Ischemic Heart Disease

2035CHAPTER 273

FIGURE 273-3 Evaluation of the patient with known or suspected ischemic heart disease. On the left of the figure is an algorithm for identifying patients who should be

referred for stress testing and the decision pathway for determining whether a standard treadmill exercise with electrocardiogram (ECG) monitoring alone is adequate. A

specialized imaging study is necessary if the patient cannot exercise adequately (pharmacologic challenge is given) or if there are confounding features on the resting ECG

(symptom-limited treadmill exercise may be used to stress the coronary circulation). Panels B–E on the next page are examples of the data obtained with ECG monitoring and

specialized imaging procedures. CMR, cardiac magnetic resonance; EBCT, electron beam computed tomography; ECHO, echocardiography; IHD, ischemic heart disease;

MIBI, methoxyisobutyl isonitrite; MR, magnetic resonance; PET, positron emission tomography. A. Lead V4

 at rest (top panel) and after 4.5 min of exercise (bottom panel).

There is 3 mm (0.3 mV) of horizontal ST-segment depression, indicating a positive test for ischemia. (Reproduced with permission from BR Chaitman, in E Braunwald et al

[eds]: Braunwald’s heart disease: A textbook of cardiovascular medicine, Single Volume (Heart Disease (Braunwald), 8th ed, Philadelphia, Saunders, 2008.) B. A 45-yearold avid jogger who began experiencing classic substernal chest pressure underwent an exercise echo study. With exercise the patient’s heart rate increased from 52

to 153 beats/min. The left ventricular chamber dilated with exercise, and the septal and apical portions became akinetic to dyskinetic (red arrow). These findings are

strongly suggestive of a significant flow-limiting stenosis in the proximal left anterior descending artery, which was confirmed at coronary angiography. (Modified from SD

Solomon, in E Braunwald et al [eds]: Primary Cardiology, 2nd ed, Philadelphia, Saunders, 2003.) C. Stress and rest myocardial perfusion single-photon emission computed

tomography images obtained with 99m-technetium sestamibi in a patient with chest pain and dyspnea on exertion. The images demonstrate a medium-size and severe

stress perfusion defect involving the inferolateral and basal inferior walls, showing nearly complete reversibility, consistent with moderate ischemia in the right coronary

artery territory (red arrows). (Images provided by Dr. Marcello Di Carli, Nuclear Medicine Division, Brigham and Women’s Hospital, Boston, MA.) D. A patient with a prior

myocardial infarction presented with recurrent chest discomfort. On cardiac magnetic resonance (CMR) cine imaging, a large area of anterior akinesia was noted (marked

by the arrows in the top left and right images, systolic frame only). This area of akinesia was matched by a larger extent of late gadolinium-DTPA enhancements consistent

with a large transmural myocardial infarction (marked by arrows in the middle left and right images). Resting (bottom left) and adenosine vasodilating stress (bottom right)

first-pass perfusion images revealed reversible perfusion abnormality that extended to the inferior septum. This patient was found to have an occluded proximal left anterior

descending coronary artery with extensive collateral formation. This case illustrates the utility of different modalities in a CMR examination in characterizing ischemic and

infarcted myocardium. DTPA, diethylenetriamine penta-acetic acid. (Images provided by Dr. Raymond Kwong, Cardiovascular Division, Brigham and Women’s Hospital,

Boston, MA.) E. Stress and rest myocardial perfusion PET images obtained with rubidium-82 in a patient with chest pain on exertion. The images demonstrate a large and

severe stress perfusion defect involving the mid and apical anterior, anterolateral, and anteroseptal walls and the left ventricular apex, showing complete reversibility,

consistent with extensive and severe ischemia in the mid-left anterior descending coronary artery territory (red arrows). (Images provided by Dr. Marcello Di Carli, Nuclear

Medicine Division, Brigham and Women’s Hospital, Boston, MA.)

A

Evaluation of the patient with known or suspected IHD

Can patient exercise adequately?

Are confounding features

present on resting ECG?

Perform treadmill

exercise test

An imaging study

should be performed

Yes No

Possible indications for stress testing of patient:

1. Dx of IHD uncertain

2. Assess functional capacity of patient

3. Assess adequacy of treatment program for IHD

4. Markedly abnormal calcium score on EBCT

2-D

Echo

Nuclear

perfusion

scan

Cardiac

MR

scan

Cardiac

PET

scan

ECG ECHO MIBI CMR PET

No Yes

The incidence of false-positive tests is significantly increased in

patients with low probabilities of IHD, such as asymptomatic men age

<40 or premenopausal women with no risk factors for premature atherosclerosis. It is also increased in patients taking cardioactive drugs,

such as digitalis and antiarrhythmic agents, and in those with intraventricular conduction disturbances, resting ST-segment and T-wave

abnormalities, ventricular hypertrophy, or abnormal serum potassium

levels. Obstructive disease limited to the circumflex coronary artery

may result in a false-negative stress test since the posterolateral portion of the heart that this vessel supplies is not well represented on the

surface 12-lead ECG. Since the overall sensitivity of an exercise stress

ECG is only ~75%, a negative result does not exclude CAD, although

it makes the likelihood of three-vessel or left main CAD extremely

unlikely.

