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

in the developed and developing world
Clinical manifestations depend on the particular
bed affected

Coronary vasculature
angina, MI, sudde
Cerebral
TIA, stroke
Peripheral
claudication, gangrene
Renal
hypertension

Atherothrombotic disease is often a diffuse conditi

multiple vascular beds
Multi-territory atherothrombosis

3-8% have symptomatic atherosclerosis in a

three territories
23-32% have involvement in two territories

Epidemiology
Risk factors
Pathogenesis
Spectrum
Prevention

Epidemiology

The three major clinical manifestations of atherosclerot

CHD
CVA
PVD

Disease impact:

In 1997, more than 5mn Americans had CVD

Currently one in five American has some form of C

Each year 1mn deaths are due to CVD (42% of all d

One-sixth of CVD deaths are in persons <65 yrs of
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

CVD still remains the leading cause of death in dev

nations
CHD & stroke are the 2nd and 3rd leading causes of
even in the developing regions

Economic impact:

Despite age adjusted decline in CVD mortality

there is paradoxic increase in economic burde

1) aging population causing actual number of

cases to remain stable
2) technologic advances causing more aggress
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 degr

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
-Markers of subclinical ASCVD
ABI
Exercise testing
EBCT/MRI
Carotid IMT

Dyslipidemia

Better term than hyperlipidemia as it includes th

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 patient
DM and low HDL

Best single predictor for CVD risk is TC/HDL rati

Ideal ratio is <3, intermediate 3-5, high risk
This ratio is also the best predictor of treat

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

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 rculati on. 199 0;81:17 21-1733 .

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

150
125
100
75
50
25
0

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 f

stroke.

Graded relationship between level of BP and outc

SBP rises with age, whereas DBP plateaus in the
life and decreases somewhat then.

Trials for isolated systolic hypertension have show

for both stroke and CHD

Systolic and diastolic hypertension increase the RR

by 1.6 times

For combined Systolic and diastolic HTN the RR is

The risk for CVD is increased even in individuals w

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

Smoking

This habit increases the risk of vascular outcome

Both, regular and filter cigarettes have same adv

Low tar/low nicotine products have not been show

the risk

Unlike other modifiable risk factors, cigarette sm

can be eliminated entirely

Benefits of quitting smoking are dramatic. Risk i

ex-smokers falls to near non-smoking levels
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)

(Circulation 1998;97:18

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,

Atherosclerotic disease can lead to stenosis and oc

as in most muscular arteries or cause ectasia
aneurysm formation as in elastic vessels (aor

Even in a given arterial bed it tends to involve cert

predisposed areas- proximal LAD,
proximal renal arteries,
carotid bifurcation

The process develops over years to decades and pr

is not linear and smooth but discontinuous w
periods of quiescence and rapid evolution.

Manifestations may be varied from asymptomatic t

stable angina/claudication to dramatic acute
stroke/sudden death.

Normal arterial wall has three layers:

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

Intima is the site at which the atherosclerotic le

Lesions can form in one of the two ways:

Positive remodelling- intimal thickening as

with dilatation of the artery,
s
lumen remains large
Negative remodeling- asymmetrical intima
thickening with lumen encroach

Endothelium:

Largest and the most extensive tissue in the body w

several functions.

-Barrier between blood and arterial wall

-non-thrombogenic surface by secreting PGI2
-highly active metabolic tissue capable of form
several
vasoactive substances and co
tissue macromolecules

Endothelial cells have receptor for several molecul

LDL
Growth factors
Pharmacological agents

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

Leukocyte recruitment (T lymphocytes, macr

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

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 g

Women:

Angina is most common first CHD event

followed by MI
Men:

MI is the most common first event follo

angina. Sudden cardiac death is not unc

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

2 decades

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

within one year

Improvement in Mortality

30-DayMortality(%)

35
30
25
20
15
10
5
0

30%
Bed
rest
13%-15%
Defibrillation
Defibrillation
Hemodyna
Hemodynamic
mic
monitoring
monitoring
-Block
-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/nonocclu

develops at the site of ruptured plaque
Vulnerable plaque
Rupture
Coagulation cascade
platelet
adhesion,
activation
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

more severe and prolonged
described as severe, crushing/squeezing/pre
worst pain ever

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

Atypical presentations:
confusion, syncope, profound wkness, arrhy

Differential diagnosis:
Pericarditis
Pulmonary embolism
Pneumothorax
Aortic dissection
Esophageal spasm

