Angina pectoris is a clinical manifestation of obstructive CAD, which in turn is usually the result of atherosclerotic plaque formation over a number of years. The term angina pectoris refers to the symptom of chest discomfort that may be described by the patient as a sensation of chest tightness or burning. Of the 18,000,000 adults in the United States with heart disease, as many as 9,400,00 have angina pectoris. It is estimated that 785,000 people experience a new ischemic episode annually, and recurrent events occur in at least 470,000 Americans each year.
Pathology
As a symptom, angina pectoris is experienced when myocardial isch- emia develops. Myocardial ischemia and angina pectoris may occur in the face of obstructive atherosclerotic plaque that limits blood flow in the face of increased demand such as exertion or emotional excitement.
Myocardial oxygen demand is directly related to increases in heart rate and blood pressure; these variables, in turn, can be manipulated with medical therapy to reduce the demand. Restricted oxygen supply, in the form of reduced blood flow, can also induce myocardial ischemia.
Blood flow reduction is a prominent feature of acute presentations of CAD such as NSTEMI and STEMI, but atherosclerosis-mediated coro- nary vasoconstriction, or coronary vasospasm, is also a potential cause of flow limitation leading to myocardial ischemia. Another example of supply limitation is anemia, whereby reduced oxygen-carrying capac- ity coupled with obstructive lesions leads to myocardial ischemia and symptoms of angina pectoris. The term stable angina pectoris refers to myocardial ischemia caused by either plaque-mediated flow limita- tion in the face of excess demand or supply limitation due to coronary vasospasm.
Clinical Presentation
Angina pectoris may manifest in either stable or unstable patterns (Table 8.2), but the symptom expression is similar. Typically, patients complain of retrosternal discomfort that they may describe as pressure,
tightness, or heaviness. The symptom can be subtle in its presentation, and inquiry as to the presence of “chest pain” may lead to a negative response in a patient experiencing angina pectoris. When taking a his- tory aimed at discerning angina pectoris, one needs to seek answers to these more nuanced descriptions of symptoms. In addition to chest discomfort, patients may have associated discomfort in the arm, throat, back, or jaw. They also may experience dyspnea, diaphoresis, or nausea associated with angina pectoris.
There is a good deal of variability in the expression of symptoms related to myocardial ischemia, although each person tends to have a unique signature of symptoms. Some have no chest discomfort but only radiated arm, throat, or back symptoms; dyspnea; or abdominal discomfort. Myocardial ischemia can also manifest in a “silent” form, particularly in the elderly and in patients with long-standing diabetes mellitus. The duration of angina pectoris varies, probably depending on the magnitude of the underlying myocardial ischemia. Exertion- related angina pectoris, the hallmark of stable obstructive CAD, typi- cally resolves with rest or with decreased intensity of exercise. In stable angina pectoris, the duration of events is usually in the range of 1 to 3 minutes. Prolonged symptoms in the 20- to 30-minute range are indic- ative of a more serious problem such as NSTEMI or STEMI.
The physical examination of patients with CAD is typically nor- mal. However, if the patient is physically examined during an episode of myocardial ischemia, either at rest or after exertion, significant changes may be present. As with any form of discomfort, there may be a reflex increase in heart rate and blood pressure. Elevated heart rate and blood pressure may act to sustain the duration of angina by increasing myocardial oxygen demand in the face of supply-lim- iting coronary stenosis. Acute mitral regurgitation can develop if the distribution of myocardial ischemia includes a papillary muscle, the supporting structure of the mitral valve. The physical examination in such cases would demonstrate a new systolic murmur consistent with mitral regurgitation. If severe enough in degree, this mitral regurgi- tation will cause decreased LV compliance and, consequently, an acute elevation in left atrial and pulmonary vein pressure leading to pulmonary congestion. In this setting, the patient will have not only
A B
Fig. 8.1 Angiograms of the right coronary artery. (A) Discrete stenosis is observed in the middle segment of the artery (arrow). (B) The same artery is shown after successful balloon angioplasty of the stenosis and placement of an intracoronary stent (arrow).
