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Ashley EA, Niebauer J. Cardiology Explained. London: Remedica; 2004.

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Cardiology Explained.

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Chapter 5Coronary artery disease

Background

Coronary artery disease (CAD) is the most common cause of mortality in the developed world. It results from the collision of ancient genes with modern lifestyles: a hunter–gatherer lifestyle – with high daily energy expenditure and rare kills – favors a tendency to eat large quantities of high-calorie food when it is available. Such predispositions sit uneasily in a modern world with motorized transport and fatty snacks on every corner. Despite this, so-called "hardening of the arteries" was first described only in the 1700s, and it was not until the 1900s that a good description of myocardial infarction (MI) was forthcoming.

The term "coronary artery disease" encompasses a range of diseases that result from atheromatous change in coronary vessels. In the past, CAD was thought to be a simple, inexorable process of artery narrowing, eventually resulting in complete vessel blockage (and MI). However, in recent years the explanatory paradigm has changed because it was realized that a whole spectrum of coronary plaques exists – from stable (lipid-poor, thick fibrous cap) to unstable (lipid-rich, thin fibrous cap) (see Figure 1). When an unstable plaque ruptures – and the more unstable it is, the more likely it is to rupture – the subsequent release of prothrombotic and vasoconstrictive factors increases the likelihood of complete occlusion of the artery. It is the balance between the body's prothrombotic and thrombolytic pathways at the rupture site that determines the clinical outcome. Transient occlusion leads to ischemia and pain; permanent occlusion leads to transmural MI (see Table 1).

Figure 1. An atherosclerotic plaque consists of a core of dead foam cells (lipid-engorged macrophages and smooth muscle cells) covered by a fibrous cap (a region of the intimal layer that has become thickened as a result of medial smooth muscle cells depositing collagen and elastin fibers).

Figure 1

An atherosclerotic plaque consists of a core of dead foam cells (lipid-engorged macrophages and smooth muscle cells) covered by a fibrous cap (a region of the intimal layer that has become thickened as a result of medial smooth muscle cells depositing (more...)

Table 1. Subgroups of coronary artery disease presentations. MI: myocardial infarction.

Table 1

Subgroups of coronary artery disease presentations. MI: myocardial infarction.

Thrombosis in Myocardial Infarction

The hypothesis that thrombosis plays a central role in myocardial infarction was first proposed by James Herrick in JAMA in 1912. This paper was the first to suggest that clots, rather than a slow accretion of plaque, are responsible for the complete occlusion that would often result in death. Importantly, he was the first to link symptoms in living patients with coronary artery disease, and to suggest that patients can survive complete blockage. These ideas were radical and new and (not surprisingly) no one believed him.

The establishment of these pathophysiological origins of CAD, together with the identification of improved clinical markers for ischemia and necrosis, has led to the proposal of a new (somewhat controversial) definition for acute MI: a rise and fall in troponin or the creatine kinase myocardial band fraction (CK-MB) (see "Markers of myocardial damage" section), plus at least one of the following:

  • ischemic symptoms
  • development of pathological Q waves on the electrocardiogram (ECG)
  • ST-segment elevation or depression on the ECG
  • coronary artery intervention (eg, angioplasty)

Angina Pectoris

William Heberden defined angina pectoris in 1768 and provided a clear description of the familiar pain. However, it was Edward Jenner and Caleb Parry who linked this "disorder of the breast" with the "hardening" of the arteries that had been described by Giovanni Morgagni 7 years earlier.

Assessment

History and examination

History-taking is the most valuable technique for differentiating between the many causes of chest discomfort. The classic symptoms of angina are well known: a sensation of a constriction of the chest with variable levels of radiation to the neck, jaw, both arms, and occasionally to the epigastrium or through to the back. The pain is worse with exertion, especially in cold air; improved by rest and nitrates; and often follows a meal. Retrosternal pain in particular (often described by patients as "pressure") suggests that angina is the cause. Pains that are localized elsewhere, described as sharp or stabbing, or reproduced by palpation are much less likely to be cardiac in origin.

The term "unstable angina" encompasses a number of presentations, including pain that:

  • occurs at rest
  • lasts longer than 30 minutes
  • is not relieved by several doses of sublingual nitrate
  • is elicited over days or weeks by gradually smaller amounts of exertion (crescendo angina)

Examination of the cardiovascular system is mandatory in any patient reporting chest pain. Sweating, nausea, and vomiting are suggestive of MI, while complications of MI – such as heart failure (third heart sound and basal crackles) ventricular septal defect (VSD), harsh systolic murmur, or papillary muscle rupture – should be excluded.

Atypical chest pain

A common presentation in general practice is chest pain accompanied by an atypical history. In such cases, it is essential that the history is accurately established and documented. The most common noncardiac cause is dyspepsia. Although chest pain following a big meal could have a cardiac, gastroesophageal, or biliary origin, pain resulting from exercise is rarely biliary. It may be difficult to differentiate esophageal spasm from cardiac pain as they are both improved by nitrate. Other noncardiac causes to consider are musculoskeletal, pericardial, and pleural.

Other forms of angina include:

  • variant angina (also known as Prinzmetal's angina), which causes an unpredictable pain – typically coming on at rest – and is associated with transient ST elevation on an ECG. It is thought to be due to coronary spasm and seems to be independent of atherosclerosis
  • syndrome X – a condition in which the history is typical of coronary disease and there is ST depression on exercise, yet the coronary arteries are angiographically normal. It is thought to reflect small vessel disease and/or abnormal ventricular function
  • dyspnea – angina can present as exertional dyspnea. Pay close attention to the pattern of onset and relief
  • silent ischemia – diabetics, an important subgroup, can suffer from silent ischemia and even silent MI. Thus, even if there are no apparent symptoms of cardiac disease, a diabetic with an ECG abnormality should undergo stress testing and echocardiography to determine whether there is any indication for catheterization. One view is that all diabetics of greater than 5 years standing should be screened for cardiovascular disease

The key message is that a patient with an atypical history should always be referred for exercise electrocardiography (see "Investigations" section). In more than 90% of cases, the existence of coronary disease can be predicted accurately from the combined results of exercise ECG and their history.

Generalist management

Risk factors

Risk factor assessment and management are central to the care of cardiac patients. The major independent and predisposing risk factors (see Tables 2 and 3) should be documented for every patient, and it is useful to include them in every referral.