A medical professional should be present throughout the exercise

test. It is important to measure total duration of exercise, the times to

the onset of ischemic ST-segment change and chest discomfort, the

external work performed (generally expressed as the stage of exercise),

and the internal cardiac work performed, i.e., by the heart rate–blood

pressure product. The depth of the ST-segment depression and the time

needed for recovery of these ECG changes are also important. Because

the risks of exercise testing are small but real—estimated at one fatality

2036 PART 6 Disorders of the Cardiovascular System

FIGURE 273-3 (Continued)

Ischemic Heart Disease

2037CHAPTER 273

TABLE 273-2 Relation of Metabolic Equivalent Tasks (METs) to Stages in Various Testing Protocols

FUNCTIONAL

CLASS CLINICAL STATUS

O2

 COST

mL/kg/min METs TREADMILL PROTOCOLS

NORMAL

AND

I

BRUCE Modified 3 min Stages BRUCE 3 min Stages

MPH %GR MPH %GR

6.0 22 6.0 22

HEALTHY, DEPENDENT ON AGE, ACTIVITY

5.5 20 5.2 20

5.0 18 5.0 18

56.0 16

52.5 15

49.0 14

45.5 13 4.2 16 4.2 16

42.0 12

38.5 11 3.4 14 3.4 14

SEDENTARY HEALTHY

35.0 10

31.5 9

28.0 8

LIMITED

24.5 7 2.5 12 2.5 12

II

SYMPTOMATIC

21.0 6

17.5 5 1.7 10 1.7 10

III

14.0 4

10.5 3 1.7 5

7.0 2 1.7 0

IV 3.5 1

Note: The standard Bruce treadmill protocol (right-hand column) begins at 1.7 MPH and 10% gradient (GR) and progresses every 3 min to a higher speed and elevation. The

corresponding oxygen consumption and clinical status of the patient are shown in the center and left-hand columns.

Abbreviations: GR, grade; MPH, miles per hour.

Source: Reproduced with permission from GF Fletcher et al: Exercise standards for testing and training. Circulation 104:1694, 2001.

and two nonfatal complications per 10,000 tests—equipment for resuscitation should be available. Modified (heart rate–limited rather than

symptom-limited) exercise tests can be performed safely in patients

as early as 6 days after uncomplicated myocardial infarction (Table

273-2). Contraindications to exercise stress testing include rest angina

within 48 h, unstable rhythm, severe aortic stenosis, acute myocarditis,

uncontrolled heart failure, severe pulmonary hypertension, and active

infective endocarditis.

The normal response to graded exercise includes progressive

increases in heart rate and blood pressure. Failure of the blood pressure to increase or an actual decrease with signs of ischemia during

the test is an important adverse prognostic sign, since it may reflect

ischemia-induced global LV dysfunction. The development of angina

and/or severe (>0.2 mV) ST-segment depression at a low workload,

i.e., before completion of stage II of the Bruce protocol, and/or STsegment depression that persists >5 min after the termination of exercise increases the specificity of the test and suggests severe IHD and a

high risk of future adverse events.

Cardiac Imaging (See also Chap. 241) When the resting ECG is

abnormal (e.g., preexcitation syndrome, >1 mm of resting ST-segment

depression, left bundle branch block, paced ventricular rhythm),

information gained from an exercise test can be enhanced by stress

myocardial radionuclide perfusion imaging after the intravenous

administration of thallium-201 or 99m-technetium sestamibi during

exercise (or with pharmacologic) stress. Contemporary data also suggest positron emission tomography (PET) imaging (with exercise or

pharmacologic stress) using N-13 ammonia or rubidium-82 as another

technique for assessing perfusion. Images obtained immediately after

cessation of exercise to detect regional ischemia are compared with

those obtained at rest to confirm reversible ischemia and regions of

persistently absent uptake that signify infarction.

A sizable fraction of patients who need noninvasive stress testing

to identify myocardial ischemia and increased risk of coronary events

cannot exercise because of peripheral vascular or musculoskeletal

disease, exertional dyspnea, or deconditioning. In these circumstances,

an intravenous pharmacologic challenge is used in place of exercise.

For example, adenosine can be given to create a coronary “steal” by

temporarily increasing flow in nondiseased segments of the coronary

vasculature at the expense of diseased segments. Alternatively, a graded

incremental infusion of dobutamine may be administered to increase

MVO2

. A variety of imaging options are available to accompany these

pharmacologic stressors (Fig. 273-3). The development of a transient

perfusion defect with a tracer such as thallium-201 or 99m-technetium

sestamibi is used to detect myocardial ischemia.

Echocardiography is used to assess LV function in patients with

chronic stable angina and patients with a history of a prior myocardial infarction, pathologic Q waves, or clinical evidence of heart

failure. Two-dimensional echocardiography can assess both global and

regional wall motion abnormalities of the left ventricle that are transient when due to ischemia. Stress (exercise or dobutamine) echocardiography may cause the emergence of regions of akinesis or dyskinesis

that are not present at rest. Stress echocardiography, like stress myocardial perfusion imaging, is more sensitive than exercise electrocardiography in the diagnosis of IHD. Cardiac magnetic resonance (CMR)

stress testing is also evolving as an alternative to radionuclide, PET, or

echocardiographic stress imaging. CMR stress testing performed with

dobutamine infusion can be used to assess wall motion abnormalities

accompanying ischemia, as well as myocardial perfusion. CMR can be

used to provide more complete ventricular evaluation using multislice

magnetic resonance imaging (MRI) studies.

Atherosclerotic plaques become progressively calcified over time,

and coronary calcification in general increases with age. For this reason, methods for detecting coronary calcium have been developed as

a measure of the presence of coronary atherosclerosis. These methods

involve computed tomography (CT) applications that achieve rapid

acquisition of images (electron beam [EBCT] and multidetector

[MDCT] detection). Coronary calcium detected by these imaging

techniques most commonly is quantified by using the Agatston score,

which is based on the area and density of calcification.

