topics

11/6/25

Ischemic Heart Disease

2043CHAPTER 273

or with conditions or drugs associated with QTc

prolongation and

when drugs that inhibit the CYP3A metabolic system (e.g., ketoconazole, diltiazem, verapamil, macrolide antibiotics, HIV protease

inhibitors, and large quantities of grapefruit juice) are being used.

Originally introduced for the management of diabetes mellitus, the sodium-glucose cotransporter-2 inhibitor (SGLT2i) drugs

have emerged as important agents with cardiovascular and renal

protective effects. They promote weight loss, lower blood pressure,

and reduce plasma volume—all of which are desirable in patients

with IHD. In addition, they decrease intraglomerular hypertension and hyperfiltration. Evidence exists that they are helpful in

patients with and without diabetes who have a reduced LV ejection fraction. Nonsteroidal anti-inflammatory drug (NSAID) use

in patients with IHD may be associated with a small but finite

increased risk of myocardial infarction and mortality. For this

reason, they generally should be avoided in IHD patients. If they

are required for symptom relief, it is advisable to coadminister

aspirin and strive to use an NSAID associated with the lowest risk

of cardiovascular events, in the lowest dose required, and for the

shortest period of time.

Another class of agents opens ATP-sensitive potassium channels

in myocytes, leading to a reduction of free intracellular calcium

ions. The major drug in this class is nicorandil, which typically is

administered orally in a dose of 20 mg twice daily for prevention of

angina. (Nicorandil is not available for use in the United States but

is used in several other countries.)

Ivabradine (2.5–7.5 mg orally twice daily) is a specific sinus node

inhibiting agent that may be helpful for preventing cardiovascular

events in patients with IHD who have a resting heart rate ≥70 beats/

min (alone or in combination with a beta blocker) and LV systolic

dysfunction.

Angina and Heart Failure Transient LV failure with angina can be

controlled by the use of nitrates. For patients with established congestive heart failure, the increased LV wall tension raises myocardial

oxygen demand. Treatment of congestive heart failure (Chap. 257)

reduces heart size, wall tension, and myocardial oxygen demand,

which helps control angina and ischemia. If the symptoms and signs

of heart failure are controlled, an effort should be made to use beta

blockers not only for angina but because trials in heart failure have

shown significant improvement in survival. A trial of the intravenous ultra-short-acting beta blocker esmolol may be useful to

establish the safety of beta blockade in selected patients. Nocturnal

angina often can be relieved by the treatment of heart failure.

The combination of congestive heart failure and angina in

patients with IHD usually indicates a poor prognosis and warrants serious consideration of cardiac catheterization and coronary

revascularization.

CORONARY REVASCULARIZATION

Clinical trials have confirmed that with the initial diagnosis of stable

IHD, it is first appropriate to initiate a medical regimen as described

above. Revascularization should be considered in the presence of

unstable phases of the disease, intractable symptoms, high-risk coronary anatomy, diabetes, and impaired LV function. Revascularization

should be employed in conjunction with but not replace the continuing

need to modify risk factors and assess medical therapy. An algorithm for

integrating medical therapy and revascularization options in patients

with IHD is shown in Fig. 273-4.

■ PERCUTANEOUS CORONARY INTERVENTION

(See also Chap. 276) PCI involving balloon dilatation usually accompanied by coronary stenting is widely used to achieve revascularization

of the myocardium in patients with symptomatic IHD and suitable

stenoses of epicardial coronary arteries. Whereas patients with stenosis of the left main coronary artery and those with three-vessel IHD

(especially with diabetes and/or impaired LV function) who require

revascularization are best treated with CABG, PCI is widely employed

in patients with symptoms and evidence of ischemia due to stenoses

of one or two vessels and even in selected patients with three-vessel

disease (and, perhaps, in some patients with left main disease) and may

offer many advantages over surgery.

Indications and Patient Selection The most common clinical

indication for PCI is symptom-limiting angina pectoris, despite medical therapy, accompanied by evidence of ischemia during a stress test.

PCI is more effective than medical therapy for the relief of angina. PCI

improves outcomes in patients with unstable angina or when used early

in the course of myocardial infarction with and without cardiogenic

shock. However, in patients with stable exertional angina, clinical trials

have confirmed that PCI does not reduce the occurrence of death or

myocardial infarction compared to optimum medical therapy. PCI can

be used to treat stenoses in native coronary arteries as well as in bypass

grafts in patients who have recurrent angina after CABG.