Table 2. American Heart Association guide to risk factors for coronary artery disease. HDL: high-density lipoprotein; LDL: low-density lipoprotein; Lp(a): lipoprotein little a. aThese are classified as major by some bodies.

Table 2

American Heart Association guide to risk factors for coronary artery disease. HDL: high-density lipoprotein; LDL: low-density lipoprotein; Lp(a): lipoprotein little a. aThese are classified as major by some bodies.

Table 3. European Society of Cardiology table of lifestyles and characteristics associated with an increased risk of a future coronary heart disease (CHD) event. HDL: high-density lipoprotein; LDL: low-density lipoprotein.

Table 3

European Society of Cardiology table of lifestyles and characteristics associated with an increased risk of a future coronary heart disease (CHD) event. HDL: high-density lipoprotein; LDL: low-density lipoprotein.

Smoking

There are a wealth of products aimed at smoking cessation. Older products such as nicotine chewing gum have been replaced by nicotine patches and nicotine inhalers, and many products have been shown to have clear benefits in helping people to stop smoking. However, if someone is to succeed at giving up smoking, it is important that certain vital support mechanisms are in place before they attempt it:

  • it is essential that the patients' families and partners are supportive
  • patients should allocate a particular date and time to stop smoking. This should be a few weeks subsequent to the decision to stop, to allow time for planning and reflection
  • patients should identify (and write down) the "at-risk" times when they envisage that temptation and craving will be greatest, for example with coffee or in a bar. They can then focus, in advance, on these situations and devise a way to avoid giving in
  • on the allotted date, patients should remove all cigarettes and smoking materials from the house
  • patients should keep diaries of their progress and report regularly to their doctor

Most people can stop smoking using these techniques. In cases where it is not successful, pharmacological help in the form of bupropion (Zyban) may be indicated. Helping patients to stop smoking is an extremely worthwhile endeavor. The risk tables (see Figures 2 and 3) show just how much there is to be gained by changing smoking status.

Figure 2. Coronary heart disease risk tables for men and women.

Figure 2

Coronary heart disease risk tables for men and women. Reproduced with permission from the European Society of Cardiology (Prevention of coronary heart disease in clinical practice. Recommendations of the Second Joint Task Force of European and other Societies (more...)

Figure 3. Coronary heart disease risk tables for men and women with diabetes.

Figure 3

Coronary heart disease risk tables for men and women with diabetes. Reproduced with permission from the European Society of Cardiology (Prevention of coronary heart disease in clinical practice. Recommendations of the Second Joint Task Force of European (more...)

Basic science

Exercise training exerts many beneficial changes at the cellular and molecular level. An exercise-induced increase in blood flow may exert its beneficial effects on vascular reactivity and structure through an increase in the elaboration of several endothelium-derived substances, such as nitric oxide, prostacyclin, and superoxide dismutase. Although prostacyclin may exert its antiatherogenic effects by inhibiting the uptake of cholesterol esters into macrophages or into smooth muscle cells, nitric oxide contributes strongly to the inhibition of monocyte adhesion, and inhibits platelet aggregation at much lower concentrations than those needed to inhibit adhesion, thereby allowing platelets to participate in the repair of the vessel wall, while at the same time preventing or limiting thrombus formation.

Flow also modulates the expression of numerous paracrine substances, including endothelial growth factors, matrix modulators, chemokines, and regulators of blood fluidity, all of which may participate in the beneficial effects of exercise-induced vascular remodeling and reactivity.

Finally, exercise-induced changes in flow also have other antiatherogenic effects. Endothelial cells exposed to shear stress elaborate less superoxide anion; this may in part be due to increased transcription of superoxide dismutase. There are also shear stress responsive elements in the promoter region of several adhesion molecules (eg, intercellular adhesion molecule) that may reduce their gene expression.

Diet

The central components of a healthy diet are well known: low in fat; low in salt; low in cholesterol; low in calories. In detail, patients should consume a diet high in fiber (>20 g/day), and low in fat (<10% of total amount of calories) and cholesterol (<300 mg/day). However, helping patients to achieve this is another matter. Dieticians and specialist nurses can give patients the advice and support they need to improve their diet.

Physical activity

It is very important that an increase in physical activity accompanies an improved diet and giving up smoking. Exercise can be an enjoyable undertaking for patients. It can help them to:

  • improve their mood
  • feel more energetic
  • be less restricted in what they eat
  • relax more
  • sleep better
  • take a break from their normal routine

With these benefits, it is surprising that anyone needs to be persuaded to exercise. Major bodies, led by the American College of Sports Medicine, recommend that patients exercise for 30 minutes on at least 3 days per week at a submaximal exercise intensity. However, exercise does not have to comprise formal exercise; it can include informal exercise, provided it is of adequate intensity. In this way, increases in physical activity can be absorbed into everyday life: for example, climbing the stairs instead of taking the elevator and walking to work instead of driving. In fact, walking, partly because it is so inefficient, is excellent exercise. Few people realize that walking a mile and running a mile use similar amounts of energy. Thus, there is no need for patients to join a gym (with all the expense that may be incurred) when daily brisk walking is ample exercise. Keeping a diary of their physical activity may help patients to sustain adequate amounts of daily exercise.

Submaximal aerobic exercise in angina

Many angina patients refrain from physical activity because they believe that the resulting pain is "dangerous". However, aside from its well-known benefits in risk reduction, exercise can be as effective as β-blockade in the management of stable angina. It has been associated with increased plaque stability and even slight plaque shrinkage. It is recommended that patients exercise for 30–45 minutes per day, 4–5 times a week.

Estimating risk

Formal risk estimation is aided by a standard set of tables that were developed using epidemiological data gathered over many years (see Figures 2 and 3). These tables are based on:

  • gender
  • age
  • presence of diabetes
  • smoking
  • systolic blood pressure
  • total cholesterol to high-density lipoprotein (HDL) ratio

Investigations

Electrocardiogram

The ECG is a vital tool for assessing patients in both stable and emergency situations. Nevertheless, generalists in primary care do not always have ready access to it. Any patient presenting with clear cardiac chest pain should undergo an ECG immediately or as soon as possible (preferably even before a history is taken) to identify whether they are at high risk, ie, ST segment change or new left bundle branch block (LBBB). This facilitates prompt referral when necessary and, for thrombolysis, a door-to-needle time of less than 30 minutes. However, the ECG is not absolute – ST-segment elevation is present in only 50% of enzyme-confirmed MIs (see "Markers of myocardial damage" section).