2038 PART 6 Disorders of the Cardiovascular System

■ CORONARY ARTERIOGRAPHY

(See also Chap. 242) This diagnostic method outlines the lumina of

the coronary arteries and can be used to detect or exclude serious

coronary obstruction. However, coronary arteriography provides no

information about the arterial wall, and severe atherosclerosis that does

not encroach on the lumen may go undetected. Of note, atherosclerotic

plaques characteristically are scattered throughout the coronary tree,

tend to occur more frequently at branch points, and grow progressively

in the intima and media of an epicardial coronary artery at first without

encroaching on the lumen, causing an outward bulging of the artery—a

process referred to as remodeling. Later in the course of the disease,

further growth causes luminal narrowing.

Indications The ISCHEMIA trial informs decision-making about

referral for coronary arteriography (with intent to perform revascularization) in patients with stable IHD and an ejection fraction >35% even

in the presence of moderate-severe ischemia on noninvasive functional

testing. Over the course of 4 years of follow-up, early referral for an

invasive strategy was not associated with a reduction in the risk of

myocardial infarction or death but was more effective than an initial

conservative, medical strategy in relieving angina. Thus, coronary

arteriography is indicated in (1) patients with chronic stable angina

pectoris who are severely symptomatic despite medical therapy and are

being considered for revascularization, i.e., a percutaneous coronary

intervention (PCI) or coronary artery bypass grafting (CABG); (2)

patients with troublesome symptoms that present diagnostic difficulties in whom there is a need to confirm or rule out the diagnosis of

IHD; (3) patients with known or possible angina pectoris who have

survived cardiac arrest; and (4) patients with angina or evidence of

ischemia on noninvasive testing with clinical or laboratory evidence of

ventricular dysfunction.

Examples of other indications for coronary arteriography include

the following:

1. Patients with chest discomfort suggestive of angina pectoris but a

negative or nondiagnostic stress test who require a definitive diagnosis for guiding medical management, alleviating psychological

stress, career or family planning, or insurance purposes.

2. Patients who have been admitted repeatedly to the hospital for a

suspected acute coronary syndrome (Chaps. 274 and 275), but

in whom this diagnosis has not been established and in whom it

is considered clinically important to determine the presence or

absence of CAD.

3. Patients with careers that involve the safety of others (e.g., pilots,

firefighters, police) who have questionable symptoms or suspicious

or positive noninvasive tests and in whom there are reasonable

doubts about the state of the coronary arteries.

4. Patients with aortic stenosis or hypertrophic cardiomyopathy and

angina in whom the chest pain could be due to IHD.

5. Male patients >45 years and females >55 years who are to undergo a

cardiac operation such as valve replacement or repair and who may

or may not have clinical evidence of myocardial ischemia.

6. Patients after myocardial infarction, especially those who are at high

risk after myocardial infarction because of the recurrence of angina

or the presence of heart failure, frequent ventricular premature contractions, or signs of ischemia on the stress test.

7. Patients in whom coronary spasm or another nonatherosclerotic cause

of myocardial ischemia (e.g., coronary artery anomaly, Kawasaki

disease) is suspected.

Noninvasive alternatives to diagnostic coronary arteriography

include CT angiography and CMR angiography (Chap. 241). Although

these new imaging techniques can provide information about obstructive lesions in the epicardial coronary arteries, their exact role in

clinical practice has not been rigorously defined. Important aspects

of their use that should be noted include the substantially higher

radiation exposure with CT angiography compared to conventional

diagnostic arteriography and the limitations on CMR imposed by

cardiac movement during the cardiac cycle, especially at high heart

rates.

■ PROGNOSIS

The principal prognostic indicators in patients known to have IHD are

age, the functional state of the left ventricle, the location(s) and severity

of coronary artery narrowing, and the severity or activity of myocardial ischemia. Angina pectoris of recent onset, unstable angina (Chap.

274), early postmyocardial infarction angina, angina that is unresponsive or poorly responsive to medical therapy, and angina accompanied

by symptoms of congestive heart failure all indicate an increased risk

for adverse coronary events. The same is true for the physical signs

of heart failure, episodes of pulmonary edema, transient third heart

sounds, and mitral regurgitation and for echocardiographic or radioisotopic (or roentgenographic) evidence of cardiac enlargement and

reduced (<0.40) ejection fraction.

Most important, any of the following signs during noninvasive testing indicates a high risk for coronary events: inability to exercise for

6 min, i.e., stage II (Bruce protocol) of the exercise test; a strongly positive exercise test showing onset of myocardial ischemia at low workloads (≥0.1 mV ST-segment depression before completion of stage II,

≥0.2 mV ST-segment depression at any stage, ST-segment depression

for >5 min after the cessation of exercise, a decline in systolic pressure

>10 mmHg during exercise, or the development of ventricular tachyarrhythmias during exercise); the development of large or multiple

perfusion defects or increased lung uptake during stress radioisotope

perfusion imaging; and a decrease in LV ejection fraction during exercise on radionuclide ventriculography or during stress echocardiography. Conversely, patients who can complete stage III of the Bruce

exercise protocol and have a normal stress perfusion scan or negative

stress echocardiographic evaluation are at very low risk for future coronary events. The finding of frequent episodes of ST-segment deviation

on ambulatory ECG monitoring (even in the absence of symptoms) is

also an adverse prognostic finding.

On cardiac catheterization, elevations of LV end-diastolic pressure

and ventricular volume and reduced ejection fraction are the most

important signs of LV dysfunction and are associated with a poor prognosis. Patients with chest discomfort but normal LV function and normal coronary arteries have an excellent prognosis. Obstructive lesions

of the left main (>50% luminal diameter) or left anterior descending

coronary artery proximal to the origin of the first septal artery are associated with a greater risk than are lesions of the right or left circumflex

coronary artery because of the greater quantity of myocardium at risk.