81 CHAPTER 8 Coronary Heart Disease
the symptom of angina pectoris but also the symptom of dyspnea and the physical finding of rales. Ischemia-induced increases in LV filling pressure due to diminished compliance also can occur independently of ischemia-induced mitral regurgitation. Decreased LV compliance can produce the abnormal heart sound S4; in the case of severe diffuse myocardial ischemia causing LV systolic dysfunction, an S3 may also be perceived. Resolution of myocardial ischemia results in not only a cessation of angina pectoris but also a return to the patient’s baseline physical examination status.
Diagnosis and Differential Diagnosis
Three basic forms of testing have played major roles in assessing patients with chest discomfort possibly due to CAD. All of these tests capitalize on the effect of myocardial ischemia on various aspects of cardiac physiology. First, myocardial ischemia induced by exercise or by spontaneous coronary occlusion results in subendocardial ische- mia, which appears on an ECG as diffuse ST depression (Fig. 8.2).
Once ischemia resolves, the ECG returns to normal. Second, myo- cardial ischemia typically affects a segment of heart muscle, and that territory develops a wall motion abnormality that can be detected by either echocardiography or nuclear scintigraphy. Third, the basis for myocardial ischemia is a decrease in coronary and myocardial blood flow. This abnormality can be detected by assessing the distribution of radioactive tracers such as thallium 201 or technetium sestamibi using specialized detectors for imaging myocardial perfusion. All stress test techniques used in diagnosing patients with possible CAD rely on these means of detecting the impact of myocardial ischemia on cardiac elec- trical activity, mechanical function, or myocardial perfusion.
Stress testing in its various forms frequently plays a pivotal role in the assessment of patients with possible CAD. In using stress testing, it is important to understand the significance of pretest probability of CAD in interpreting the results of any stress test method. For a patient with a high pretest probability of CAD, a positive test is highly predictive of underlying CAD, and a negative test carries the weight of being falsely negative. The opposite is true in a patient with a low pretest probability of CAD: A negative test is associated with a high negative predicative value for the presence of CAD, but a positive test is likely to be falsely positive.
Stress testing is useful not only as a diagnostic tool but also in the long-term management of established CAD. Exercise stress test- ing, through its ability to quantify exercise capacity, can monitor the
effectiveness of medical therapy directed at reducing myocardial isch- emia. The findings of an exercise stress test also have predictive value in that patients with ischemia induced at low workloads are more likely to have extensive multivessel disease, whereas those who achieve high workloads are less prone to ischemic complications of CAD. A higher risk for poor outcomes related to CAD is implied by (1) ECG changes of ST depression early during exercise and persisting late into recovery;
(2) exercise-induced reduction in systolic blood pressure; and (3) poor exercise tolerance (<6 minutes on the Bruce stress test protocol).
Patients with a normal resting ECG can reliably be assessed by stan- dard exercise stress testing with ECG monitoring (Fig. 8.3). The spec- ificity of ST changes with exertion is significantly reduced in the face of baseline ECG abnormalities related to LV hypertrophy, left bundle branch block (LBBB), preexcitation, or use of digoxin. Various imag- ing techniques (echocardiography, nuclear scintigraphy, magnetic resonance imaging) have been developed to overcome the impact of baseline ECG abnormalities on the validity of stress testing. Because women also have lower specificity for ECG changes during exercise testing than men, an imaging technique is frequently used in the assessment of women. Overall, the addition of an imaging technique to stress testing significantly improves the sensitivity, specificity, and predictive value of the stress test but also greatly increases its cost.
Radionuclide stress testing is a common form of imaging-based stress test. Near peak exertion, a radionuclide tracer (thallium-201, technetium-99, or tetrofosmin) is administered intravenously. The tracer is distributed to the myocardium in a quantity directly propor- tional to blood flow. This type of image testing relies on a disparity of tracer uptake to detect an area of ischemia. Thallium-201 redistrib- utes over 4 hours to viable myocardium, allowing for comparison of stress-induced ischemia to a baseline state. The other tracers do not share this redistribution feature, and tests using technetium-99 or tetrofosmin require both “rest” and “stress” injections of tracer to differentiate ischemic myocardium. Patients with normal perfusion studies have a low risk of coronary events (<1%/year). The presence of a positive perfusion study confers a risk of about 7%/year for coro- nary events, with the risk increasing relative to the extent of perfusion abnormality.
