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Coronary Artery Disease
Punit Goel, MDAsst Professor in Cardiology, University of
Missouri Hospital & ClinicsStaff Cardiologist, Harry Truman VA Hospital
Epidemiology
Risk factors
Pathogenesis
Spectrum
Prevention
Atherosclerosis is the leading cause of death and disabilityin the developed and developing world
Clinical manifestations depend on the particular vascular bed affected
Coronary vasculature angina, MI, sudden deathCerebral TIA, strokePeripheral claudication, gangreneRenal hypertension
Atherothrombotic disease is often a diffuse condition involvingmultiple vascular beds
Multi-territory atherothrombosis
• 3-8% have symptomatic atherosclerosis in allthree territories
• 23-32% have involvement in two territories
Epidemiology
Risk factors
Pathogenesis
Spectrum
Prevention
EpidemiologyEpidemiology
The three major clinical manifestations of atherosclerotic CVD are:
CHDCVAPVD
Disease impact:
In 1997, more than 5mn Americans had CVDCurrently 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
Annually1.5mn Americans have MI0.5mn die from CHD0.5mn have stroke0.15mn 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 andextensive 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 cholesterolLow 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
ABIExercise testingEBCT/MRICarotid IMT
DyslipidemiaDyslipidemia
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 CVDHDL cholesterol- inversely related to CVDVLDL 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 >5This ratio is also the best predictor of treatment benefits
0
25
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75
100
125
150
Gotto AM Jr, e t al . Ci rcula ti on. 1990;81:17 21-1733 .
Ca ste lli WP. Am J Med. 1984;76:4-12.
Relationship Between Cholesterol and CHD Risk:Epidemiologic Trials
10-y
ear
CH
D d
eath
ra
te(D
eat
hs/
100
0)
Serum cholesterol (mg/dL)
1% reduct ion in total cholesterolresulted in a 2% decrease in CHD risk
CH
D i
ndic
atio
ns
per
100
0Each 1% increase in total cholesterol level isassociated with a 2% increase in CHD risk
Serum cholesterol (mg/100 mL)
Framingham Study (n=5209)Multiple Risk Factor Intervention Trial
(MRFIT) (n=361,662)
204 205-234 235-264 265-294 295150 200 250 3000
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10
HypertensionHypertension
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 CVDby 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)
SmokingSmoking
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 reducethe 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.
ObesityObesity
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 MellitusDiabetes 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 inchesWomen >35 inches
-Triglycerides >150 mg/dl
-HDLMen <40 mg/dlWomen <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
PathogenesisPathogenesisAtherosclerosis 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 accumulation2. Accumulation of intimal SMC,
macrophages, T-lymphocytes
3. Formation of connective tissue matrix by proliferated
SMC
Atherosclerotic disease can lead to stenosis and occlusionas in most muscular arteries or cause ectasia oraneurysm formation as in elastic vessels (aorta)
Even in a given arterial bed it tends to involve certainpredisposed areas- proximal LAD,
proximal renal arteries, carotid bifurcation
The process develops over years to decades and progressionis not linear and smooth but discontinuous withperiods of quiescence and rapid evolution.
Manifestations may be varied from asymptomatic to chronicstable angina/claudication to dramatic acute MI/stroke/sudden death.
Normal arterial wall has three layers:intima- limited by internal elastic laminamedia- between internal and external elastic laminaadventitia
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 performsseveral functions.
-“Barrier” between blood and arterial wall-non-thrombogenic surface by secreting PGI2-highly active metabolic tissue capable of forming
several vasoactive substances and connectivetissue macromolecules
Endothelial cells have receptor for several molecules:LDLGrowth factorsPharmacological agents
Initiation of atherosclerosis
Lipoprotien accumulation and modificationfatty streak formationlipid oxidationnonenzymatic 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 Increased adherenceMacrophages and migration of T-cells,
monocytes from the lumen into the wall
Foam Cell
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 plaquesThin fibrous capLarge lipid coreHigh macrophage content
Stable plaquesThick capDense extracellular matrixLess lipid rich core
Epidemiology
Risk factors
Pathogenesis
Spectrum
Prevention
Spectrum of coronary artery disease
Silent ischemia
Chronic stable angina
Acute coronary syndromesUnstable anginaNSTEMISTEMI
10/00 medslides.com 2
Clinical presentation of CHD depends on age and gender
Women:Angina is most common first CHD eventfollowed by MI
Men:MI is the most common first event followed byangina. 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 thesedeaths occur before hospitalization
Mortality after admission has decreased by 30% in last2 decades
1 in 25 pts (4%) who survive till hospital discharge diewithin one year
PTCA, percutaneous transluminal coronary angioplasty.
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25
30
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30-D
ay
Mo
rta
lity
(%
)
5.0%- 6.5%5.0%- 6.5%
13%-15%13%-15%
30%30%
Defibrillation
Hemodynamicmonitoring
-Blockade
Defibrillation
Hemodynamicmonitoring
-BlockadeAspirin, PTCA,
Lysis Aspirin, PTCA,
Lysis
BedrestBedrest
Pre-CCU Era CCU Era Reperfusion Era
Improvement in MortalityImprovement in MortalityImprovement in Mortality
Pathophysiology
AMI results when thrombus (occlusive/nonocclusive)develops at the site of ruptured plaque
Vulnerable plaque
Rupture
Coagulation cascade platelet adhesion, activationactivation,aggregation Fibrin and platelet clot
Coronary occlusion
MI
Antman EM. In: Braunwald E, ed. Heart Disease: A Textbook in Cardiovascular Medicine, 5th ed. Philadelphia, Pa: WB Saunders; 1997.
