Coronary Artery DiseasePunit Goel, MDAsst Professor in Cardiology, University ofMissouri 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 deathCerebralTIA, strokePeripheralclaudication, gangreneRenalhypertension

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

EpidemiologyThe 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

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 stable2) technologic advances causing more aggressive andextensive treatment

Epidemiology

Risk factors

Pathogenesis

Spectrum

Prevention

Concept of risk factors for CAD evolved from prospectiveepidemiological studies in US and Europe whichdemonstrated 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:

ObesityDisinclination to exercise

Atherogenic diet

Major (traditional risk factors):

-Age-Male gender-DyslipidemiaHigh 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 ASCVDABIExercise testingEBCT/MRICarotid IMT

DyslipidemiaBetter 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 5This 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)

Gotto AM Jr, et al. Circulation. 1990;81:1721-1733.Castelli WP. Am J Med. 1984;76:4-12.

10-year CHD death rate (Deaths/1000)

Serum cholesterol (mg/dL)

1% reduction in total cholesterol resulted in a 2% decrease in CHD risk

CHD indications per 1000

Each 1% increase in total cholesterol level is associated with a 2% increase in CHD risk

Serum cholesterol (mg/100 mL)

Framingham Study (n=5209)

204

205-234

235-264

265-294

295

150

200

250

300

0

5040302010

HypertensionPotent 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)

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 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.

Obesity

It contributes independently to CVD risk and also aggravates knownCVD 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 factorsacting in concert. Also control of one risk factor provides substantial benefit in persons with multiple risk factors

Diabetes MellitusPatients 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 100 mg/dl(presence of 3 or more criteria constitutes metabolic syndrome)

Epidemiology

Risk factors

Pathogenesis

Spectrum

Prevention

PathogenesisAtherosclerosis is a progressive disease

The term was first proposed by pathologist Felix Marchandin 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-lymphocytes3. 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 largeNegative 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 severalvasoactive substances and connectivetissue macromolecules

Endothelial cells have receptor for several molecules:LDLGrowth factorsPharmacological agents

Initiation of atherosclerosisLipoprotien accumulation and modificationfatty streak formationlipid oxidationnonenzymatic glycation

Leukocyte recruitment (T lymphocytes, macro)foam cell formation

Evolution and complicationsSMC involvement

LDL

Binds to receptor on endothelial cell surface

Internalized

Oxidized to oxidized-LDL

Ingested by Increased adherenceMacrophagesand 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 foratherosclerosis. It proliferates in the intima to formintermediate 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

medslides.com

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

Improvement in Mortality

PTCA, percutaneous transluminal coronary angioplasty.

5.0%- 6.5%

13%-15%

30%

Defibrillation

Hemodynamicmonitoring

-Blockade

Aspirin, PTCA,Lysis

Bed rest

Pre-CCU Era

CCU Era

Reperfusion Era

Lecture NotesThirty-day mortality is the generally accepted benchmark of clinical efficacy in AMI therapy.A 50% reduction in 30-day mortality was noted between the pre-CCU (cardiac care unit) era and the CCU era.Mortality rates have decreased further (about 56%) with the advent of reperfusion therapiesmore than 78% from the pre-CCU era to the present.These dramatic reductions in 30-day mortality demonstrate the importance of the continuing development of more effective AMI therapies.

Pathophysiology

AMI results when thrombus (occlusive/nonocclusive)develops at the site of ruptured plaqueVulnerable plaque

Rupture

Coagulation cascadeplatelet adhesion, activationactivation,aggregation Fibrin and platelet clot

Coronary occlusion

MI

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

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

Angiographic thrombus0%-1%75%>90% Increased FPA/TAT0%-5% 60%-80%80%-90% Activated platelets0%-5% 70%-80%80%-90%

Acute coronary occlusion0%-1% 10%-25% >90%

Mortality1%-2%3%-8%6%-15%

Stable angina

Unstableangina

NonQ-waveAMI

Q-waveAMI

Lecture Notes Plaque rupture is the common pathophysiologic substrate of acute coronary syndromes (ACS) that range from unstable angina to Q-wave acute myocardial infarction (AMI), as shown in this slide. Progression from unstable angina to Q-wave AMI across the ACS spectrum is associated with an increasing incidence of angiographically detected thrombi and evidence of activation of the coagulation cascadethe release of fibrinopeptide A (FPA). Also associated with progression are generation of thrombin-antithrombin (TAT) complexes, activation and aggregation of platelets, and, ultimately, complete occlusion of the culprit coronary artery.Higher mortality rates are related to the increased size of myocardial damage and greater diminution of coronary blood flow in patients with 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/pressureworst 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 suggestiveof AMIThose with anterior MI may have sympathetic overactivitywhereas those with inferior MI may have para-sympathetic overactivityS3/S4Transient systolic murmur due to dysfunction of mitral apparatus leading to mitral regurgitation