Atherosclerotic plaques in epicardial arteries with fissuring or filling

defects indicate increased risk. These lesions go through phases of

inflammatory cellular activity, degeneration, endothelial dysfunction,

abnormal vasomotion, platelet aggregation, and fissuring or hemorrhage. These factors can temporarily worsen the stenosis and cause

thrombosis and/or abnormal reactivity of the vessel wall, thus exacerbating the manifestations of ischemia. The recent onset of symptoms,

the development of severe ischemia during stress testing (see above),

and unstable angina pectoris (Chap. 274) all reflect episodes of rapid

progression in coronary lesions.

With any degree of obstructive CAD, mortality is greatly increased

when LV function is impaired; conversely, at any level of LV function,

the prognosis is influenced importantly by the quantity of myocardium

perfused by critically obstructed vessels. Therefore, it is essential to collect all the evidence substantiating past myocardial damage (evidence

of myocardial infarction on ECG, echocardiography, radioisotope

imaging, or left ventriculography), residual LV function (ejection fraction and wall motion), and risk of future damage from coronary events

(extent of coronary disease and severity of ischemia defined by noninvasive stress testing). The larger the quantity of established myocardial

necrosis is, the less the heart is able to withstand additional damage and

the poorer the prognosis is. Risk estimation must include age, presenting symptoms, all risk factors, signs of arterial disease, existing cardiac

damage, and signs of impending damage (i.e., ischemia).

The greater the number and severity of risk factors for coronary

atherosclerosis (advanced age [>75 years], hypertension, dyslipidemia,

diabetes, morbid obesity, accompanying peripheral and/or cerebrovascular disease, previous myocardial infarction), the worse the prognosis

of an angina patient. Evidence exists that elevated levels of CRP in the

Ischemic Heart Disease

2039CHAPTER 273

plasma, extensive coronary calcification on EBCT (see above), and

increased carotid intimal thickening on ultrasound examination also

indicate an increased risk of coronary events.

TREATMENT

Stable Angina Pectoris

Once the diagnosis of IHD has been made, each patient must be

evaluated individually with respect to his or her level of understanding, expectations and goals, control of symptoms, and prevention of adverse clinical outcomes such as myocardial infarction

and premature death. The degree of disability and the physical and

emotional stress that precipitates angina must be recorded carefully

to set treatment goals. The management plan should include the

following components: (1) explanation of the problem and reassurance about the ability to formulate a treatment plan, (2) identification and treatment of aggravating conditions, (3) recommendations

for adaptation of activity as needed, (4) treatment of risk factors

that will decrease the occurrence of adverse coronary outcomes, (5)

drug therapy for angina, and (6) consideration of revascularization.

EXPLANATION AND REASSURANCE

Patients with IHD need to understand their condition and realize

that a long and productive life is possible even though they have

angina pectoris or have experienced and recovered from an acute

myocardial infarction. Offering results of clinical trials showing

improved outcomes can be of great value in encouraging patients to

resume or maintain activity and return to work. A planned program

of rehabilitation can encourage patients to lose weight, improve

exercise tolerance, and control risk factors with more confidence.

IDENTIFICATION AND TREATMENT OF AGGRAVATING

CONDITIONS

A number of conditions may increase oxygen demand or decrease

oxygen supply to the myocardium and may precipitate or exacerbate

angina in patients with IHD. LVH, aortic valve disease, and hypertrophic cardiomyopathy may cause or contribute to angina and

should be excluded or treated. Obesity, hypertension, and hyperthyroidism should be treated aggressively to reduce the frequency

and severity of anginal episodes. Decreased myocardial oxygen

supply may be due to reduced oxygenation of the arterial blood

(e.g., in pulmonary disease or, when carboxyhemoglobin is present, due to cigarette or cigar smoking) or decreased oxygencarrying capacity (e.g., in anemia). Correction of these abnormalities, if present, may reduce or even eliminate angina pectoris.

ADAPTATION OF ACTIVITY

Myocardial ischemia is caused by a discrepancy between the

demand of the heart muscle for oxygen and the ability of the

coronary circulation to meet that demand. Most patients can be

helped to understand this concept and utilize it in the rational

programming of activity. Many tasks that ordinarily evoke angina

may be accomplished without symptoms simply by reducing the

speed at which they are performed. Patients must appreciate the

diurnal variation in their tolerance of certain activities and should

reduce their energy requirements in the morning, immediately after

meals, and in cold or inclement weather. On occasion, it may be

necessary to recommend a change in employment or residence to

avoid physical stress.

Physical conditioning usually improves the exercise tolerance

of patients with angina and has substantial psychological benefits.

A regular program of isotonic exercise that is within the limits of

the individual patient’s threshold for the development of angina

pectoris and that does not exceed 80% of the heart rate associated

with ischemia on exercise testing should be strongly encouraged.

Based on the results of an exercise test, the number of metabolic

equivalent tasks (METs) performed at the onset of ischemia can be

estimated (Table 273-2) and a practical exercise prescription can be

formulated to permit daily activities that will fall below the ischemic

threshold (Table 273-3).

