Coronary Artery Disease

Knowledge - Students shall have an in-depth database on the following:

1. Identify risk factors for the development of coronary heart disease:
   1. Age and gender
   2. Family history of sudden death or premature CAD
   3. Personal history of peripheral vascular or cerebrovascular disease
   4. Smoking
   5. Lipid abnormalities (includes dietary history of saturated fat and cholesterol)
   6. Diabetes mellitus
   7. Hypertension
   8. Obesity
   9. Sedentary lifestyle
   10. Cocaine use
   11. Estrogen use
   12. Chronic inflammation
2. Be able to define and describe the primary and secondary prevention of ischemic heart disease through the reduction of cardiovascular risk factors (e.g. controlling hypertension and dyslipidemia, aggressive diabetes management, avoiding tobacco, and aspirin prophylaxis). (note overlap with chest pain objectives).
3. Identify factors that may be responsible for provoking or exacerbating symptoms of ischemic chest pain by:
   1. Increasing myocardial oxygen demand
   2. Tachycardia or tachyarrhythmia
   3. Hypertension
   4. Increased wall stress (aortic stenosis, cardiomyopathy)
   5. Hyperthyroidism
   6. Decreasing myocardial oxygen supply
   7. Anemia
   8. Hypoxemia
4. Be able to define and describe the pathogenesis, signs and symptoms of the acute coronary syndromes:
   1. Unstable angina
   2. Non-ST-elevation myocardial infarction (NSTEMI)
   3. ST-elevation myocardial infarction (STEMI)
5. Be able to define and describe the typical clinical course of the acute coronary syndromes.
6. Be able to define and describe the atypical presentations of cardiac ischemia/infarction (note overlap with chest pain)
7. Be able to define and describe the ECG findings and macromolecular markers (myoglobin, CK-MB, troponin-I, troponin-T) of acute ischemia/MI.
8. Be able to define and describe the utility of echocardiography in acute MI.
9. Be able to define and describe the importance of monitoring for and immediate treatment of ventricular fibrillation in acute MI.
10. Be able to define and describe the therapeutic options for acute MI and how they may differ for NSTEMI and STEMI, including:
    1. Aspirin
    2. Morphine
    3. Nitroglycerine
    4. Oxygen
    5. Heparin
    6. Antiplatelet agents (glycoprotein IIb/IIIa inhibitors)
    7. Beta-blockers
    8. ACE-I/ARB
    9. HMG-CoA reductase inhibitors
    10. Thrombolytic agents
    11. Emergent cardiac catheterization with percutaneous coronary intervention
11. Be able to define and describe the pathogenesis, signs and symptoms of the complications of acute MI, including arrhythmias, reduced ventricular function, cardiogenic shock, pericarditis, papillary muscle dysfunction/rupture, acute valvular dysfunction, and cardiac free wall rupture.
12. Symptoms and signs of chest pain that are characteristic of angina pectoris (note overlap with chest pain)
13. Symptoms and signs of chest pain due to other cardiac causes such as: (note overlap with chest pain):
    1. Atypical or variant angina (coronary vasospasm, Prinzmetal angina)
    2. Cocaine-induced chest pain
    3. Pericarditis
    4. Aortic disssection
    5. Valvular heart disease (aortic stenosis, mitral valve prolapse)
    6. Non-ischemic cardiomyopathy
    7. Syndrome X

Skills:

1. Take an accurate and complete history in order to identify a patients risk profile for atherosclerosis.
2. Detect on physical exam findings that may represent risk for the presence of atherosclerosis.

• Xanthelasma
• Xanthomas
• Diabetic skin lesions
• Carotid bruits
• Cardiomegaly
• Left ventricular 4^th Heart Sound
• Levine's sign
• Peripheral vascular exam

3. Recognize the EKG changes indicative of coronary ischemia both on the resting 12 lead EKG and stress test.
4. Be able to treat active chest pain with sublingual nitroglycerin.
5. Know the role of the cardiac markers referred to in Figure 244-3 in the classification of patients with high risk unstable angina. Call the laboratory or refer to a lab result sheet and record here the normal values used at the hospital you are doing your rotation at.
6. Take the center box of figure 244-3 "Stabilize on medical RX" and write specific orders for the following patients:

• 56 year old with severe reactive airway disease and Intermediate risk unstable angina
• 62 year old with no contraindication to beta blockers and high risk unstable angina

Attitude:

Big rough and tough Mike Ditka (Chicago Bears Coach : Footballs Hall of Fame) said the scariest time of his life was when he developed chest pain and thought he was having a heart attack. The students must develop a confidence in the approach to the patient with CAD that puts the patient at ease. This comes about by being thorough and proficient in the History and physical examination of patients with CAD. Once a patients risk is assigned the work up and treatment plan must be individualized.