Chest radiograph

A chest x-ray (CXR) may be used to help rule out aortic dissection in an acute presentation, although the gold standard is computed tomography (CT). Otherwise, it is rarely helpful. It should not be carried out on a routine basis.

Pharmacological management of angina

Stable disease is treated with aspirin and agents that offload or reduce the workload of the heart. Thus, standard medication for stable angina includes β-blockers, aspirin, and, if still symptomatic, long-acting nitrates.

Aspirin

The evidence for aspirin is so strong that it has to be part of the drug regimen of every patient with CAD. If aspirin is not tolerated, clopidogrel may be given instead. In cases in which warfarin (Coumadin) has to be administered (eg, coronary disease and atrial fibrillation), aspirin is usually omitted, since oral anticoagulation with an international normalized ratio (INR) of 3–4 has been shown to be safe and effective.

Oral long-acting nitrate

Nitrates are smooth muscle relaxants with the ability to vasodilate both the arteriolar and venous circulation. This leads to reductions in both preload (venous return) and afterload (blood pressure). However, nitrate-free periods are necessary to avoid tolerance.

Beta-blockers and calcium-channel blockers

Beta-blockers work by reducing the heart rate (lengthening diastole increases the time for coronary perfusion) and reducing the effects of catecholamine-mediated increases in cardiac workload. Calcium-channel blockers cause coronary artery dilation and subsequently decrease cardiac workload by reducing the contractility of myocardial smooth muscle cells. Calcium-channel blockers can be divided into rate-limiting (eg, verapamil, diltiazem) and nonrate-limiting (dihydropyridines, eg, amlodipine). Dihydropyridines are generally prescribed for hypertension, whereas the others tend to be used in cases of angina because of their ability to reduce the heart rate. However, verapamil should not be used with β-blockers, which block the action of sympathetic hormones (resulting in a lower heart rate and blood pressure) (see Chapter 6, Hypertension).

Potassium-channel openers

Potassium-channel openers, such as nicorandil, are a new class of agents for the treatment of angina. They exert both direct action on cardiac mitochondria and a nitrate-like effect. These are not yet available in the US.

Lipid-lowering agents

Lipids are insoluble in water. Hence, they are transported around the body as lipoproteins. Lipoproteins are made up of cholesterol, triglycerides, phospholipids, and protein. The major classes of lipoproteins (which vary in density, size, and triglyceride/cholesterol ratio) are:

  • chylomicrons (the largest and least dense)
  • very low-density lipoproteins (VLDLs)
  • low-density lipoproteins (LDLs)
  • HDLs

Lipids originate from two sources: endogenous lipids, synthesized in the liver, and exogenous lipids, ingested and processed in the intestine (see Figure 4).

Figure 4. Lipid transport and pharmacotherapeutic agents in hyperlipidemia (see "Lipid-lowering agents" text).

Figure 4

Lipid transport and pharmacotherapeutic agents in hyperlipidemia (see "Lipid-lowering agents" text). BA: bile acid; Chol: cholesterol; Chylo: chylomicron; Chylo rem: chylomicron remnant; FA: fatty acid; HDL: high-density lipoprotein; HMG-CoA: hydroxymethylglutaryl (more...)

Dietary cholesterol and triglycerides are packaged into chylomicrons in the intestine, before passing into the bloodstream via lymphatics. Chylomicrons are broken down by lipoprotein lipase (LPL) in the capillaries of muscle and adipose tissue to fatty acids, which then enter the cells. The chylomicron remnants, which have lost much of their triglyceride content, are taken up by the liver for disposal.

The liver synthesizes triglycerides and cholesterol, and packages them as VLDLs before releasing them into the blood. When VLDLs (which consist mainly of triglyceride) reach muscle and adipose blood vessels, their triglycerides are hydrolyzed by LPL to fatty acids. The fatty acids that are released are taken up by the surrounding muscle and adipose cells. During this process, the VLDLs become progressively more dense and turn into LDLs. While most of the resulting LDLs are taken up by the liver for disposal, some circulate and distribute cholesterol to the rest of the body tissues.

HDLs, which are also secreted from the liver and intestine, have the task of preventing lipid accumulation. They remove surplus cholesterol from tissues and transfer it to LDLs that return it to the liver.

To regulate cholesterol uptake, cells vary the expression of their LDL receptors. Elevated concentrations of lipid (hyperlipidemia) can lead to the development of atherosclerosis and CAD. VLDLs and LDLs are atherogenic lipoproteins, whereas HDL concentrations are inversely related to the incidence of CAD. Hence, treatments for hyperlipidemia aim to reduce LDL levels and raise HDL levels. Pharmacotherapeutic options in hyperlipidemia include:

  • statins, which inhibit hydroxymethylglutaryl coenzyme A reductase (HMG-CoA), the rate-limiting enzyme of cholesterol synthesis in the liver. A reduction in cholesterol synthesis causes the liver to increase the number of LDL receptors, reducing circulating concentrations of both cholesterol and triglyceride
  • cholestyramine, which is a lipid-lowering drug that acts by sequestering bile acids in the gut, thus increasing the synthesis of bile acids from cholesterol
  • fibrates, which reduce the level of VLDL by increasing the activity of the VLDL-hydrolyzing enzyme LPL

Guidelines for the use of lipid-lowering therapy have become more aggressive over the past few years following the results of major trials showing mortality benefit for the use of statins. Most guidelines recommend statin treatment for a patient with CAD with a 10-year risk that is greater than 20% (high risk) once a trial of dietary therapy has been unsuccessful. However, treatment can be cost effective with a 10-year risk of 10%. Recent trials have identified anti-inflammatory properties of statins and benefit even in patients with normal cholesterol levels. Dosage should be adjusted according to cholesterol levels. As part of secondary prevention, the following levels should be reached: total cholesterol, <200 mg/dL (5.2 mmol/L); HDL, >40 mg/dL (1 mmol/L); LDL, <100 mg/dL (2.6 mmol/L); triglyceride, <200 mg/dL (2.3 mmol/L).