Risks When coronary stenoses are discrete and symmetric, two and

even three vessels can be treated in sequence. However, case selection is

essential to avoid a prohibitive risk of complications, which are usually

due to dissection or thrombosis with vessel occlusion, uncontrolled

ischemia, and ventricular failure (Chap. 276). Oral aspirin, a P2Y12

antagonist, and an antithrombin agent are given to reduce coronary

thrombus formation. Left main coronary artery stenosis generally is

Initiate medical therapy:

1. Decrease demand ischemia

2. Minimize IHD risk factors

3. ASA (clopidogrel if ASA intolerant)

Any high-risk features?

Low exercise capacity or ischemia at low workload,

EF <40%, ACS presentation

No Yes

Are exertional

symptoms controlled?

Refer for coronary

arteriography

Yes No

Single-vessel

disease

LM +/or multivessel disease

PCI Assess:

PCI vs CABG

Consider

unconventional

treatments

Continue medical therapy periodic stress assessment

(see Fig. 273-3)

Anatomy suitable

for revascularization?

FIGURE 273-4 Algorithm for management of a patient with ischemic heart disease.

All patients should receive the core elements of medical therapy as shown at the

top of the algorithm. If high-risk features are present, as established by the clinical

history, exercise test data, and imaging studies, the patient should be referred for

coronary arteriography. Based on the number and location of the diseased vessels

and their suitability for revascularization, the patient is treated with a percutaneous

coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery or should

be considered for unconventional treatments. See text for further discussion. ACS,

acute coronary syndrome; ASA, aspirin; EF, ejection fraction; IHD, ischemic heart

disease; LM, left main.

2044 PART 6 Disorders of the Cardiovascular System

regarded as a lesion that should be treated with CABG. In selected

cases such as patients with prohibitive surgical risks, PCI of an unprotected left main can be considered, but such a procedure should be

performed only by a highly skilled operator; importantly, there are

regional differences in the use of this approach internationally.

Efficacy Primary success, with relief of angina, is achieved in >95%

of cases. Recurrent stenosis of the dilated vessels occurs in ~20% of

cases within 6 months of PCI with bare metal stents, and angina will

recur within 6 months in 10% of cases. Restenosis is more common in

patients with diabetes mellitus, arteries with small caliber, incomplete

dilation of the stenosis, long stents, occluded vessels, obstructed vein

grafts, dilation of the left anterior descending coronary artery, and stenoses containing thrombi. In diseased vein grafts, procedural success

has been improved by the use of capture devices or filters that prevent

embolization, ischemia, and infarction.

It is usual clinical practice to administer oral aspirin indefinitely

and a P2Y12 antagonist for 1–3 months after the implantation of a bare

metal stent. Although aspirin in combination with a thienopyridine

may help prevent coronary thrombosis during and shortly after PCI

with stenting, there is no evidence that these medications reduce the

incidence of restenosis.

The use of current-generation drug-eluting stents that locally deliver

antiproliferative drugs can reduce restenosis to <5%. Advances in PCI,

especially the availability of drug-eluting stents, have vastly extended

the use of this revascularization option in patients with IHD. Of note,

however, the delayed endothelial healing in the region of a drugeluting stent also extends the period during which the patient is at risk

for subacute stent thrombosis. Aspirin should be administered indefinitely and a P2Y12 antagonist daily (dual antiplatelet therapy [DAPT])

for at least 1 year after implantation of a drug-eluting stent. Evidence

exists of a benefit of continuing DAPT for up to 30 months, albeit at the

cost of a higher risk of bleeding.

Efforts are underway to develop new antithrombotic regimens.

These include (1) shortening the duration of DAPT by eliminating

aspirin after 3 months and continuing a potent P2Y12 antagonist (e.g.,

ticagrelor) and (2) switching from DAPT to dual pathway inhibition

with an antiplatelet agent and a low-dose direct oral anticoagulant (a

particularly attractive option for IHD patients who also have atrial

fibrillation). The relative benefits of such new regimens have not been

established and no consensus has been achieved, as yet.

When a situation arises in which temporary discontinuation of

antiplatelet therapy is necessary, the clinical circumstances should be

reviewed with the operator who performed the PCI and a coordinated

plan should be established for minimizing the risk of late stent thrombus; central to this plan is the discontinuation of antiplatelet therapy

for the shortest acceptable period. The risk of stent thrombosis is

dependent on stent size and length, complexity of the lesions, age, diabetes, and technique. However, compliance with DAPT and individual

responsiveness to platelet inhibition are very important factors as well.

Successful PCI produces effective relief of angina in >95% of cases.

The majority of patients with symptomatic IHD who require revascularization can be treated initially by PCI. Successful PCI is less invasive

and expensive than CABG and permits savings in the initial cost of

care. Successful PCI avoids the risk of stroke associated with CABG

surgery and allows earlier return to work and resumption of an active

life. However, the early health-related and economic benefits of PCI

are reduced over time because of the greater need for follow-up and

the increased need for repeat procedures. When directly compared in

patients with diabetes or three-vessel or left main CAD, CABG was

superior to PCI in preventing major adverse cardiac or cerebrovascular

events over a 12-month follow-up.