"CLINICAL" TOP 10 FACTS
MODELED AFTER DAVID LETTERMAN'S TOP TEN

1. Is common, very common.
2. More of us have "it" than do not.
3. Starts as a subendothelial process and is focal not diffuse.
4. The presence of atherosclerosis is not the same as the risk the disease presents. More people die with atherosclerosis than die of it!
5. Has many associated risk factors but it appears cholesterol is a key ingredient.
6. Can be clinically silent, subtle, or loud!
7. Can be clinically predictable or unpredictable.
8. Is the substrate of acute myocardial infarction and the majority of "sudden death".
9. Is clinically detectable.
10. Is clinically treatable.

Definition:

Atherosclerosis is an intimal disease of large to medium sized arteries including the aorta, carotid, coronary and cerebral arteries. Atherosclerotic plaques contain connective tissue matrix with collagen, elastin, and proteoglycans produced by smooth muscle cells, T-lymphocytes and lipids both intracelluar in lipid laden macrophages and extracellular. You can see it is a busy, crowded, active neighborhood.

Epidemiologic and animal data suggest that the disease is a response to damage in the arterial wall caused by lipids being deposited. A very small percent of atherosclerosis will be due to predominantly smooth muscle cell proliferation. This is seen with endothelial injry in the absence of hyperlipidemia (Eg..Vasculitis like Kawasaki's Disease, and balloon injury).

Most atherosclerosis is large epicardial, with the intramyocardial arteries < 1000u usually immune except in diabetics and severe hyperlipidemia. This holds true of native vessel CAD with the pathophysiology of vein graft, post-angioplasty/stent and transplant arteriopathy being a different process with some shared common features.

THIS PROCESS STARTS EARLY, VERY EARLY!

Figure 1 is a normal artery. It consists of 3 layers: Intima, Media, Adventitia. The Intima consists of 3 layers:

1. A single layer of cells, the endothelium.
2. Subendothelial matrix
3. Longitudinal oriented smooth muscle cells

Figure 2 is the macroscopic stage: the lipid streak.

Fatty streaks first appear in childhood and can progress, regress or vanish. In South African Bantu children there are a large number of fatty streaks yet adults have few later-stage plaques. Some consider the fatty streak almost a physiologic event since just about everyone on the planet gets them.

The process starts with an intact endothelium onto which circulating monocytes adhere and migrate into the subendothelial zone where the basic process of atherosclerosis is initiated. Figure 3 outlines this process.

Autopsy studies performed on young soldiers who died during their time in service have provided valuable insight into the process of atherosclerosis.

Figure 4 is a non-obstructive plaque (23.3%) from a 27 year old female trauma victim.

The evolution of a streak into a plaque occurs in the 2-4th decade of life with the number of plaques related to risk factors which we will examine later. The key element is the appearance of extracellular lipid. The lipid first appears in the extracellular matrix then as a lipid core. The lipid core is primarily acellular with loads of oxidized lipid and margins surrounded by numerous lipid-laden macrophages. These macrophages express Tissue Factor which makes the core area the most thrombogenic part of the plaque. The smooth muscle cells (SMC) produce collagen to encapsulate and limit the lipid core however activated Macrophages produce enzymes (eg…Metalloproteinases) capable of breaking down the connective tissue matrix. It's a war in there!

Figure 5 outlines this process.

Meet the Players:

Endothelium: Single layer of cells that plays the key role in regulation of hemostasis and thrombosis.

The intact endothelium expresses:

Platelet Factors

Antithrombotic: Nitric Oxide, Prostaglandin I2, ecto-ADPase
Prothrombotic: vWF secretion, platelet activating factor, Tissue Factor expression

Coagulation Factors

Antithrombotic: Thrombomodulin, Protein S, Heparan sulfate
Prothrombotic: Binding of factors IX and X, Phospholipid membrane, Factor V secretion

Fibrinolytic Factors

Antithrombotic: tPA secretion, scu-PA secretion, binding fibrinolytic factors
Prothrombotic : P AI-1 secretion (inactivates plaminogen)

Vasomotor Factors

Antithrombotic: Nitric Oxide, PGI2
Prothrombotic: Thromboxane A2, endothelin

Smooth Muscle cells produce the extracellular matrix which is primarily collagen. Without collagen plaques would disintegrate. Smooth muscle cell migration and proliferation are controlled by numerous factors. See Figure 6

Macrophages are derived from circulating monocytes. The endothelium has on its luminal surface areas, points, receptors, sticky parts to which the monocytes can adhere. The endothelium does not have to be disrupted exposing the subendothelial goo. Two of these areas are intracellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM). Once in the subendothelial space the moncyte (turned macrophage) engulfs oxidised LDL cholesterol giving rise to the Foam Cell. Macrophage death then releases lipid to form the core. Macrophages stimulate SMC growth which stimulates connective tissue matrix synthesis while at the same time producing metalloproteinases which is destroying the matrix. As my kids would say……….Go figure!