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%
Stable anginaStable angina UnstableUnstableanginaangina
Non–Q-waveNon–Q-waveAMIAMI
Q-waveQ-waveAMIAMI
Spectrum of Acute Coronary Syndromes: HematologicFindings in Q-Wave AMISpectrum of Acute Coronary Syndromes: HematologicSpectrum of Acute Coronary Syndromes: HematologicFindings in Q-Wave AMIFindings in Q-Wave AMI
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 butmore severe and prolongeddescribed 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:
PericarditisPulmonary embolismPneumothoraxAortic dissectionEsophageal spasm
Examination:
Anxiety, pallor, restlessnessSubsternal chest pain with diaphoresis is strongly suggestive
of AMIThose with anterior MI may have sympathetic overactivity
whereas those with inferior MI may have para-sympathetic overactivity
S3/S4Transient systolic murmur due to dysfunction of mitral
apparatus leading to mitral regurgitation
Laboratory findings:
EKG specific but insensitive tool for diagnosis of myocardialischemia
Total occlusion of infarct related artery leads to STelevation (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 MIand normalize by 48-72 hrsnot specific for myocardial necrosis
MB isoenzyme of CK is more specific
Cardiac specific troponins: more sensitive and specific than CK and CKMB for identificationof myocardial necrosis
Myoglobin- first serum marker to rise after MI, but lacks specificity.
Cardiac imaging
2D echocardiographyreveals regional wall motion abnormalityalso useful to identify mechanical complications
of MI
Radionuclide imagingused infrequently in the diagnosis of acute MImainly used to risk stratify patients with CHD
Management
Prehospital care:
Major elements includeRecognition 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 buccalabsorption, inhibition of cyclooxygenase in plateletsand reduction of TXA2
Oxygen by nasal cannula if hypoxemia is present
Sublingual nitroglycerine followed by IV infusion if needed
Intravenous betablockers (decrease myocardial oxygendemand, control chest pain andreduce mortality)
Morphine for pain relief (given IV in small doses)
STEMI
ASA, beta blockers, antithrombin therapy
<12 hrs >12 hrs
Eligible forLytic therapy
Lytic C/I Not a candidateFor reperfusion
Persistentsymptoms
Thrombolysis Primary PCI no yes
Other medical therapy Consider reperfusion(ACEI, nitrates, beta blockers, antiplatelets, antithrombin,statins)
Time is muscle
Adapted from Tiefenbrunn AJ, Sobel BE. Circulation. 1992;85:2311-2315.
Time-Dependent Benefit of Reperfusion TherapyTime-Dependent Benefit of Reperfusion TherapyTime-Dependent Benefit of Reperfusion Therapy
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60
80
100
0 2 4 6 8 10 12
Reperfusion Time (hours)
% B
enef
it
Reimer/Jennings 1977
Bergmann 1982
GISSI-I 1986
Adapted from Lee KL, et al. Circulation. 1995;91:1659-1668.
Importance of Time-to-Treatment: Results of GUSTO-IImportance of Time-to-Treatment: Results of GUSTO-IImportance of Time-to-Treatment: Results of GUSTO-I
0
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4
6
8
10
12
0 1 2 3 4 5 6 7 8 9 10 11 12
Time From Onset of Symptoms to Treatment (hours)
2=149 (1 df )
30-D
ay M
ort
alit
y (
%)
Time of OnsetTime of OnsetTime of Onset
ED Time Point 1:DOOR
ED Time Point 1:ED Time Point 1:DOORDOOR
ED Time Point 2:DATA
ED Time Point 2:ED Time Point 2:DATADATA
ED Time Point 3:DECISION
ED Time Point 3:ED Time Point 3:DECISIONDECISION
ED Time Point 4:DRUG
ED Time Point 4:ED Time Point 4:DRUGDRUG
Time Interval IIIDecision to drug
Time Interval IIECG to decision to treat
Time Interval IDoor to ECG
NHAAP Recommendations. U.S. Department of Health NIH Publication: 1997:97-3787.
The Four DsThe Four DsThe Four Ds
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 antagonistBetablockers(calcium channel blockers)
Assess clinical status
High risk/unstable Stable
(Recurrent ischemia, LV dysfunctionWidespread EKG changes, positive
enzyme markers)
Cardiac catheterization Severe ischemia
Revascularization (PCI/CABG) Medical therapy
Stress test
yes
no
Chronic Stable Angina:
Patients with stable angina should undergo detailed evaluationincluding history, focused physical examinationand risk factor assessment
Initial laboratory evaluation should include:hemoglobin, fasting glucose, fasting lipid profileEKG and chest x-ray
Precipitating factors for angina (anemia, arrhythmias, valvulardisease) 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 undergostress 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 mayproceed with coronary angiography and subsequentrevascularisation
Epidemiology
Risk factors
Pathogenesis
Spectrum
Prevention
Prevention:
Opportunity for treating the underlying process of atherosclerosis and preventing its acute complicationspresents enormous challenge and opportunity
Prospective community based Framingham heart studyprovided support for the fact that hyperlipidemia,hypertension and other risk factors correlated withcardiovascular 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
Others130-160 mg/dl
Circulation 2004;110:227-239
Diabetes mellitus:
Diabetic dyslipidemia is characterized by:normal LDL- but more dense and atherogeniclow HDLelevated triglycerides
Having diabetes places individuals at same risk as thosewith established CVD
Strict glycemic control helps to decrease microvascularcomplications but not CHD events. However, statintherapy has demonstrated unequivocal benefit in diabetic patients
Hypertension:
Trials have shown that pharmacologic therapy of HTN reducesthe 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 diseaseat 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 ofsubjects who have never smoked
Lung Health Study
Annals of Internal Med, 2005