■ CORONARY ARTERY BYPASS GRAFTING

Anastomosis of one or both of the internal mammary arteries or a

radial artery to the coronary artery distal to the obstructive lesion is

the preferred procedure. For additional obstructions that cannot be

bypassed by an artery, a section of a vein (usually the saphenous) is

used to form a venous bypass conduit between the aorta and the coronary artery distal to the obstructive lesion.

Although some indications for CABG are controversial, certain

areas of agreement exist:

1. The operation is relatively safe, with mortality rates <1% in patients

without serious comorbid disease and normal LV function and

when the procedure is performed by an experienced surgical team.

2. Intraoperative and postoperative mortality rates increase with the

severity of ventricular dysfunction, comorbidities, age >80 years,

and lack of surgical experience. The effectiveness and risk of CABG

vary widely depending on case selection and the skill and experience

of the surgical team.

3. Occlusion of venous grafts is observed in 10–20% of patients during

the first postoperative year and in ~2% per year during 5- to 7-year

follow-up and 4% per year thereafter. Long-term patency rates

are considerably higher for internal mammary and radial artery

implantations than for saphenous vein grafts. In patients with left

anterior descending coronary artery obstruction, survival is better

when coronary bypass involves the internal mammary artery rather

than a saphenous vein. Graft patency and outcomes are improved

by meticulous treatment of risk factors, particularly dyslipidemia.

4. Angina is abolished or greatly reduced in ~90% of patients after

complete revascularization. Although this usually is associated with

graft patency and restoration of blood flow, the pain may also have

been alleviated as a result of infarction of the ischemic segment or

a placebo effect.

5. Survival may be improved by operation in patients with stenosis of

the left main coronary artery as well as in patients with three- or

two-vessel disease with significant obstruction of the proximal left

anterior descending coronary artery. The survival benefit is greater

in patients with abnormal LV function (ejection fraction <50%).

Survival may also be improved in the following patients: (a) patients

with obstructive CAD who have survived sudden cardiac death or

sustained ventricular tachycardia; (b) patients who have undergone

previous CABG and have multiple saphenous vein graft stenoses,

especially of a graft supplying the left anterior descending coronary

artery; and (c) patients with recurrent stenosis after PCI and highrisk criteria on noninvasive testing.

6. Minimally invasive CABG through a small thoracotomy and/or offpump surgery can reduce morbidity and shorten convalescence in

suitable patients but does not appear to reduce significantly the risk

of neurocognitive dysfunction postoperatively.

7. Among patients with type 2 diabetes mellitus and multivessel

coronary disease, CABG surgery plus optimal medical therapy is

superior to optimal medical therapy alone in preventing major

cardiovascular events, a benefit mediated largely by a significant

reduction in nonfatal myocardial infarction. The benefits of CABG

are especially evident in diabetic patients treated with an insulinsensitizing strategy as opposed to an insulin-providing strategy.

CABG has also been shown to be superior to PCI (including the use

of drug-eluting stents) in preventing death, myocardial infarction,

and repeat revascularization in patients with diabetes mellitus and

multivessel IHD.

Indications for CABG usually are based on the severity of symptoms, coronary anatomy, and ventricular function. The ideal candidate

has no other complicating disease and has troublesome or disabling

angina that is not adequately controlled by medical therapy or does not

tolerate medical therapy. Great symptomatic benefit can be anticipated

if a patient wishes to lead a more active life and has severe stenoses of

two or three epicardial coronary arteries with objective evidence of

myocardial ischemia as a cause of the chest discomfort. Congestive

heart failure and/or LV dysfunction, advanced age (>80 years), reoperation, urgent need for surgery, and the presence of diabetes mellitus are

all associated with a higher perioperative mortality rate.

LV dysfunction can be due to noncontractile or hypocontractile

segments that are viable but are chronically ischemic (hibernating

myocardium). As a consequence of chronic reduction in myocardial

blood flow, these segments downregulate their contractile function.

They can be detected by using radionuclide scans of myocardial perfusion and metabolism, PET, cardiac MRI, or delayed scanning with

Ischemic Heart Disease

2045CHAPTER 273

Stent

Coronary

artery

Bypass

graft

Lesion

Future

culprit

lesion

Future

culprit

lesion

PCI

CABG

FIGURE 273-5 Difference in the approach to the lesion with percutaneous coronary intervention

(PCI) and coronary artery bypass grafting (CABG). PCI is targeted at the “culprit” lesion or lesions,

whereas CABG is directed at the epicardial vessel, including the culprit lesion or lesions and

future culprits, proximal to the insertion of the vein graft, a difference that may account for the

superiority of CABG, at least in the intermediate term, in patients with multivessel disease. (From

BJ Gersh: Methods of coronary revascularization—Things may not be as they seem. N Engl J Med

Massachusetts Medical Society.)

thallium-201 or by improvement of regional functional

impairment provoked by low-dose dobutamine. In such

patients, revascularization improves myocardial blood

flow, can return function, and can improve survival.