Refer with confidence

Early management of stable coronary disease is mostly done in the community. Risk factor and stepwise pharmacological management of stable angina are appropriate. If there is any doubt about the diagnosis, a noninvasive test for coronary disease – such as an exercise ECG – should be carried out. Exercise ECG is increasingly carried out by generalists in primary care and hospitals. Pain that is resistant to medical therapy or crescendo symptoms warrants immediate presentation to an emergency room to rule out MI. The patient should then be referred to a cardiologist for further investigation, if needed. When referring patients who have had prior intervention, try to summarize the details of previous revascularization. For example:

  • two-vessel disease (left anterior descending [LAD], circumflex artery)
  • previous left internal mammary artery (LIMA) graft to LAD, percutaneous transluminal coronary angioplasty (PTCA) to right coronary artery (RCA)
  • previous saphenous vein graft (SVG) to circumflex artery

Including this type of detail will greatly increase the usefulness of a referral letter.

Specialist management

Stable angina: assessment

Exercise electrocardiography

Exercise ECG is the mainstay test for the diagnosis of CAD. It is usually carried out on a treadmill, but bicycle exercise can also be used. The patient exercises according to a set protocol from rest to maximum exertion, which should be reached in 8–12 minutes. The protocol most commonly used was originally described by Robert Bruce and bears his name (see Figure 5). There are, however, good reasons to consider a protocol that is individualized for each patient. Diagnostic exercise tests focus predominantly on the ST segment, which must fall more than 1 mm from rest and be horizontal or downsloping to be significant. ST depression does not localize ischemia so it cannot reveal anything about a suspected coronary lesion, but it does enable a classification of mild, intermediate, or severe CAD to be made.

Figure 5. (a) The Bruce exercise protocol.

Figure 5

(a) The Bruce exercise protocol. The patient starts exercising at a speed of 2.7 km/h on a gradient of 10%. The workload is intensified every 3 minutes by increasing the speed and the incline of the treadmill, until the endpoint is achieved. (b) The modified (more...)

The exercise test is also useful for recording other variables, ie, work capacity; maximum heart rate and chronotropic incompetence; blood pressure rise and recovery; and heart rate recovery. Work capacity (presumably reflecting left ventricular [LV] function) and heart rate recovery are very strong prognostic indicators for CAD. Contraindications to exercise testing and reasons for stopping an exercise test are outlined in Table 4.

Table 4. Contraindications to and reasons for stopping an exercise test. HCM: hypertrophic cardiomyopathy; LBBB: left bundle branch block.

Table 4

Contraindications to and reasons for stopping an exercise test. HCM: hypertrophic cardiomyopathy; LBBB: left bundle branch block.

It is important to appreciate where the value of the exercise test lies:

  • exercise ECG on its own has low sensitivity (<50%) but high specificity (>90%) – ie, it is very good at ruling disease in, but not good at ruling it out
  • the meaning of the test results is significantly affected by the pretest probability of disease (see Table 5). For example, exercise-induced ST depression in a young woman with no risk factors is likely to be a false positive
  • incorporating clinical and demographic information into the basic test result by calculating diagnostic "scores" can increase the sensitivity and specificity to >90% (see Figure 6)
  • patients without a clear diagnosis from the exercise tolerance test should have another noninvasive test

Table 5. Pretest likelihood of coronary artery disease (CAD) in symptomatic patients according to age and sex – each value represents the percentage of patients found to have significant CAD on catheterization. Reproduced with permission from Lippincott Williams & Wilkins (Gibbons RJ, Chatterjee K, Daley J et al. ACC/AHA/ACP-ASIM Guidelines for the Management of Patients with Chronic Stable Angina: Executive Summary and Recommendations. Circulation 1999;99:2829–48).

Table 5

Pretest likelihood of coronary artery disease (CAD) in symptomatic patients according to age and sex – each value represents the percentage of patients found to have significant CAD on catheterization. Reproduced with permission from Lippincott (more...)

Figure 6. The Duke score, which is the most commonly used risk score, can be used for diagnosis as well as prognosis.

Figure 6

The Duke score, which is the most commonly used risk score, can be used for diagnosis as well as prognosis. To use this nomogram: determine (i) the maximum amount of downsloping or planar ST depression, and (ii) the type of angina during exercise. Connect (more...)

A diagnostic algorithm for CAD is outlined in Figure 7. Most guidelines suggest the use of an alternative test if the preprobability is low. If the preprobability is high, exercise testing adds little in the way of diagnosis, but is useful for risk stratification. The primary role of exercise testing is where preprobability is intermediate.

Figure 7. Diagnostic algorithm for coronary artery disease.

Figure 7

Diagnostic algorithm for coronary artery disease. MRI: magnetic resonance imaging.

Nuclear cardiology

Isotopes such as thallium-201 or technetium (Tc)-99m can be used to provide information on cardiac function.

Perfusion imaging is used to assess regional blood flow by comparing the relative distribution of isotope at rest and under conditions of stress. Stress is provided either by exercise or by pharmacological tools such as inotropes (eg, dobutamine) or vasodilators (eg, adenosine or dipyridamole). The isotope is injected at the peak of exercise and the image captured with a gamma camera. Rest images are usually achieved several hours later. The "exercise" and "rest" images are compared to identify perfusion defects that are either "fixed" (eg, the scar of an old MI) or "reversible" (ischemic disease). Thallium-201 has been the isotope of choice for many years, but more recently centers have been using Tc-99m-labeled compounds, such as sestamibi, which achieve a higher resolution from a lower dose of radiation. Single photon emission CT (SPECT) is a technique that employs a gamma camera head that rotates around the patient to provide three-dimensional images.

Isotopes are also used in ventriculography. Estimates of LV function arrived at using this imaging technique are more accurate and reproducible than those resulting from echo. Consequently, ventriculography is indicated in:

  • cardiomyopathy assessment
  • pretransplant work-up
  • any situation where accurate risk assessment is critical

Two types of protocol are used: equilibrium and first-pass. The former, which is more common, uses a sample of the patient's blood labeled with Tc-99m. Information is gathered from each heartbeat over the time of equilibration (a few minutes) then averaged to give the final reading. In the first-pass technique, a bolus of radionuclide is injected and information is gathered over a much shorter time with a fast gamma camera.