Laboratory findings:

EKG specific but insensitive tool for diagnosis of myocardialischemiaTotal occlusion of infarct related artery leads to STelevation (STEMI) and subsequent evolution of Q wavesPartial 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 necrosisMB isoenzyme of CK is more specific

Cardiac specific troponins: more sensitive and specific than CK and CKMB for identificationof myocardial necrosisMyoglobin- first serum marker to rise after MI, but lacks specificity.

Cardiac imaging

2D echocardiographyreveals regional wall motion abnormalityalso useful to identify mechanical complicationsof 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 attentionRapid deployment of EMS capable of resuscitation and defibrillationExpeditious 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)

STEMIASA, beta blockers, antithrombin therapy12 hrsEligible forLytic therapyLytic C/INot a candidateFor reperfusionPersistentsymptomsThrombolysisPrimary PCInoyesOther medical therapyConsider reperfusion(ACEI, nitrates, beta blockers, antiplatelets, antithrombin,statins)

Time is muscle

Time-Dependent Benefit of Reperfusion Therapy

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

Lecture NotesIn the GISSI-I trial, patients who received fibrinolytic therapy within 1 hour of symptom onset had a 47% reduction in 21-day mortality compared with placebo; benefit declined as the interval increased. Initiation of treatment between 1 and 3 hours after symptom onset was associated with a mortality reduction of 14%. (GISSI, 1986)The benefit of therapy for patients treated beyond 2 hours is more modest but still significant, and may reflect the ability of the late reperfusion to prevent ventricular enlargement or improve electrophysiologic stability as well as salvage myocardium.The results of other controlled clinical trials of fibrinolytic therapy also support the dramatic relationship between early restoration of patency and myocardial salvage. Using data from the studies by Reimer et al, Bergmann et al, and the GISSI-I clinical trial, Tiefenbrunn and Sobel constructed a reperfusion time-benefit curve that depicts the time-dependent benefit of intervention for AMI. A nonlinear curve provided the best fit for the data. A similar curve was developed by Boersma and colleagues in their analysis of a data set of 22 randomized clinical trials of fibrinolytic therapy. (Reimer et al, 1977; Bergmann et al, 1982; Boersma et al, 1996; Tiefenbrunn and Sobel, 1992)

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

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

2=149 (1 df )

30-Day Mortality ( %)

Lecture Notes Lee and colleagues (1995) developed a multivariable statistical model for risk assessment in candidates for fibrinolytic therapy. By using GUSTO-I data, a comprehensive analysis of the relationships between baseline characteristics and 30-day mortality was plotted.This slide plots the relationship between 30-day mortality and time from symptom onset to treatment based on logistical regression.The mean time from symptom onset to treatment was 120 minutes (overall population) and 135 minutes in patients who died.In this model, each additional hour from symptom onset to treatment was associated with a measurable increase in the risk of death. However, the relation is not linear and the reasons for this are unknown.

The Four Ds

NHAAP Recommendations. U.S. Department of Health NIH Publication: 1997:97-3787.

Lecture NotesIn an effort to reduce the time from symptom onset to the initiation of fibrinolytic therapy, the National Heart Attack Alert Program (NHAAP) has identified four critical and recordable time points, called the four Ds. These are identified as:Door (Time Point 1): The patient arrives at the emergency department (ED).Data (Time Point 2): An initial electrocardiogram (ECG) is obtained.Decision (Time Point 3): A decision is made to initiate fibrinolytic therapy.Drug (Time Point 4): Fibrinolytic therapy is initiated.The intervals between these time points were designated intervals I through III for the purpose of identifying and reducing in-hospital delays in treatment.

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 statusHigh risk/unstableStable(Recurrent ischemia, LV dysfunctionWidespread EKG changes, positiveenzyme markers)Cardiac catheterizationSevere ischemiaRevascularization (PCI/CABG)Medical therapyStress testyesno

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:

Aaspirin and anti-anginals

Bbeta-blockers and blood pressure control

Ccholesterol and cigarettes

Ddiet and diabetes

Eeducation 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 individualshaving 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%

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 StudyAnnals of Internal Med, 2005