The Choice Between PCI and CABG All the

clinical characteristics of each individual patient must be

used to decide on the method of revascularization (e.g.,

LV function, diabetes, lesion complexity). A number of

randomized clinical trials have compared PCI and CABG

in patients with multivessel CAD who were suitable

technically for both procedures. The redevelopment of

angina requiring repeat coronary angiography and repeat

revascularization is higher with PCI. This is a result of

restenosis in the stented segment (a problem largely solved

with drug-eluting stents) and the development of new

stenoses in unstented portions of the coronary vasculature. It has been argued that PCI with stenting focuses on

culprit lesions, whereas a bypass graft to the target vessel

also provides a conduit around future culprit lesions proximal to the anastomosis of the graft to the native vessel

(Fig. 273-5). By contrast, stroke rates are lower with PCI.

Based on available evidence, it is now recommended

that patients with an unacceptable level of angina despite

optimal medical management be considered for coronary

revascularization. Patients with single- or two-vessel disease with normal LV function and anatomically suitable

lesions ordinarily are advised to undergo PCI (Chap.

276). Patients with three-vessel disease (or two-vessel disease that includes the proximal left descending coronary

artery) and impaired global LV function (LV ejection

fraction <50%) or diabetes mellitus and those with left

main CAD or other lesions unsuitable for catheter-based

procedures should be considered for CABG as the initial

method of revascularization. In light of the complexity

of the decision-making, it is desirable to have a multidisciplinary team, including a cardiologist and a cardiac

surgeon in conjunction with the patient’s primary care

physician, provide input along with ascertaining the patient’s preferences before committing to a particular revascularization option.

■ UNCONVENTIONAL TREATMENTS FOR IHD

On occasion, clinicians will encounter a patient who has persistent,

disabling angina despite maximally tolerated medical therapy and for

whom revascularization is not an option (e.g., small diffusely diseased

vessels not amenable to stent implantation or acceptable targets for

bypass grafting). In such situations, unconventional treatments should

be considered.

Enhanced external counterpulsation utilizes pneumatic cuffs on

the lower extremities to provide diastolic augmentation and systolic

unloading of blood pressure to decrease cardiac work and oxygen

consumption while enhancing coronary blood flow. Clinical trials have

shown that regular application improves angina, exercise capacity, and

regional myocardial perfusion. Experimental approaches, such as stem

cell therapies and cardiac repair with small noncoding RNA molecules

(miRNA), are also under active study.

ASYMPTOMATIC (SILENT) ISCHEMIA

Obstructive CAD, acute myocardial infarction, and transient myocardial ischemia can occur in the absence of symptoms. During

continuous ambulatory ECG monitoring, the majority of ambulatory

patients with typical chronic stable angina are found to have objective

evidence of myocardial ischemia (ST-segment depression) during episodes of chest discomfort while they are active outside the hospital. In

addition, many of these patients also have more frequent episodes of

asymptomatic ischemia. Frequent episodes of ischemia (symptomatic

and asymptomatic) during daily life appear to be associated with an

increased likelihood of adverse coronary events (death and myocardial

infarction). In addition, patients with asymptomatic ischemia after a

myocardial infarction are at greater risk for a second coronary event.

The widespread use of exercise ECG during routine examinations

has also identified some of these previously unrecognized patients

with asymptomatic CAD. Longitudinal studies have demonstrated an

increased incidence of coronary events in asymptomatic patients with

positive exercise tests.

TREATMENT

Asymptomatic Ischemia

The management of patients with asymptomatic ischemia must be

individualized. When coronary disease has been confirmed, the

aggressive treatment of hypertension and dyslipidemia is essential

and will decrease the risk of infarction and death. In addition, the

physician should consider the following: (1) the degree of positivity of the stress test, particularly the stage of exercise at which

ECG signs of ischemia appear; the magnitude and number of the

ischemic zones of myocardium on imaging; and the change in LV

ejection fraction that occurs on radionuclide ventriculography or

echocardiography during ischemia and/or during exercise; (2) the

ECG leads showing a positive response, with changes in the anterior

precordial leads indicating a less favorable prognosis than changes

in the inferior leads; and (3) the patient’s age, occupation, and general medical condition.