Examination:

Anxiety, pallor, restlessness

Substernal chest pain with diaphoresis is strongly
of AMI
Those with anterior MI may have sympathetic over
whereas those with inferior MI may have para
sympathetic overactivity
S3/S4
Transient systolic murmur due to dysfunction of m
apparatus leading to mitral regurgitation

Laboratory findings:

EKG specific but insensitive tool for diagnosis of m

ischemia

Total occlusion of infarct related artery leads

elevation (STEMI) and subsequent
evolution of Q waves
Partial occlusion/early recanalization/rich col
leads to NSTEMI (non-ST elevation MI)

Serum cardiac markers:

Released into the circulation from necrotic heart m

CK (creatine kinase) rises 4-8 hrs after onset

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 identific
of myocardial necrosis

Myoglobin- first serum marker to rise after M

lacks specificity.

Cardiac imaging

2D echocardiography
reveals regional wall motion abnormality
also useful to identify mechanical complicatio
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
prompt medical attention
Rapid deployment of EMS capable of
resuscitation and defibrillation

Expeditious implementation of reperfus

Goals of Initial management in ED

Control of cardiac pain

Rapid identification of patients suitable for re

Triage of low risk patients for subsequent care

Avoiding inappropriate discharge of patients w

Aspirin: 160-325 mg chewable aspirin leads to rapi

absorption, inhibition of cyclooxygenase in pla
and reduction of TXA2
Oxygen by nasal cannula if hypoxemia is present

Sublingual nitroglycerine followed by IV infusion if

Intravenous betablockers (decrease myocardial oxy

demand, control chest pain an
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

Reimer/Jennings1977
Bergmann1982
GISSI-I 1986

100

%Benefit

80
60
40
20
0

4
6
8
ReperfusionTime(hours)

Ada pte d from Tiefenbrunn AJ, Sobel BE . Circu latio n. 1992 ;85 :231 1-2315 .

10

12

30-Day Mortality ( %)

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

12
10
8
6
4
2
0

2=149 (1 df )

9 10 11 12

TimeFromOnsetofSymptomstoTreatment(hours)

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

The
The Four
Four Ds
Ds
ED Time Point 4:
DRUG
ED Time Point
Point 3:
3:
DECISION
ED Time Point 2:
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 lication : 1997:97-3 787.

Door to needle time- 30 min

(for patients receiving thrombolytic th

Door to balloon time-90 + 30 min

(for patients undergoing primary angio

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

Revascularization (PCI/CABG)

Stable
Stress test

Severe ischemia
no

Medical therapy

Chronic Stable Angina:

Patients with stable angina should undergo detai

including history, focused physical examinat
and risk factor assessment

Initial laboratory evaluation should include:

hemoglobin, fasting glucose, fasting lipid pr
EKG and chest x-ray

Precipitating factors for angina (anemia, arrhyth

disease) should be identified and treated

Ten important treatment elements of stable angina

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 u

stress testing for diagnostic and prognostic pu

Patients with high probability of CAD may also unde

stress testing for prognostic purpose

Individuals with high risk characteristics on stress

proceed with coronary angiography and subse
revascularisation

Epidemiology
Risk factors
Pathogenesis
Spectrum
Prevention

Prevention:

Opportunity for treating the underlying process of

atherosclerosis and preventing its acute comp
presents enormous challenge and opportunity

Prospective community based Framingham heart st

provided support for the fact that hyperlipide
hypertension and other risk factors correlated
cardiovascular risk

Seven countries study provided a link between diet

habits, serum cholesterol and cardiovascular

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

NCEP recommends that target LDL for:

Individuals with established CVD/ DM/ estimated 1

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;110:227-23

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 t

with established CVD

Strict glycemic control helps to decrease microvasc

complications but not CHD events. However, s
therapy has demonstrated unequivocal benefit
diabetic patients

Hypertension:

Trials have shown that pharmacologic therapy of HT

the risk of stroke and CHF.
But evidence for reduction in coronary events
been so strong.

Smoking cessation:

In FHS, smoking was found to increase the risk for

stroke, heart failure, and peripheral vascular
at all levels of blood pressure

Smoking cessation in hypertensive patients who sm

1 ppd was estimated to reduce cardiovascular
by 35-40%

2-3 yrs after cessation, the risk for CAD declines to

subjects who have never smoked

Lung Health Study

Annals of Internal Med, 2