Plaque disruption/ulceration exposes the core and activates the clotting cascade. This makes anticoagulation/antiplatelet therapy pivotal in the treatment of the ulcerated plaque.

Figure 7 is the aorta with extensive plaques at different stages of development including an ulcerated plaque with a thrombotic component.

FIBRINOGEN AND PLAQUE EVOLUTION

This is shown in Figure 8. Like LDL cholesterol, Fibrinogen is able to traverse the endothelium entering the subendothelial space. There it is converted to fibrin and with thrombin generated from macrophages stimulates SMC proliferation.

CALCIFICATION

This process is seen in two patterns:

1. Nodular - In relation to lipid core in macrophage rich areas
2. Diffuse plate like in connective tissue areas where SMC predominate.

Macrophages and SMC express osteopontin, Gelatinase B, Bone Protein-2, Osteocalin which result in calcification.

The degree of calcification is a weak predictor of future ischemix events in an individual. However if you see calcification you can be darn sure you have got atherosclerosis (Foreshadowing of things to come with the Electron Beam Computed Tomography - EBCT (Alias HEART CHECK AMERICA, 1-800-NEW TEST)

TIME FOR A BASIC SCIENCE TOP TEN FOR ATHEROSCLEROSIS

1. The process starts very early with the conversion of a lipid streak to a raised plaque.
2. Lipids in the form of oxidized LDL play a pivotal role in plaque core development.
3. The initiating process does not require endothelial disruption as monocytes can adhere and LDL cholesterol traverse the endothelium.
4. All plaques have smooth muscle cells.
5. Plaques are dynamic sites that change their characteristic. Some are lipid laden while others are more SMC matrix.
6. Calcification is a part of plaque evolution.
7. The lipid core contents are extremely thrombogenic.
8. Smooth muscle cell proliferation is under the influence of macrophage, platelet, endothelial cell and T lymphocytes.
9. The coagulation system is an important part in plaque evolution.
10. Plaque evolution is not predictable.

CLINICAL SYMPTOMS

Chronic obstruction due to plaque that is sufficiently severe to be flow limiting on exercise is usually at least a 50% diameter reduction. The etiology of stable angina is a flow limiting plaque. If the angina remains stable and predictable with about the same level of demand (exercise) then the plaque is usually a stable plaque. Stable plaques have a thick fibrous cap, a small lipid core, and a large component of collagen. The lesion reached a 50% diameter stenosis by either the primary atherosclerotic process or the healing phase of a previous thrombotic event.

Acute manifestations are the result of a disrupted plaque of varying diameter stenosis that results in thrombus in relation to a plaque. This leads to further narrowing acutely. This process is the Acute Coronary Syndrome. Total occlusion usually presents as an acute myocardial infarction. A non-occluding thrombus presents as unstable angina or Non-Q wave myocardial infarction (This is Chest pain with an elevation of "serum markers" which we call enzymes.)

Thrombosis occurs at plaques due to either:

1. Erosion (Denudation) which exposes collagen, vWF, fibronectin all leading to platelet adhesion.

2. Disruption (Rupture/Ulceration) which exposes the lipid core and thrombus initially occurs in the plaque. This thrombus can extend into the lumen. Plaques that are prone to disruption are called vulnerable plaques which are characterized by :

Large lipid core (>40% of plaque volume)
Decreased internal collagen matrix
Thin plaque cap
Increased macrophages
Decreased smooth muscle cells in the cap

Macrophages secrete metalloproteinases which can destroy any of the connective tissue compounds. Plasmin activate the metalloproteinases. Once again demostrating the interrealtion of the clotting cascade and plaque matrix.

FOOD FOR THOUGHT:

Lipid lowering therapy probably decreases the lipid core and makes the internal plaque more favorable to SMC proliferation which "stabilizes" the plaque and decreases the flux of LDL cholesterol into the plaque shutting off or at least turnig down the process.

Antiplatelet therapy is beneficial when the endothelium is denuded.

Anticoagulation is beneficial when platelets get activated and when plaques get disrupted.

Beta blockers are beneficial as a demand limiter by their action on heart rate and blood pressure but do not have much to do with supply.

Nitroglycerin is the exogenous supply on nitric oxide (just in case the endothelium is not doing its' job)

Angioplasty is an effective but barbaric treatment of a diseased endothelium. It is the epitomy of endothelial injury and then our attempts to limit healing.

REFERENCES:

1. Harrison's Principles of Internal Medicine 15^th Edition

• Pages 1377-1386 The Pathogenesis of Atherosclerosis
• Pages 1399-1409 Ischemic Heart Disease