Most would agree that an asymptomatic 45-year-old commercial

airline pilot with significant (0.4-mV) ST-segment depression in leads

to V4

during mild exercise should undergo coronary arteriography, whereas an asymptomatic, sedentary 85-year-old retiree with

0.1-mV ST-segment depression in leads II and III during maximal

activity need not. However, there is no consensus about the most

appropriate approach in the large majority of patients for whom

the situation is less extreme. Asymptomatic patients with silent

2046 PART 6 Disorders of the Cardiovascular System

ischemia, three-vessel CAD, and impaired LV function may be

considered appropriate candidates for CABG.

The treatment of risk factors, particularly lipid lowering and

blood pressure control as described above, and the use of aspirin,

statins, and beta blockers after infarction have been shown to

reduce events and improve outcomes in asymptomatic as well as

symptomatic patients with ischemia and proven CAD. Although

the incidence of asymptomatic ischemia can be reduced by treatment with beta blockers, calcium channel blockers, and long-acting

nitrates, it is not clear whether this is necessary or desirable in

patients who have not had a myocardial infarction.

■ FURTHER READING

Eshoj O et al: Pharmacologic approaches to glycemic treatment: Standards of medical care in diabetes. Diabetes Care 43(Suppl 1):S98, 2020.

Ferrari R et al: Treating angina. Eur Heart J Suppl 21(Suppl G):G1,

2019.

Fihn SD et al: ACC/AHA/AATS/PCNA/SCAI/STS focused update

of the guideline for the diagnosis and management of patients with

stable ischemic heart disease: A report of the American College of

Cardiology/American Heart Association Task Force on Practice

Guidelines, and the American Association for Thoracic Surgery,

Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic

Surgeons. Circulation 130:1749, 2014.

Kaski JC: Role of ivabradine in management of stable angina in

patients with different clinical profiles. Open Heart 5:e000725, 2018.

Katsiki N et al: Sodium-glucose cotransporter 2 inhibitors (SGLT2i):

Their role in cardiometabolic risk management. Curr Pharm Des

23:1522, 2017.

Knuuti J et al: 2019 ESC guidelines for the diagnosis and management

of chronic coronary syndromes. Eur Heart J 41:407, 2020.

Levine GN et al: 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery

disease: A report of the American College of Cardiology/American

Heart Association Task Force on Clinical Practice Guidelines: An

update of the 2011 ACCF/AHA/SCAI Guideline for Percutaneous

Coronary Intervention, 2011 ACCF/AHA Guideline for Coronary

Artery Bypass Graft Surgery, 2012 ACC/AHA/ACP/AATS/PCNA/

SCAI/STS Guideline for the Diagnosis and Management of Patients

with Stable Ischemic Heart Disease, 2013 ACCF/AHA Guideline

for the Management of ST-Elevation Myocardial Infarction, 2014

AHA/ACC Guideline for the Management of Patients with Non-STElevation Acute Coronary Syndromes, and 2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of

Patients Undergoing Noncardiac Surgery. Circulation 134:e123, 2016.

Lytvyn Y et al: Sodium glucose cotransporter-2 inhibition in heart

failure: Potential mechanisms, clinical applications, and summary of

clinical trials. Circulation 136:1643, 2017.

Mannsverk J et al: Trends in modifiable risk factors are associated

with declining incidence of hospitalized and nonhospitalized acute

coronary heart disease in a population. Circulation 133:74, 2016.

Maron DJ et al: International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial:

Rationale and design. Am Heart J 201:124, 2018.

Mensah GA et al: The global burden of cardiovascular diseases and

risk factors: 2020 and beyond. J Am Coll Cardiol 74:2529, 2019.

Michos ED et al: Lipid management for the prevention of atherosclerotic cardiovascular disease. N Engl J Med 381:1557, 2019.

Omland T, White HD: State of the art: Blood biomarkers for risk

stratification in patients with stable ischemic heart disease. Clin

Chem 63:165, 2017.

Timmis A et al; and the European Society of Cardiology:

European Society of Cardiology: Cardiovascular disease statistics

2019. Eur Heart J 41:12, 2020.

Virani SS et al: Heart disease and stroke statistics 2021 update: A

report from the American Heart Association. Circulation 143:e254,

2021.

Patients with acute coronary syndrome (ACS) are commonly classified into two groups to facilitate evaluation and management, namely

patients with acute myocardial infarction (MI) with ST-segment

elevation (STEMI) on their presenting electrocardiogram (ECG)

(Chap. 275) and those with non-ST-segment elevation acute coronary

syndrome (NSTE-ACS). The latter include patients with non-STsegment elevation MI (NSTEMI), who, by definition, have evidence of

myocyte necrosis, and those with unstable angina (UA), who do not

(Fig. 274-1).