TABLE 273-3 Energy Requirements for Some Common Activities

LESS THAN 3 METs 3–5 METs 5–7 METs 7–9 METs MORE THAN 9 METs

Self-Care

Washing/shaving Cleaning windows Easy digging in garden Heavy shoveling Carrying loads upstairs (objects >90 lb)

Dressing Raking Level hand lawn mowing Carrying objects (60–90 lb) Climbing stairs (quickly)

Light housekeeping Power lawn mowing Carrying objects (30–60 lb) Shoveling heavy snow

Desk work Bed making/stripping

Driving auto Carrying objects (15–30 lb)

Occupational

Sitting (clerical/assembly) Stocking shelves (light objects) Carpentry (exterior) Digging ditches (pick and

shovel) 

Heavy labor

Desk work Light welding/carpentry Shoveling dirt

Standing (store clerk) Sawing wood

Recreational

Golf (cart) Dancing (social) Tennis (singles) Canoeing Squash

Knitting Golf (walking) Snow skiing (downhill) Mountain climbing Ski touring

Sailing Light backpacking Vigorous basketball

Tennis (doubles) Basketball

Stream fishing

Physical Conditioning

Walking (2 mph) Level walking (3–4 mph) Level walking (4.5–5.0 mph) Level jogging (5 mph) Running more than 6 mph

Stationary bike Level biking (6–8 mph) Bicycling (9–10 mph) Swimming (crawl stroke) Bicycling (more than 13 mph)

Very light calisthenics Light calisthenics Swimming, breast stroke Rowing machine Rope jumping

Heavy calisthenics Walking uphill (5 mph)

Bicycling (12 mph)

Abbreviation: METs, metabolic equivalent tasks.

Source: Modified from WL Haskell: Rehabilitation of the coronary patient, in NK Wenger, HK Hellerstein (eds): Design and Implementation of Cardiac Conditioning Program.

New York, Churchill Livingstone, 1978.

2040 PART 6 Disorders of the Cardiovascular System

TABLE 273-4 Nitrate Therapy in Patients with Ischemic Heart Disease

PREPARATION OF AGENT DOSE SCHEDULE

Nitroglycerina

Ointment 0.5–2 in. Two or three times daily

Transdermal patch 0.2–0.8 mg/h Every 24 h; remove at bedtime

for 12–14 h

Sublingual tablet 0.3–0.6 mg As needed, up to three doses

5 min apart

Spray One or two sprays As needed, up to three doses

5 min apart

Isosorbide dinitratea

Oral 10–40 mg Two or three times daily

Oral sustained release 80–120 mg Once or twice daily (eccentric

schedules)

Isosorbide 5-mononitrate

Oral 20 mg Twice daily (given 7–8 h apart)

Oral sustained release 30–240 mg Once daily

a

A 10- to 12-h nitrate-free interval is recommended.

Source: Reproduced with permission from DA Morrow, WE Boden: Stable ischemic

heart disease. In RO Bonow et al (eds): Braunwald’s Heart Disease: A Textbook of

Cardiovascular Medicine, 9th ed. Philadelphia, Saunders, 2012.

TABLE 273-5 Properties of Beta Blockers in Clinical Use for Ischemic

Heart Disease

DRUGS SELECTIVITY

PARTIAL

AGONIST

ACTIVITY USUAL DOSE FOR ANGINA

Acebutolol β1 Yes 200–600 mg twice daily

Atenolol β1 No 50–200 mg/d

Betaxolol β1 No 10–20 mg/d

Bisoprolol β1 No 10 mg/d

Esmolol

(intravenous)a

β1 No 50–300 μg/kg/min

Labetalolb None Yes 200–600 mg twice daily

Metoprolol β1 No 50–200 mg twice daily

Nadolol None No 40–80 mg/d

Nebivolol β1

 (at low doses) No 5–40 mg/d

Pindolol None Yes 2.5–7.5 mg 3 times daily

Propranolol None No 80–120 mg twice daily

Timolol None No 10 mg twice daily

a

Esmolol is an ultra-short-acting beta blocker that is administered as a continuous

intravenous infusion. Its rapid offset of action makes esmolol an attractive agent

to use in patients with relative contraindications to beta blockade. b

Labetolol is a

combined alpha and beta blocker.

Note: This list of beta blockers that may be used to treat patients with angina

pectoris is arranged alphabetically. It is preferable to use a sustained-release

formulation that may be taken once daily to improve the patient’s compliance with

the regimen.

Source: Data from RJ Gibbons et al: J Am Coll Cardiol 41:159, 2003.

TREATMENT OF RISK FACTORS

A family history of premature IHD is an important indicator of

increased risk and should trigger a search for treatable risk factors

such as hyperlipidemia, hypertension, and diabetes mellitus. Obesity impairs the treatment of other risk factors and increases the risk

of adverse coronary events. In addition, obesity often is accompanied by three other risk factors: diabetes mellitus, hypertension, and

hyperlipidemia. The treatment of obesity and these accompanying

risk factors is an important component of any management plan.

A diet low in saturated and trans-unsaturated fatty acids and a

reduced caloric intake to achieve optimal body weight are a cornerstone in the management of chronic IHD. It is especially important

to emphasize weight loss and regular exercise in patients with the

metabolic syndrome or overt diabetes mellitus.

Cigarette smoking accelerates coronary atherosclerosis in both

sexes and at all ages and increases the risk of thrombosis, plaque

instability, myocardial infarction, and death. In addition, by

increasing myocardial oxygen needs and reducing oxygen supply,

it aggravates angina. Smoking cessation studies have demonstrated

important benefits with a significant decline in the occurrence of

these adverse outcomes. Noncombustible tobacco in the form of

electronic cigarettes (nicotine delivery systems) may also increase

the frequency of anginal episodes. The physician’s message must be

clear and strong and supported by programs that achieve and monitor abstinence from all tobacco product use (Chap. 454).

