
elevation (STEMI) and subsequent
evolution of Q waves
Partial occlusion/early recanalization/rich collaterals
leads to NSTEMI (non-ST elevation MI)

Serum cardiac markers:

Released into the circulation from necrotic heart muscle
CK (creatine kinase) rises 4-8 hrs after onset of MI
and normalize by 48-72 hrs
not specific for myocardial necrosis
MB isoenzyme of CK is more specific
Cardiac specific troponins: more sensitive and
specific than CK and CKMB for identification
of myocardial necrosis
Myoglobin- first serum marker to rise after MI, but
lacks specificity.

Cardiac imaging
2D echocardiography
reveals regional wall motion abnormality
also useful to identify mechanical complications
of MI

Radionuclide imaging
used infrequently in the diagnosis of acute MI
mainly used to risk stratify patients with CHD

Management
Prehospital care:
Major elements include
Recognition of symptoms by the patient and
prompt medical attention
Rapid deployment of EMS capable of
resuscitation and defibrillation

Expeditious implementation of reperfusion

Goals of Initial management in ED

Control of cardiac pain
Rapid identification of patients suitable for reperfusion
Triage of low risk patients for subsequent care
Avoiding inappropriate discharge of patients with MI

Aspirin: 160-325 mg chewable aspirin leads to rapid buccal

absorption, inhibition of cyclooxygenase in platelets
and reduction of TXA2
Oxygen by nasal cannula if hypoxemia is present
Sublingual nitroglycerine followed by IV infusion if needed
Intravenous betablockers (decrease myocardial oxygen
demand, control chest pain and
reduce mortality)
Morphine for pain relief (given IV in small doses)

STEMI
ASA, beta blockers, antithrombin therapy

<12 hrs

Eligible for
Lytic therapy
Thrombolysis

>12 hrs

Lytic C/I

Not a candidate
For reperfusion

Primary PCI

Other medical therapy

Persistent
symptoms

no

yes

Consider reperfusion

(ACEI, nitrates, beta blockers, antiplatelets, antithrombin,statins)

Time is muscle

Time-Dependent Benefit of Reperfusion Therapy

100

Reimer/Jennings 1977
Bergmann 1982
GISSI-I 1986

% Benefit

80
60
40
20
0
0

Reperfusion Time (hours)

Adapted from Tiefenbrunn AJ, Sobel BE. Circulation. 1992;85:2311-2315.

10

12

Importance
Importance of
of Time-to-Treatment:
Time-to-Treatment: Results
Results of
of GUSTO-I
GUSTO-I

30-Day Mortality ( %)

12
10
8
6

c2=149 (1 df )

4
2
0
0

10

11

Time From Onset of Symptoms to Treatment (hours)

Adapted fr om Lee KL , et al. Circulation. 1995;91:1659- 1668.

12

The
The Four
Four Ds
Ds
ED Time Point 4:
DRUG
ED Time Point 3:
DECISION
ED Time Point 2:
DATA
ED Time Point 1:
DOOR

Time Interval III

Decision to drug

Time Interval II
ECG to decision to treat

Time Interval I
Door to ECG

Time of Onset

NHAAP Reco mmend atio ns. U.S. Depa rtment of Health NIH Pub lica tion : 1997:97-3 787.

Door to needle time- 30 min

(for patients receiving thrombolytic therapy)
Door to balloon time-90 + 30 min
(for patients undergoing primary angioplasty)

Unstable angina/NSTEMI
Aspirin, antithrombin, nitrates, GP IIb-IIIa
antagonist
Betablockers(calcium channel blockers)
Assess clinical status
High risk/unstable
(Recurrent ischemia, LV dysfunction
Widespread EKG changes, positive
enzyme markers)
Cardiac catheterization

yes

Stable

Stress test

Severe ischemia
no

Revascularization (PCI/CABG)

Medical therapy

Chronic Stable Angina:

Patients with stable angina should undergo detailed evaluation
including history, focused physical examination
and risk factor assessment
Initial laboratory evaluation should include:
hemoglobin, fasting glucose, fasting lipid profile
EKG and chest x-ray
Precipitating factors for angina (anemia, arrhythmias, valvular
disease) should be identified and treated

Ten important treatment elements of stable angina include:

A

aspirin and anti-anginals

beta-blockers and blood pressure control

cholesterol and cigarettes

diet and diabetes

education and exercise

Patients with intermediate probability of CAD may undergo

stress testing for diagnostic and prognostic purpose
Patients with high probability of CAD may also undergo
stress testing for prognostic purpose
Individuals with high risk characteristics on stress testing may
proceed with coronary angiography and subsequent
revascularisation

Epidemiology

Risk factors
Pathogenesis

Spectrum
Prevention

Prevention:
Opportunity for treating the underlying process of
atherosclerosis and preventing its acute complications
presents enormous challenge and opportunity
Prospective community based Framingham heart study
provided support for the fact that hyperlipidemia,
hypertension and other risk factors correlated with
cardiovascular risk

Seven countries study provided a link between dietary

habits, serum cholesterol and cardiovascular risk

Dyslipidemia:
It is the most established and best understood risk
factor for atherosclerosis. National guidelines
recommend cholesterol screening with fasting
lipid profile in all adults.
Individuals with dyslipidemia should have dietary
modification
Normal total cholesterol should not reassure individuals
having other risk factors or low HDL

Primary and secondary prevention trials in individuals

with not only high but even average total and
LDL cholesterol have shown significant decrease
in CHD events by 24-31%.

NCEP recommends that target LDL for:

Individuals with established CVD/ DM/ estimated 10 yrs
risk for CHD events>20%
<100mg/dl

Individuals with 2 or more risk factors for CAD

100-130 mg/dl

Others
130-160 mg/dl

Circulation 2004;110:227-239

Diabetes mellitus:
Diabetic dyslipidemia is characterized by:
normal LDL- but more dense and atherogenic
low HDL
elevated triglycerides

Having diabetes places individuals at same risk as those

with established CVD
Strict glycemic control helps to decrease microvascular
complications but not CHD events. However, statin
therapy has demonstrated unequivocal benefit in
diabetic patients

Hypertension:
Trials have shown that pharmacologic therapy of HTN reduces
the risk of stroke and CHF.
But evidence for reduction in coronary events has not
been so strong.

Smoking cessation:
In FHS, smoking was found to increase the risk for CAD,
stroke, heart failure, and peripheral vascular disease
at all levels of blood pressure
Smoking cessation in hypertensive patients who smoke
1 ppd was estimated to reduce cardiovascular risk
by 35-40%
2-3 yrs after cessation, the risk for CAD declines to that of
subjects who have never smoked

Lung Health Study

Annals of Internal Med, 2005