The incidence of NSTEMI is rising due to the increasing burden of

obesity, diabetes, and chronic kidney disease in an aging population

and the increasing detection of myocardial necrosis by troponin (see

below), whereas the incidence of STEMI is declining due to greater use

of aspirin, statins, and less smoking. Among patients with NSTE-ACS,

the proportion with NSTEMI is increasing while that with UA is falling

because of the wider use of highly sensitive troponin (hsTn) assays (see

below) with enhanced detection of myocyte necrosis, thereby reclassifying UA to NSTEMI.

■ PATHOPHYSIOLOGY

NSTE-ACS is caused by an imbalance between myocardial oxygen supply

and demand resulting from one or more of three processes that lead to

coronary arterial thrombosis: (1) plaque fissure with inflammation—the

inflammatory response is reflected by an increased activity of effector

T cells as part of an adaptive immunity dysregulation; (2) plaque fissure

without inflammation; and (3) plaque erosion, which is present in at

least one-third of ACS and is recognized with increasing frequency

(Fig. 274-2). The so-called “vulnerable plaques” responsible for ACS

may show an eccentric stenosis with scalloped or overhanging edges

and a narrow neck on coronary angiography. Such plaques usually are

composed of a lipid-rich core with a thin fibrous cap. Patients with

NSTE-ACS frequently have multiple such plaques that are at risk of

disruption. A fourth process, without thrombosis, may be caused by

epicardial or microvascular spasm or increased myocardial oxygen

demand in the presence of fixed epicardial coronary obstruction.

Among patients with NSTE-ACS studied at angiography, ~10%

have stenosis of the left main coronary artery, 35% have three-vessel

coronary artery disease, 20% have two-vessel disease, 20% have singlevessel disease, and 15% have no apparent critical epicardial coronary

artery stenosis; some of the latter may have obstruction of the coronary

microcirculation and/or spasm of the epicardial vessels.

■ CLINICAL PRESENTATION

Diagnosis The diagnosis of NSTE-ACS is based largely on a combination of the history and clinical findings (age, the electrocardiogram,

and circulating troponin) (Table 274-1, Fig. 274-3).

History and Physical Examination Typically, chest discomfort

is severe and has at least one of three features: (1) occurrence at rest

(or with minimal exertion), lasting >10 min; (2) of relatively recent

onset (i.e., within the prior 2 weeks); and/or (3) a crescendo pattern,

i.e., distinctly more severe, prolonged, or frequent than previous episodes. The diagnosis of NSTEMI is established if a patient with any of

274 Non-ST-Segment

Elevation Acute Coronary

Syndrome (Non-STSegment Elevation

Myocardial Infarction

and Unstable Angina)

Robert P. Giugliano, Christopher P. Cannon,

Eugene Braunwald

Non-ST-Segment Elevation Acute Coronary Syndrome (Non-ST-Segment Elevation Myocardial Infarction and Unstable Angina)

2047CHAPTER 274

epigastric discomfort, nausea, or weakness may occur instead of

chest discomfort. These equivalents are more frequent in women, the

elderly, and patients with diabetes mellitus. The physical examination

resembles that in patients with stable angina (Chap. 273) and may be

unremarkable. However, if the patient has a large area of myocardial

ischemia or a large NSTEMI, the physical findings can include diaphoresis; pale, cool skin; sinus tachycardia; a third and/or fourth heart

sound; basilar rales; and hypotension.

Electrocardiogram New ST-segment depression occurs in about

one-third of patients with NSTE-ACS. It may be transient but can persist for as long as several days following NSTEMI. T-wave changes are

more common but are a less specific sign of ischemia, unless they are

new and deep T-wave inversions (≥0.3 mV).

Cardiac Biomarkers Patients with NSTEMI have elevated biomarkers of necrosis, such as cardiac troponin (cTn) I or T (cTnI or cTnT).

cTns are sensitive, relatively specific, and the preferred markers of myocardial necrosis. Elevated levels of cTn with a dynamic early change

Low likelihood

1. Presentation

2. ECG

3. Troponin

4. Diagnosis Non-cardiac Other

cardiac UA NSTEMI STEMI

High likelihood

FIGURE 274-1 Assessment of patients with suspected acute coronary syndromes. The initial assessment is based on the integration of low-likelihood and/or high-likelihood

features derived from clinical presentation (i.e., symptoms, vital signs), 12-lead electrocardiogram (ECG), and cardiac troponin. The proportion of the final diagnoses

derived from the integration of these parameters is visualized by the size of the respective boxes. NSTEMI, non-ST-segment elevation myocardial infarction; STEMI,

ST-segment elevation myocardial infarction; UA, unstable angina. (Reproduced with permission from M Roffi et al: ESC Guidelines for the management of acute coronary

syndromes in patients presenting without persistent ST-segment elevation: task force for the management of acute coronary syndromes in patients presenting without

persistent st-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 37:267, 2016. https://doi.org/10.1093/eurheartj/ehv320, Translated and reproduced

by permission of Oxford University Press on behalf of the European Society of Cardiology.)