Hypertension (Chap. 277) may coexist with other risk factors for

IHD and is associated with an increased risk of adverse clinical events

from coronary atherosclerosis as well as stroke. In addition, the LVH

that results from sustained hypertension aggravates ischemia. There

is evidence that long-term effective treatment of hypertension can

decrease the occurrence of adverse coronary events (Chap. 277).

Diabetes mellitus (Chap. 403) accelerates coronary and peripheral atherosclerosis and is frequently associated with dyslipidemia

and increases in the risk of angina, myocardial infarction, and sudden coronary death. Aggressive control of the dyslipidemia (target

LDL cholesterol <70 mg/dL) and hypertension (blood pressure

<130/80 mmHg) that are frequently found in diabetic patients is

highly effective and therefore essential, as described below.

DYSLIPIDEMIA

The treatment of dyslipidemia is central in aiming for long-term

relief from angina, reduced need for revascularization, and reduction in myocardial infarction and death. The control of lipids can

be achieved by the combination of a diet low in saturated and

trans-unsaturated fatty acids, exercise, and weight loss. Nearly

always, HMG-CoA reductase inhibitors (statins) are required and

can lower LDL cholesterol (25–50%), raise HDL cholesterol (5–9%),

and lower triglycerides (5–30%). A powerful treatment effect of statins on atherosclerosis, IHD, and outcomes is seen regardless of the

pretreatment LDL cholesterol level. Fibrates, niacin, and icosapent

ethyl can be used to lower triglycerides (Chap. 407). Controlled

trials with lipid-regulating regimens have shown equal proportional

benefit for men, women, the elderly, diabetic patients, and smokers.

Injectable monoclonal antibodies against PCSK9 are now available

and are important disease-modifying treatments capable of producing dramatic lowering of LDL cholesterol beyond that achieved with

a statin alone or a combination of a statin plus ezetimibe.

Compliance with the health-promoting behaviors listed above is

generally very poor, and a conscientious physician must not underestimate the major effort required to meet this challenge. Many

patients who are discharged from the hospital with proven coronary

disease do not receive adequate treatment for dyslipidemia. In light

of the proof that treating dyslipidemia brings major benefits, physicians need to establish treatment pathways, monitor compliance,

and follow up regularly.

RISK REDUCTION IN WOMEN WITH IHD

The incidence of clinical IHD in premenopausal women is very

low; however, after menopause, the atherogenic risk factors increase

(e.g., increased LDL) and the rate of clinical coronary events

accelerates to the levels observed in men. Diabetes mellitus, which

is more common in women, greatly increases the occurrence of

clinical IHD and amplifies the deleterious effects of hypertension,

hyperlipidemia, and smoking. Cardiac catheterization and coronary

revascularization are underused in women and are performed at a

later and more severe stage of the disease than in men. When cholesterol lowering, beta blockers after myocardial infarction, and CABG

are applied in the appropriate patient groups, women benefit to the

same degree as men.

DRUG THERAPY

The commonly used drugs for the treatment of angina pectoris are

summarized in Tables 273-4 through 273-6. Pharmacotherapy

for IHD is designed to reduce the frequency of anginal episodes,

Ischemic Heart Disease

2041CHAPTER 273

TABLE 273-6 Calcium Channel Blockers in Clinical Use for Ischemic

Heart Disease

DRUGS USUAL DOSE

DURATION OF

ACTION SIDE EFFECTS

Dihydropyridines

Amlodipine 5–10 mg qd Long Headache, edema

Felodipine 5–10 mg qd Long Headache, edema

Isradipine 2.5–10 mg bid Medium Headache, fatigue

Nicardipine 20–40 mg tid Short Headache, dizziness,

flushing, edema

Nifedipine Immediate release:a

30–90 mg daily

orally

Slow release:

30–180 mg orally

Short Hypotension, dizziness,

flushing, nausea,

constipation, edema

Nisoldipine 20–40 mg qd Short Similar to nifedipine

Nondihydropyridines

Diltiazem Immediate release:

30–80 mg 4 times

daily

Short Hypotension, dizziness,

flushing, bradycardia,

edema

Slow release:

120–320 mg qd

Long

Verapamil Immediate release:

80–160 mg tid

Short Hypotension,

myocardial depression,

Slow release:

120–480 mg qd

Long heart failure, edema,

bradycardia

a

May be associated with increased risk of mortality if administered during acute

myocardial infarction.

Note: This list of calcium channel blockers that may be used to treat patients

with angina pectoris is divided into two broad classes, dihydropyridines and

nondihydropyridines, and arranged alphabetically within each class. Among

the dihydropyridines, the greatest clinical experience has been obtained with

amlodipine and nifedipine. After the initial period of dose titration with a shortacting formulation, it is preferable to switch to a sustained-release formulation that

may be taken once daily to improve patient compliance with the regimen.

Source: Data from RJ Gibbons et al: J Am Coll Cardiol 41:159, 2003.

myocardial infarction, and coronary death. Trial data emphasize

how important medical management is when added to the healthpromoting behaviors discussed above. To achieve maximum benefit

from medical therapy for IHD, it is frequently necessary to combine agents from different classes and titrate the doses as guided

by the individual profile of risk factors, symptoms, hemodynamic

responses, and side effects.

NITRATES

The organic nitrates are a valuable class of drugs in the management

of angina pectoris (Table 273-4). Their major mechanisms of action

include systemic venodilation with concomitant reduction in LV

end-diastolic volume and pressure, thereby reducing myocardial

wall tension and oxygen requirements; dilation of epicardial coronary vessels; and increased blood flow in collateral vessels. When

metabolized, organic nitrates release nitric oxide (NO) that binds

to guanylyl cyclase in vascular smooth muscle cells, leading to an

increase in cyclic guanosine monophosphate, which causes relaxation of vascular smooth muscle. Nitrates also exert antithrombotic

activity by NO-dependent activation of platelet guanylyl cyclase,

impairment of intraplatelet calcium flux, and platelet activation.