Stress echocardiography

Stress echo is gaining in popularity because it has:

  • a higher predictive value than exercise ECG
  • a lower cost and better safety profile than perfusion scintigraphy

Ultrasound is used to detect the difference in wall movement between ischemic and nonischemic myocardium (nonischemic myocardium moves less). Furthermore, the location of the wall-motion abnormalities enables the coronary disease pattern to be predicted – this is not possible from ST-segment depression on an exercise ECG. Stress echo is thus indicated when:

  • LBBB is present on the resting ECG
  • the exercise ECG is inconclusive for other reasons
  • immobility or lung disease precludes the practical use of exercise as a cardiac stress (pharmacological stress echo only)

Stress echo can also provide information on stunned or hibernating myocardium. The former is myocardium that after a period of acute ischemia and reperfusion remains, for a time, hypokinetic at rest. Hibernating myocardium is a more chronic situation in which the blood flow of a segment is not adequate for function, yet is sufficient for it to remain viable. During periods of stress, these areas of myocardium "recover" and their viability can be detected as improvements (compared with at rest) in segmental contraction on exposure to low-dose pharmacological stress.

Stress echo is a useful technique in the hands of an experienced operator in a patient with a good echo window. Views can also be greatly improved by the use of a supine bicycle.

Electron beam computed tomography

This is a new technique that relies on imaging calcium in coronary lesions. It can quantify the "atherosclerotic burden" in the form of a calcium score to give an estimate of risk or to monitor the effect of, for example, lipid-lowering therapy. However, there is some doubt over how much information this measure adds to standard risk factors. Furthermore, vulnerable plaque often does not contain much calcium. The "holy grail" is a test that can locate and quantify "vulnerable" plaque, but this has not yet been found.

Magnetic resonance imaging

Most cardiologists agree that the future of noninvasive imaging of the heart lies with MRI. This technology can fulfill many of the functions of traditional tests and in most cases improve on them:

  • cardiac anatomy and morphology can be assessed with a high degree of spatial resolution using "black-blood" imaging
  • in cine mode (like two-dimensional echo), resolutions can be achieved that are significantly greater than those obtained with ultrasound and good views can be imaged and processed in under 30 seconds
  • LV function – including under exercise/pharmacological stress – can be achieved with a single breath-hold and the circumferential shortening calculated
  • wall-motion abnormalities can be assessed using tagging techniques
  • perfusion imaging can be carried out with a single breath-hold and two R–R intervals

In fact, the only technique that is still some way from routine clinical application is magnetic resonance angiography (MRA) of the coronary vessels (larger vessel MRA has been possible for some time). However, as new technology moves the field forward, this is likely to become more attainable, and with it the tempting prospect of cross-sectional imaging and plaque characterization.

Stable angina: treatment

Cardiac catheterization

Since cardiac MRI is still only available in the bigger centers, coronary artery catheterization remains the diagnostic gold standard in CAD. As the conduit for coronary intervention, its position is also safe from advances in imaging technology. Catheterization can also be used in a variety of settings aside from CAD, such as ventricular dysfunction, valve disease, detection and quantification of shunts, and other congenital and acquired structural abnormalities.

The basic procedure of PTCA involves cannulation of the femoral artery, with manipulation of a catheter over a guide wire to the site of stenosis. Dye is injected into each coronary artery in turn to assess flow. Flow is graded using a system first put forward by the TIMI (Thrombolysis in Myocardial Infarction) investigators (see Table 6). In balloon angioplasty a balloon is inflated (using the image-enhancing contrast dye) to compress the atheroma and dilate the artery (see Figure 8). Until recently, this was the intervention of choice. However, balloon angioplasty has a restenosis rate of 30% over 6 months and a high rate of coronary artery dissection. Consequently, the use of coronary artery stents (see Figure 8), which have lower rates of restenosis and artery dissection, has become common practice. These are deployed using a balloon. Most recent work has focussed on drug-eluting stents (which elute anti-inflammatory or anti-proliferative agents), which seem dramatically to reduce the incidence of restenosis.

Table 6. System (devised by the TIMI [Thrombolysis in Myocardial Infarction] investigators) used to grade the flow of contrast dye that has been injected into coronary arteries during percutaneous transluminal coronary angioplasty.

Table 6

System (devised by the TIMI [Thrombolysis in Myocardial Infarction] investigators) used to grade the flow of contrast dye that has been injected into coronary arteries during percutaneous transluminal coronary angioplasty.

Figure 8. Balloon angioplasty is used to compress atherosclerotic narrowing and dilate the artery.

Figure 8

Balloon angioplasty is used to compress atherosclerotic narrowing and dilate the artery. A balloon is directed over a guidewire to the site of stenosis where it is inflated (by contrast medium) to push open the narrowing or deploy the stent.

Pioneers

In 1929, Werner Forssmann – a German cardiologist – went against the express advice of his boss and, with the help of a nurse, inserted a catheter through an arm vein into his own heart. This was the first time a human heart had ever been catheterized. He saw the successful catheterization images on a fluoroscope screen – only by using a mirror. A pioneer of cardiology, he published his paper in Klinische Wochenschrift in 1929 and, although he catheterized only one patient's heart, he went on to catheterize his own heart another eight times.

Other, less common percutaneous techniques include radioactive stents and atherectomy (where the atheroma is physically removed from the artery).

Insertion of a metal object into an artery is a prothrombotic event. Hence, stenting is carried out in conjunction with antithrombotic therapy. Infusional antithrombotic agents (eg, abciximab – see below) are used as an adjunct during angioplasty while oral antiplatelet agents, such as ticlopidine and clopidogrel, are used for 1 month post stent. (However, ticlopidine has been plagued by problems of bone marrow suppression.)

Abciximab – a chimeric murine–human Fab1 fragment monoclonal antibody – and the small molecule inhibitors tirofiban and eptifibatide are members of a new class of antithrombotics. These agents function by inhibiting glycoprotein (GP)IIb/IIIa, a receptor abundant on platelets. When platelets are activated, this receptor binds fibrinogen and von Willebrand factor, leading to platelet aggregation.

The benefit from these agents almost certainly relates to microembolization since:

  • there is good evidence from autopsy studies that, following spontaneous or instrumented coronary plaque disruption, small aggregates of platelets, cholesterol, or other plaque material can be found in distal microvessels
  • it has been demonstrated, using filter devices and contrast echo, that microembolization is common following percutaneous coronary intervention (PCI) and is almost certainly the basis of "no reflow" – when perfusion is limited following PCI despite adequate restoration of flow in the infarct-related artery
  • troponin levels, which are thought to be a sensitive marker for this type of damage, are elevated following approximately 40% of procedures. (Note that, in unstable angina, the benefit of GPIIb/IIIa inhibitors is not limited to those with elevated troponin levels.)

