Transcript Coronary Artery Disease - University of Missouri

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
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
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205-234
235-264
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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
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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 Non–Q-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
2
4
6
8
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
1
2
3
4
5
6
7
8
9
10
11
Time From Onset of Symptoms to Treatment (hours)
Adapted fr om Lee KL , et al. Circulation. 1995;91:1659- 1668.
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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
B
beta-blockers and blood pressure control
C
cholesterol and cigarettes
D
diet and diabetes
E
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