The absorption of these agents is rapid and complete through

mucous membranes. For this reason, nitroglycerin is most commonly administered sublingually in tablets of 0.4 or 0.6 mg. Patients

with angina should be instructed to take the medication both to

relieve angina and also ~5 min before activities that are likely to

induce an episode.

Nitrates improve exercise tolerance in patients with chronic

angina and relieve ischemia in patients with unstable angina as well

as patients with Prinzmetal’s variant angina (Chap. 274). A diary of

angina and nitroglycerin use may be valuable for detecting changes

in the frequency, severity, or threshold for discomfort that may

signify the development of unstable angina pectoris and/or herald

an impending myocardial infarction.

Long-Acting Nitrates None of the long-acting nitrates is as

effective as sublingual nitroglycerin for the acute relief of angina.

These organic nitrate preparations can be swallowed, chewed, or

administered as a patch or paste by the transdermal route (Table

273-4). They provide effective plasma levels for up to 24 h, but

the therapeutic response is highly variable. Different preparations

and/or administration during the daytime should be tried only to

prevent discomfort while avoiding side effects such as headache

and dizziness. Individual dose titration is important to prevent side

effects. To minimize the effects of nitrate tolerance, the minimum

effective dose should be used and a minimum of 8 h each day kept

free of the drug to restore any useful response(s).

a-Adrenergic Blockers These drugs represent an important component of the pharmacologic treatment of angina pectoris (Table

273-5). They reduce myocardial oxygen demand by inhibiting the

increases in heart rate, arterial pressure, and myocardial contractility caused by adrenergic activation. Beta blockade reduces these

variables most strikingly during exercise but causes only small

reductions at rest. Long-acting beta-blocking drugs or sustainedrelease formulations offer the advantage of once-daily dosing (Table

273-5). The therapeutic aims include relief of angina and ischemia.

These drugs also can reduce mortality and reinfarction rates in

patients after myocardial infarction and are moderately effective

antihypertensive agents.

Relative contraindications include asthma and reversible airway

obstruction in patients with chronic lung disease, atrioventricular

conduction disturbances, severe bradycardia, Raynaud’s phenomenon, and a history of mental depression. Side effects include fatigue,

reduced exercise tolerance, nightmares, impotence, cold extremities, intermittent claudication, bradycardia (sometimes severe),

impaired atrioventricular conduction, LV failure, bronchial asthma,

worsening claudication, and intensification of the hypoglycemia

produced by oral hypoglycemic agents and insulin. Reducing the

dose or even discontinuation may be necessary if these side effects

develop and persist. Since sudden discontinuation can intensify

ischemia, the doses should be tapered over 2 weeks. Beta blockers

with relative β1

-receptor specificity such as metoprolol and atenolol

may be preferable in patients with mild bronchial obstruction and

insulin-requiring diabetes mellitus.

Calcium Channel Blockers Calcium channel blockers (Table 273-6)

are coronary vasodilators that produce variable and dose-dependent

reductions in myocardial oxygen demand, contractility, and arterial

pressure. These combined pharmacologic effects are advantageous

and make these agents as effective as beta blockers in the treatment of angina pectoris. They are indicated when beta blockers

are contraindicated, poorly tolerated, or ineffective. Because of

differences in the dose-response relationship on cardiac electrical

activity between the dihydropyridine and nondihydropyridine

calcium channel blockers, verapamil and diltiazem may produce

symptomatic disturbances in cardiac conduction and bradyarrhythmias. They also exert negative inotropic actions and are more likely

to aggravate LV failure, particularly when used in patients with

LV dysfunction, especially if the patients are also receiving beta

blockers. Although useful effects usually are achieved when calcium

channel blockers are combined with beta blockers and nitrates,

individual titration of the doses is essential with these combinations. Variant (Prinzmetal’s) angina responds particularly well to

calcium channel blockers (especially members of the dihydropyridine class), supplemented when necessary by nitrates (Chap. 274).

Verapamil ordinarily should not be combined with beta blockers

because of the combined adverse effects on heart rate and contractility. Diltiazem can be combined with beta blockers in patients

with normal ventricular function and no conduction disturbances.

Amlodipine and beta blockers have complementary actions on coronary blood supply and myocardial oxygen demands. Whereas the

2042 PART 6 Disorders of the Cardiovascular System

former decreases blood pressure and dilates coronary arteries, the

latter slows heart rate and decreases contractility. Amlodipine and

the other second-generation dihydropyridine calcium antagonists

(nicardipine, isradipine, long-acting nifedipine, and felodipine) are

potent vasodilators and are useful in the simultaneous treatment of

angina and hypertension. Short-acting dihydropyridines should be

avoided because of the risk of precipitating infarction, particularly

in the absence of concomitant beta blocker therapy.

Choice Between Beta Blockers and Calcium Channel Blockers for

Initial Therapy Since beta blockers have been shown to improve

life expectancy after acute myocardial infarction (Chaps. 274 and

275) and calcium channel blockers have not, the former may also

be preferable in patients with angina and a damaged left ventricle.