Overall, complications from cardiac catheterization are relatively rare (totaling ~5%). They include:

  • contrast allergy response (very rare due to modern dyes)
  • local hemorrhage from puncture sites with subsequent thrombosis
  • false aneurysm or arteriovenous (AV) malformation
  • vasovagal reactions
  • coronary dissection
  • aortic dissection or ventricular perforation
  • air or atheroma embolism, which can occur in either the coronary or other arterial circulations with consequent ischemia or stroke
  • ventricular dysrhythmias, which are seen and may even cause death in the setting of left main stem disease

The First Human Coronary Angiogram

The first human coronary angiogram was, in fact, carried out by mistake by Mason Sones of the Cleveland Clinic in Ohio, USA, in 1958. Carrying out a standard LV angiogram, he paused – leaving the catheter in the aorta – to have a midprocedure smoke with his second operator. He returned, and relying on a pressure reading rather than direct visualization to determine the position of the catheter, he injected the RCA instead of the left ventricle. Realizing the mistake immediately from the outline of the RCA on the fluoroscope screen, he rapidly removed the catheter – just as his patient arrested. Hesitating, with scalpel in hand prepared for open chest defibrillation, he noticed the rhythm was asystole and not ventricular fibrillation. Thinking he might be able to help clear the dye without resorting to direct application of the paddles onto the myocardium, he pounded his patient's chest shouting "Cough! Cough!" Perhaps it was a cough, or maybe the precordial thump, or perhaps even its repeated applicationa that restarted the patient's heart, but certainly the fact that the patient recovered was the spark that ignited a revolution in diagnostic medicine.

(aPresaging CPR – a technique not practiced for several years subsequently.)

Overall mortality rates are quoted at less than one in 1,000 cases, but this increases to one in 100 for higher risk cases.

Coronary artery bypass grafting

Coronary artery bypass grafting (CABG) is the technique of choice for three-vessel disease with depressed LV function and left main stem coronary disease. However, since coronary interventions have become much more sophisticated some studies have shown equal benefit from percutaneous treatment as compared with surgical treatment in patients with three-vessel disease. During surgery, the patient undergoes sternotomy followed by heart–lung bypass and cardiac arrest. A portion of the saphenous vein is dissected from the leg, reversed (to orientate the venous valves in the appropriate direction), and attached proximally to the aortic root and distally to the coronary artery (see Figure 9). The LIMA, which originates from the left subclavian artery, can also be used as a conduit. It is disconnected at its distal end only and the cut end is connected to the LAD. In the same way, the right internal mammary artery (RIMA) can be connected to the RCA. A clear benefit of LIMA/RIMA CABG is improved graft patency, both perioperatively and in the long term (10 years). Other arteries that can be used include the radial and the gastroepiploic.

Figure 9. Sites of heart bypass grafting: a saphenous vein graft and a left internal mammary artery graft are shown.

Figure 9

Sites of heart bypass grafting: a saphenous vein graft and a left internal mammary artery graft are shown.

Due to the risks of heart–lung bypass – such as postbypass cognitive deficit – some centers now practice beating heart surgery. In this procedure the heart is not arrested: the section of the heart that is to be operated on is stabilized locally by the "suckers" (vacuum-operated suction clamps) of a device known as an octopus. Another technique is minimally invasive bypass, which uses small incisions and LIMA grafts.

Evidence base

With these rapid advances in both surgical and percutaneous techniques, much of the evidence base is out of date. For example, there are no definitive data indicating that angioplasty saves lives in stable CAD. Previous trials have shown that CABG can benefit outcome in: symptomatic, significant left main stem disease; symptomatic proximal three-vessel disease; and two-vessel disease including the proximal LAD. Patients with moderately impaired LV function benefit more from CABG than those with poor LV function, who have greater operative mortality (overall mortality is around 2.8%, but rises to 3.7%–12% for an emergency procedure).

Most cardiologists believe that new trials will demonstrate a mortality benefit for coronary stenting, possibly for three-vessel disease and perhaps even over and above that of bypass.

Acute coronary syndromes: assessment

Risk assessment is the key to in-hospital management of acute coronary syndromes (ACS). Patients with ST elevation need to be considered immediately for thrombolysis or acute intervention. Other patients should be closely monitored (preferably in a coronary care unit) if they have risk factors, previous infarction, poor ventricular function, and changing ST segments. In this situation, the key investigation is the measurement of cardiac enzymes.

Markers of myocardial damage

A number of markers for not only infarction, but also noninfarct ischemia, are now available. The transaminases aspartate aminotransferase (AST) and alanine aminotransferase (ALT) no longer offer any advantage over the other markers and in fact often cause false-positive results. Timescales of the variation in levels of the most commonly used markers for myocardial damage are outlined in Table 7 and Figure 10. Of the markers in Table 7, troponin I or T are the most specific and sensitive markers to rule acute MI out or in.

Table 7. Timescales for the variation in levels of markers for myocardial damage. CK-MB: creatine kinase myocardial band fraction; LDH1: lactate dehydrogenase 1. aCreatine kinase has three isoenzymes, of which CK-MB is the most cardiac specific. However, other organs also possess this enzyme in small quantities. It has been suggested that a CK-MB/CK ratio of over 2.5 is very specific for myocardial infarction in the context of chest pain. However, even this is inaccurate in situations of significant acute or chronic skeletal injury, where CK levels are also high.

Table 7

Timescales for the variation in levels of markers for myocardial damage. CK-MB: creatine kinase myocardial band fraction; LDH1: lactate dehydrogenase 1. aCreatine kinase has three isoenzymes, of which CK-MB is the most cardiac specific. However, other (more...)

Figure 10. Appearance of cardiac markers in the blood after onset of symptoms.

Figure 10

Appearance of cardiac markers in the blood after onset of symptoms. CK: creatine kinase; CK-MB: creatine kinase myocardial band fraction; LDH: lactate dehydrogenase.

Acute coronary syndromes: treatment

Pharmacological agents

The first-line treatment of any ACS is oxygen, aspirin, heparin, and β-blockade. Clopidogrel is an alternative to aspirin and diltiazem is an alternative to β-blockade. Low molecular-weight heparins have advantages over heparin, such as:

  • simple administration
  • better bioavailability
  • no requirement for monitoring
  • enhanced antifactor Xa activity
  • lower rates of heparin-induced thrombocytopenia (HIT)

Nitrates can be given intravenously for closer control of pain, unless there is hypotension or suspicion of a posterior infarction that needs higher filling pressures. Tolerance to nitrates occurs very quickly (24–36 hours) so the quicker the infusion can be weaned, the better. Opiate analgesia is also used for pain. In both cases, there may be benefit from GPIIb/IIIa inhibitors (see above). Patients with positive troponin levels should undergo immediate catheterization. Otherwise, patients should rest until they are pain-free. After 48 hours without pain, patients should undergo cardiac catheterization.