Lipid core

Fibrous

cap

*Red*

thrombus

Lumen

Media

Adventitia

Ruptured Plaque

• Thin fibrous cap

• Collagen-poor fibrous

cap

• Large lipid core

• Many macrophages

• Fibrin-rich thrombus

Eroded Plaque

• Protcoglycan,

Glycosaminoglycan

rich

• Little or no lipid core

• Neutrophils and NETs

• Many smooth muscle

cells

• Platelet-rich thrombus

Intima

White

thrombus

Lumen

Media

Adventitia

FIGURE 274-2 Comparison of the characteristics of human atheromata complicated

by thrombosis and causing acute coronary syndrome. The column on the left

highlights some of the characteristics demonstrated by analyses of human coronary

arterial lesions that have undergone thrombosis by these two diverse mechanisms.

NETs, neutrophil extracellular traps (Reproduced with permission from P Libby et al:

Reassessing the mechanisms of acute coronary syndromes the “vulnerable plaque”

and superficial erosion. Circ Res 124:150, 2019.)

these features (without electrocardiographic ST-segment elevations)

develops evidence of myocardial necrosis, as reflected in abnormally

elevated levels of circulating troponin, in the absence of another

explanation (see below). The chest discomfort is typically located in

the substernal region and radiates to the left arm, left shoulder, and/or

superiorly to the neck and jaw. Anginal equivalents such as dyspnea,

TABLE 274-1 TIMI Risk Score for NSTE-ACS

RISK MARKERS

• Age ≥65 years

• Known CAD (≥50% stenosis)

• ST deviation >0.5mm on

presenting ECG

• ↑ cardiac markers

• ≥2 original episodes in prior 24 h

• Prior angina

• ≥3 CAD risk factors

NO. OF RISK MARKERS INCIDENCE OF ADVERSE CARDIAC EVENTS*

(%)

0/1 5

2 8

3 13

4 20

5 26

6/7 41

Risk at 14 days of death, new or recurrent MI, or severe recurrent ischemia

requiring urgent revascularization.

Abbreviations: CAD, coronary artery disease; ECG, electrocardiogram; NSTEACS, non-ST-segment elevation acute coronary syndrome; TIMI, Thrombolysis in

Myocardial Infarction.

2048 PART 6 Disorders of the Cardiovascular System

distinguish patients with NSTEMI from those with UA. In patients

with NSTEMI, there is a characteristic temporal rise of the plasma

concentration, peaking at 12–24 h after onset of symptoms and gradually decreasing thereafter. There is a direct relationship between the

degree of elevation and mortality. The 1-h rapid rule-out MI algorithm

(no abnormal elevation of hsTn at 0 or 1 hour after presentation) has

been recommended by recent practice guidelines. It is important to

distinguish myocardial injury from myocardial necrosis; the former

is defined by elevations of cTn >99th percentile of the upper reference

limit in patients without a clear clinical history or electrocardiographic

features of acute myocardial ischemia. Myocardial injury may be

caused by a variety of noncardiac and cardiac conditions other than

MI (Table 274-2).

■ IMAGING

Coronary computed tomographic angiography (CCTA) may be useful

in improving the accuracy and speed of the diagnostic evaluation. The

goals are to recognize or exclude epicardial coronary artery disease.

■ RISK STRATIFICATION

Patients with documented NSTE-ACS exhibit a wide spectrum of

early (30 days) risk of death, ranging from 1 to 10%, and a recurrent ACS rate of 5–15% during the first year. Assessment of risk

can be accomplished by one of several clinical risk scoring systems,

including those developed from the Thrombolysis in Myocardial

Infarction (TIMI) Trials, the Global Registry of Acute Coronary

Event (GRACE), and the HEART (history, electrocardiogram, age,

risk factors, troponin) score (Fig. 274-3). Multibiomarker strategies

are now gaining favor, both to define more fully the pathophysiologic

mechanisms underlying a patient’s presentation and to stratify the

patient’s risk further. Early risk assessment is useful in identifying

patients who would derive the greatest benefit from an early invasive

strategy (see below).

TREATMENT

Non-ST-Segment Elevation Acute Coronary

Syndrome

Patients with a low likelihood of ischemia can usually be managed in

an emergency department or a dedicated “chest pain unit.” Evaluation

of such patients includes clinical monitoring for recurrent ischemic

discomfort and continuous monitoring of ECGs, stress testing to

detect and grade ischemia (Chap. 273), CCTA to assess epicardial

coronary artery obstruction, and serum troponin.

