Coronary Artery Disease Punit Goel, MD Asst Professor in Cardiology, University of Missouri Hospital...

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

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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

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ear

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Serum cholesterol (mg/dL)

1% reduct ion in total cholesterolresulted in a 2% decrease in CHD risk

CH

D i

ndic

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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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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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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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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

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Time From Onset of Symptoms to Treatment (hours)

2=149 (1 df )

30-D

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%)

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