Myocardial infarction

If MI is confirmed by history and ST elevation (1 mm in limb leads, 2 mm in chest leads, or new LBBB) or elevated troponin plus either of these, the patient must quickly be taken to the catheterization laboratory. If this facility is not available, the doctor should immediately: (1) rule out contraindications to thrombolysis (see "Thrombolysis" section) and (2) arrange for analgesia and thrombolysis to be set up, before (3) completing the history and examination.

Primary PTCA

Recently – primarily due to improvements in devices, adjunctive therapy (GPIIb/IIIa inhibitors), and user experience – in cases of acute MI, the superiority of PTCA over thrombolysis alone has become clear. Most lesions (80%) are suitable for PTCA, particularly if they are discrete, proximal, uncalcified, subtotally occluded, without thrombus, and away from the side branches or divisions of a vessel. As such, primary PTCA is the procedure of choice for patients within 12 hours of the onset of MI symptoms. Current evidence suggests that patients of less than 75 years with cardiogenic shock (occurring within 36 hours of MI) benefit most from primary PTCA (within 18 hours of onset of shock) in an appropriate center with experienced personnel. In cases of poor LV function, intra-aortic balloon pumping (see Chapter 7, Heart failure) is useful in the setting of proximal LAD or mainstem stenting.

Thrombolysis

Thrombolysis is given as an infusion of (typically) streptokinase or tissue plasminogen activator (tPA) over 30 minutes to 1 hour, depending on the protocol. Aspirin and (intravenous) β-blocker should also be given acutely. Thrombolysis is beneficial up to 12 hours after the onset of pain, but may be given up to 24 hours afterwards in the context of continuing pain or a deteriorating condition.

The choice of thrombolytic agent is controversial. tPA and similar recombinant agents are still from 5- to 7-times more expensive than streptokinase and thus only tend to be used in the following situations:

  • where streptokinase has been administered previously
  • where recent proven streptococcal throat infections have occurred
  • in cases of hypotension

However, even with large anterior MI in younger patients presenting within 4 hours (a situation where tPA is often recommended first-line), the absolute added mortality benefit is only 1% above streptokinase.

Intracranial hemorrhage (ICH) can be an important complication of thrombolysis. Since heparin is associated with an increased risk of ICH (streptokinase treatment has a lower rate of ICH when it is administered without heparin), there is particular concern with respect to the administration of tPA (as it is usually given with heparin) to hypertensive patients above 65 years of age who are less than 70 kg in weight. Partly as a result of these concerns, several centers have explored the use of low-dose thrombolytic treatment in combination with GPIIb/IIIa inhibition. The results of these trials have been encouraging.

Recanalization is achieved following thrombolysis in approximately 70% of cases (compared with 15% of cases without thrombolysis). As this leaves a significant minority needing further attention, all patients should be reviewed 2 hours following thrombolysis. Rethrombolysis or coronary intervention should be considered if there is no resolution in the ST segment.

There are few absolute contraindications to thrombolysis and risks must be weighed against benefits in each individual case, particularly in the face of a large anterior infarct in a patient where access to primary PTCA is unavailable. However, there are some absolute contraindications and some notable relative contraindications.

Absolute contraindications are:

  • suspected aortic dissection (demands urgent CT, which is the gold standard, MRI, or transesophageal echo)
  • active internal bleeding or uncontrollable external bleeding (excluding menses)
  • recent head trauma (<2 weeks)
  • intracranial neoplasms
  • history of proven hemorrhagic stroke or cerebral infarction within 12 months
  • untreated diabetic hemorrhagic/proliferative retinopathy
  • BP >180/110 mm Hg uncontrolled (reduce with nitrates, β-blockade, angiotensin-converting enzyme inhibitors)

Relative contraindications are:

  • pregnancy
  • traumatic prolonged CPR
  • anticoagulation or INR >1.8
  • bleeding disorders
  • recent surgery (within 3 weeks)
  • probable intracardiac thrombus (eg, atrial fibrillation with mitral stenosis)
  • active peptic ulcer

Basic science

Atherosclerosis is initiated by a combination of circulating factors, such as cholesterol, and hemodynamic forces (common sites for atherosclerosis are areas where arteries branch). LDL and circulating leukocytes penetrate the arterial wall at regions of high shear stress (turbulent flow). In its atherogenic oxidized form, LDL enters macrophages, converting them to foam cells in the process. Oxidized LDL also enhances the growth factor-mediated migration of monocytes and smooth muscle cells to the intima, where the latter differentiate to form the fibrous cap of the mature atherosclerotic plaque. Figure 11 shows the layers of a vessel wall.

As a result of our understanding of these processes, there is much experimental interest in factors that contribute to the attraction and adhesion of leukocytes (chemokines and adhesion molecules), the receptors that modulate LDL uptake (scavenger receptors), enzymes that degrade the cap (matrix metalloproteinases), and protective species (such as nitric oxide). With inflammation a central component of our current appreciation of atherosclerosis, there is much interest in circulating markers (such as C-reactive protein) and pharmaceutical interventions that decrease inflammation (aspirin and statins).

Figure 11. The walls of normal blood vessels are composed of distinct layers: the intima is the innermost layer.

Figure 11

The walls of normal blood vessels are composed of distinct layers: the intima is the innermost layer. It consists of a single layer of endothelial cells lining the vessel, supported by a layer of connective tissue. The media is composed of smooth muscle (more...)

Arrhythmia

Reperfusion arrhythmias are common in the first 2 hours following thrombolysis. In addition to ensuring that plasma potassium is above 4.5, intravenous amiodarone and therapeutic-dose magnesium are indicated for sustained ventricular tachycardia or in ventricular fibrillation as adjuncts to defibrillation. Amiodarone is usually given via a central line, but can also be administered via a large antecubital cannula, although the latter has a slightly higher risk of local necrosis. Arrhythmias occurring more than 48 hours after an acute MI are associated with a worse prognosis and should be investigated further by coronary angiography to rule out hemodynamically relevant coronary stenoses, and electrophysiological studies to rule out scar-tissue substrate.