However, calcium channel blockers are indicated in patients with

the following: (1) inadequate responsiveness to the combination

of beta blockers and nitrates; many of these patients do well with a

combination of a beta blocker and a dihydropyridine calcium channel blocker; (2) adverse reactions to beta blockers such as depression, sexual disturbances, and fatigue; (3) angina and a history of

asthma or chronic obstructive pulmonary disease; (4) sick-sinus

syndrome or significant atrioventricular conduction disturbances;

(5) Prinzmetal’s angina; or (6) symptomatic peripheral arterial

disease.

A comparison of the common side effects, contraindications,

and potential drug interactions of many of the frequently presented

antianginal agents is shown in Table 273-7.

Antiplatelet Drugs Aspirin is an irreversible inhibitor of platelet cyclooxygenase and thereby interferes with platelet activation.

Chronic administration of 75–325 mg orally per day has been shown

to reduce coronary events in asymptomatic adult men over age 50,

patients with chronic stable angina, and patients who have or have

survived unstable angina and myocardial infarction. There is a

dose-dependent increase in bleeding when aspirin is used chronically. It is preferable to use an enteric-coated formulation in the range

of 81–162 mg/d. Administration of this drug should be considered

in all patients with IHD in the absence of gastrointestinal bleeding, allergy, or dyspepsia. Clopidogrel (300–600 mg loading and

75 mg/d) is an oral agent that blocks P2Y12 ADP receptor–mediated

platelet aggregation. It provides benefits similar to those of aspirin

in patients with stable chronic IHD and may be substituted for

aspirin if aspirin causes the side effects listed above. Clopidogrel

combined with aspirin reduces death and coronary ischemic events

in patients with an acute coronary syndrome (Chap. 274) and also

reduces the risk of thrombus formation in patients undergoing

implantation of a stent in a coronary artery (Chap. 276). Alternative antiplatelet agents that block the P2Y12 platelet receptor such as

prasugrel and ticagrelor have been shown to be more effective than

clopidogrel for prevention of ischemic events after placement of a

stent for an acute coronary syndrome but are associated with an

increased risk of bleeding. Although combined treatment with clopidogrel and aspirin for at least a year is recommended in patients

with an acute coronary syndrome treated with implantation of a

drug-eluting stent, studies have not shown any benefit from the

routine addition of clopidogrel to aspirin in patients with chronic

stable IHD.

OTHER THERAPIES

The ACE inhibitors are widely used in the treatment of survivors

of myocardial infarction, patients with hypertension or chronic

IHD including angina pectoris, and those at high risk of vascular

diseases such as diabetes. The benefits of ACE inhibitors are most

evident in IHD patients at increased risk, especially if diabetes mellitus or LV dysfunction is present, and those who have not achieved

adequate control of blood pressure and LDL cholesterol on beta

blockers and statins. However, the routine administration of ACE

inhibitors to IHD patients who have normal LV function and have

achieved blood pressure and LDL goals on other therapies does not

reduce the incidence of events and therefore is not cost-effective.

Despite treatment with nitrates, beta blockers, or calcium channel blockers, some patients with IHD continue to experience

angina, and additional medical therapy is now available to alleviate

their symptoms. Ranolazine, a piperazine derivative, may be useful

for patients with chronic angina despite standard medical therapy

(Table 273-7). Its antianginal action is believed to occur via inhibition of the late inward sodium current (INa). The benefits of INa

inhibition include limitation of the Na overload of ischemic myocytes and prevention of Ca2+ overload via the Na+–Ca2+ exchanger.

A dose of 500–1000 mg orally twice daily is usually well tolerated.

Ranolazine is contraindicated in patients with hepatic impairment

TABLE 273-7 Antianginal Agents

AGENT COMMON SIDE EFFECTS CONTRAINDICATIONS POTENTIAL DRUG INTERACTIONS

Agents That Have a Physiologic Effect

Short-acting and long-acting

nitrates

Headache, flushing, hypotension,

syncope and postural hypotension,

reflex tachycardia, methemoglobinemia

Hypertrophic obstructive cardiomyopathy Phosphodiesterase type 5 inhibitors

(sildenafil and similar agents), betaadrenergic blockers, calcium channel

blockers

Beta blockers Fatigue, depression, bradycardia,

heart block, bronchospasm, peripheral

vasoconstriction, postural hypotension,

impotence, masked signs of

hypoglycemia

Low heart rate or heart conduction disorder,

cardiogenic shock, asthma, severe peripheral

vascular disease, decompensated heart failure,

vasospastic angina; use with caution in patients

with COPD (cardioselective beta blockers may be

used if patient receives adequate treatment with

long-acting beta agonists)

Heart rate–lowering calcium channel

blockers, sinus node or AV conduction

depressors

Calcium-channel blockers

Heart rate–lowering agents Bradycardia, heart conduction defect,

low ejection fraction, constipation,

gingival hyperplasia

Cardiogenic shock, severe aortic stenosis,

obstructive cardiomyopathy

CYP3A4 substrates (digoxin, simvastatin,

cyclosporine)

Dihydropyridine Headache, ankle swelling fatigue,

flushing, reflex tachycardia

Low heart rate or heart rhythm disorder, sick-sinus

syndrome, congestive heart failure, low blood

pressure

Agents with cardiodepressant effects

(beta blockers, flecainide), CYP3A4

substrates

Agents That Affect Myocardial Metabolism

Ranolazine Dizziness, constipation, nausea, QT

interval prolongation

Liver cirrhosis CYP3A4 substrates (digoxin, simvastatin,

cyclosporine), drugs that prolong the

corrected QT interval

Abbreviations: AV, atrioventricular; COPD, chronic obstructive pulmonary disease; CYP3A4, cytochrome P450 3A4.

Source: Data from SE Husted: Lancet 386:691, 2015, and EM Ohman: N Engl J Med 374:1167, 2016.