MEDICAL TREATMENT

Patients who “rule-in” for NSTE-ACS by clinical features, cTn, or

ST-T-wave changes on the ECG should be admitted to the hospital. Patients should be placed on bed rest with continuous ECG

monitoring for ST-segment deviation and cardiac arrhythmias,

preferably on a specialized cardiac unit. Ambulation is permitted

if the patient shows no recurrence of ischemia (symptoms or ECG

changes) and does not develop an elevation of cTn for 24 h. They

may proceed to stress testing to detect ischemia and, if it is present,

to assess its severity.

Medical therapy consists of an acute phase focused on the clinical symptoms and stabilization of the culprit lesion(s) and a longerterm phase that involves therapies directed at the prevention of

disease progression and future recurrent NSTE-ACS.

ANTI-ISCHEMIC TREATMENT (TABLE 274-3)

To provide relief of pain and discomfort, initial treatment, in

addition to bed rest, includes nitrates, β-adrenergic blockers, and

inhaled oxygen in patients with hypoxemia (arterial O2

saturation

<90%) and/or in those with heart failure and rales.

Nitrates Nitroglycerin should first be given sublingually or by

buccal spray (0.3–0.6 mg) if the patient is experiencing ischemic

discomfort. If symptoms persist after three doses given 5 min

apart, intravenous nitroglycerin (5–10 μg/min, using nonabsorbing

tubing) is recommended. The infusion rate may be increased by

10 μg/min every 3–5 min until symptoms are relieved, systolic arterial pressure falls to <90 mmHg, or the dose reaches 200 μg/min.

Topical or oral nitrates (Chap. 273) can be used when the pain has

resolved, or they may replace intravenous nitroglycerin when the

patient has been symptom-free for 12–24 h. The only absolute contraindications to the use of nitrates are hypotension or the recent

use of a phosphodiesterase type 5 (PDE-5) inhibitor, sildenafil or

vardenafil (within 24 h), or tadalafil (within 48 h).

a-Adrenergic Blockers and Other Agents Beta blockers are the

other mainstay of anti-ischemic treatment because they reduce

myocardial oxygen needs. They may be started by the intravenous

route in patients with severe ischemia but should be avoided in

the presence of acute or severe heart failure, low cardiac output,

hypotension, or contraindications (e.g., high-degree atrioventricular block, active bronchospasm). Ordinarily, oral beta blockade

targeted to a heart rate of 50–60 beats/min is recommended.

Heart rate–slowing calcium channel blockers, e.g., verapamil

or diltiazem, are recommended for patients who have persistent

symptoms or ECG signs of ischemia after treatment with full-dose

nitrates and beta blockers and in patients with contraindications

to either class of these agents. Patients who have continuing severe

TABLE 274-2 Reasons for the Elevation of Cardiac Troponin Values as a

Result of Myocardial Injury

Myocardial injury related to acute myocardial infarction

Atherosclerotic plaque disruption or erosion with thrombosis

Myocardial injury related to acute myocardial ischemia because of

oxygen supply/demand imbalance

Reduced myocardial perfusion

• Coronary artery spasm, microvascular dysfunction

• Coronary embolism

• Coronary artery dissection

• Sustained bradyarrhythmia

• Hypotension or shock

• Respiratory failure

• Severe anemia

Increased myocardial oxygen demand

• Sustained tachyarrhythmia

• Severe hypertension

Other causes of myocardial injury

Cardiac conditions

• Heart failure

• Myocarditis

• Cardiomyopathy (any type)

• Takotsubo syndrome

• Recent coronary revascularization

• Cardiac procedure other than revascularization

• Catheter ablation

• Defibrillator shocks

• Cardiac contusion

Systemic conditions

• Sepsis

• Chronic kidney disease

• Stroke, subarachnoid hemorrhage

• Pulmonary embolism

• Infiltrative diseases, e.g., amyloidosis, sarcoidosis

• Chemotherapeutic agents

• Critical illness

• Strenuous exercise

Note: For a more comprehensive listing, see the Fourth Universal Definition of

Myocardial Infarction (source).

Source: Reproduced with permission from K Thygesen et al: Fourth universal

definition of myocardial infarction (2018). Circulation 72:2231, 2018.

Non-ST-Segment Elevation Acute Coronary Syndrome (Non-ST-Segment Elevation Myocardial Infarction and Unstable Angina)

2049CHAPTER 274

No Yes

HEART score*

0–3

Serial troponins

Early

discharge

Cardiology

consult &

admission

Observation

or admission

Stress testing or

angiography

Initial troponin

<99th % ≥99th % <99th %

≥4

Patients with acute chest pain

ECG

Ischemic STEMI

STEMI

guidelines

(see Collet JP, et al in

topics

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