Other therapy

Glycemic control should be optimized in all diabetic patients, preferably with the use of sliding-scale insulin.

Oral inotropes should be avoided since almost all randomized trials have shown an increased mortality over placebo.

Angiotensin-converting enzyme inhibitors and β-blockers are given within the first 24 hours post-MI (in the absence of hypotension or other specific contraindications). However, although there is clear evidence for the benefit of each agent individually, there are few data on their effect when used in combination. Until further data are available, both should be given together.

Short-acting calcium-channel blockers of the dihydropyridine type are contraindicated in acute MI. The longer-acting dihydropyridines may reduce reinfarction in patients with a first non-Q-wave infarction or inferior infarction in the absence of LV dysfunction and pulmonary edema. However, their benefit over aspirin and β-blockade in the context of MI is unclear.

Although warfarin provides no general benefit, in those patients with mural LV thrombus following a large acute anterior MI, it can reduce the overall rate of cerebrovascular complications (2%–3%) by more than half. Thus, it is recommended for up to 6 months following infarction, or longer if the thrombus is still nonlaminar on echo.

Refer with confidence

Practices vary enormously from center to center, but it is still common for hospital generalists to manage non-ST elevation, low-risk ACS, and even MI where no facilities for intervention are available. In these situations, the most common scenarios for referral to cardiology would be:

  • recurrent pain following proven MI
  • unstable pain that refuses to settle
  • recurrent episodes of atypical pain with no ECG change or enzyme rise

Cardiac rehabilitation

Although the general phenomenon of MI has been recognized for about 100 years, for the first 70 years our approach to its treatment was diametrically opposite to that which we now propose. Complete immobilization for anything from 4 to 8 weeks – even to the point where patients were fed, washed, and shaved – was thought to help the heart to form a firm scar. Exercise was thought to increase the risk of ventricular aneurysm, cardiac rupture, congestive heart failure, and sudden death.

How bold then were the early pioneers, such as Terry Kavanagh at the Toronto Rehab center, who in 1973 entered seven post-MI patients for the Boston Marathon (all seven finished). Not long after that, as the medical profession gained confidence in this new-found approach, the Journal of Cardiac Rehabilitation was founded by Mike Pollock and Victor Froelicher, and other pioneers were soon taking the field forward. Today, controlled trials have demonstrated that cardiac rehabilitation is not only safe and saves lives (25% reduction in mortality at 3 years), but is more cost-effective than other post-MI treatment interventions, such as thrombolytic therapy, coronary bypass surgery, and cholesterol-lowering drugs (though less cost-effective than smoking cessation programs).

Effective cardiac rehabilitation is multilayered and involves permanent lifestyle changes – such as the incorporation of regular physical activity into everyday life –to improve the risk profile. The many components of rehabilitation are outlined in Table 8. Programs are usually run by specialist nurses and physiologists, together with a cardiologist. However, in the absence of a local formal program, most of the components can be managed in the community. The potential benefits are enormous. The dramatic effect of cardiac rehabilitation is thought to be due to improvements in lipid profile, endothelial function, body composition, autonomic tone, fibrinolysis, and psychological well-being.

Table 8. Elements of a cardiac rehabilitation program.

Table 8

Elements of a cardiac rehabilitation program.

Further reading

  1. Ashley EA, Myers J, Froelicher V. Exercise testing in clinical medicine. Lancet. 2000;356:1592–7. [PubMed: 11075788]
  2. Balady GJ, Ades PA, Comoss P. et al. Core components of cardiac rehabilitation/secondary prevention programs: A statement for healthcare professionals from the American Heart Association and the American Association of Cardiovascular and Pulmonary Rehabilitation Writing Group. Circulation. 2000;102:1069–73. [PubMed: 10961975]
  3. Braunwald E, Antman E, Beasley J. et al. ACC/AHA Guidelines for the management of patients with unstable angina and non-ST segment elevation myocardial infarction: executive summary and recommendations. Circulation. 2001;102:1193–209. [PubMed: 10973852]
  4. Gibbons R, Chatterjee K, Daley J. et al. ACC/AHA/ACP-ASIM Guidelines for the management of patients with chronic stable angina: executive summary and recommendations. Circulation. 1999;99:2829–48. [PubMed: 10351980]
  5. Grundy S, Balady GH, Criqui et al. Primary Prevention of Coronary Heart Disease: Guidance from Framingham. Circulation. 1998;97:1876–87. [PubMed: 9603549]
  6. Grundy SM, Pasternak R, Greenland P. Assessment of cardiovascular risk by use of multiple risk factor assessment equations. Circulation. 1999;100:1481–92. [PubMed: 10500053]
  7. Klaidman S. Saving the Heart. New York, Oxford University Press, 2000.
  8. Myocardial infarction redefined – A consensus document of the Joint European Society of Cardiology/American College of Cardiology Committee for the Redefinition of myocardial infarction. Eur Heart J. 2000;21:1502–13. [PubMed: 10973764]
  9. Niebauer J, Dulak J, Chan JR. et al. Gene transfer of nitric oxide synthase: effects on endothelial biology. J Am Coll Cardiol. 1999;34:1201–7. [PubMed: 10520813]
  10. Niebauer J, Hambrecht R, Velich T. et al. Attenuated progression of coronary artery disease after 6 years of multifactorial risk intervention: role of physical exercise. Circulation. 1997;96:2534–41. [PubMed: 9355890]
  11. Ryan TJ, Antman EM, Brooks NH. et al. 1999 update: ACC/AHA guidelines for the management of patients with acute myocardial infarction. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction) J Am Coll Cardiol. 1999;34:890–911. [PubMed: 10483976]
  12. Schuler G, Hambrecht R, Schlierf G. et al. Regular physical exercise and low fat diet: effects on progression of coronary artery disease. Circulation. 1992;86:1–11. [PubMed: 1617762]
  13. Wood D, De Backer G, Faergeman O. et al. Prevention of coronary heart disease in clinical practice. Recommendations of the Second Joint Task Force of European and other Societies on coronary prevention. Eur Heart J. 1998;19:1434–503. [PubMed: 9820987]
  14. Wood D, Durrington P, Poulter N. et al. Joint British recommendations on prevention of coronary heart disease in clinical practice. Heart. 1998;80(Suppl. 2):1–29.
Copyright © 2004, Remedica.
Bookshelf ID: NBK2216

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