An alternative means of imaging for exercise testing is the use of echocardiography to detect ischemia-induced wall motion abnormal- ities. This form of testing is increasingly favored because there is no TABLE 8.2
Angina Pectoris
Type Pattern ECG Abnormality Medical Therapy
Stable Stable pattern, induced by physical exertion, exposure to cold, eating, emotional stress
Baseline often normal or non-
specific ST-T changes ≥70% Luminal narrowing of one or more coronary arteries from atherosclerosis
Aspirin
Sublingual nitroglycerin Lasts 5-10 min
Relieved by rest or nitroglycerin
Signs of previous MI ST-segment depression during
angina
Anti-ischemic medications Statin
Unstable Increase in anginal frequency, severity, or duration
Angina of new onset or now occurring at low level of activity or at rest May be less responsive to sublingual
nitroglycerin
Same as stable angina, although changes during discomfort may be more pronounced
Occasional ST-segment eleva- tion during discomfort
Plaque rupture with plate- let and fibrin thrombus, causing worsening coronary obstruction
Aspirin and clopidogrel Anti-ischemic medications Heparin or LMWH
Glycoprotein IIb/IIIa inhibitors
Prinzmetal or variant angina
Angina without provocation, typically occurring at rest
Transient ST-segment elevation during pain
Often with associated AV block or ventricular arrhythmias
Coronary artery spasm Calcium-channel blockers Nitrates
AV, Atrioventricular; ECG, electrocardiography; LMWH, low-molecular-weight heparin; MI, myocardial infarction.
radiation associated with its use, whereas radionuclide tracers expose the patient to a significant dose of radiation. Stress echocardiography carries with it the same enhancement in sensitivity, specificity, and pre- dictive value as radionuclide imaging. An additional benefit of echocar- diography imaging is more discrete anatomic data on valve function. If it is coupled with Doppler flow imaging, information regarding exer- cise-induced mitral regurgitation can be obtained.
Another means of assessing for exercise-induced wall motion abnormalities is the use of radionuclide ventriculography or mul- tigated acquisition scanning (MUGA). This technique is usually included as part of the interpretation of an exercise stress radionuclide
study. This imaging technique does not provide the anatomic detail associated with echocardiography, and it has the negative feature of significant radiation exposure.
An additional imaging technique for stress testing is the use of mag- netic resonance imaging. Radiation is not a concern, and cardiac struc- tural imaging can match echocardiography (or exceed it in patients with poor images on echocardiography). The technique is not as easy to execute as echocardiography and is not as frequently utilized.
Not all patients who require noninvasive testing for CAD are able to exercise to a degree sufficient to induce ischemia, and for some patients exercise testing is not an option at all. For these patients, I
II
III
aVR
Boston University Hospital 1 MAR 1999
aVL
aVF
V1
V2
V3
V4
V5
V6
I
A
B
II
III
aVR
aVL
aVF
V1
V2
V3
V4
V5
V6
Fig. 8.2 Electrocardiogram obtained during angina (A) and after the administration of sublingual nitroglycerin and subsequent resolution of angina (B). During angina, transient ST-segment depression and T wave abnor- malities are present.
83 CHAPTER 8 Coronary Heart Disease
pharmacologic stress testing has evolved as a viable alternative to exer- cise testing. The prognostic benefit of exercise workload is not available from this form of testing, but information regarding the presence of ischemia-inducing atherosclerosis is obtainable. One common form of pharmacologic testing relies on inducing coronary vasodilation (as with dipyridamole, adenosine, or regadenoson), which produces a disparity of myocardial blood flow based on the presence of coronary stenosis. Radionuclide administered during the infusion of the coro- nary vasodilator allows for detection of myocardial ischemia similar to that observed with exercise testing. An alternative pharmacologic approach uses the inotropic and chronotropic effects of dobutamine to increase myocardial oxygen demand and induce segmental ischemia.
Echocardiography is commonly used to detect dobutamine-induced wall motion abnormalities with this approach, although radionuclide or magnetic resonance imaging could also be used.
All of the stress testing techniques discussed here are able to assess for the presence of inducible myocardial ischemia associated with CAD. The presence of CAD can also be determined by assessment of coronary calcification using either EBCT or the now more common MDCT. Coronary calcification is present only because of underlying CAD. Although detecting its presence does not directly indicate the presence of obstructive CAD as would an abnormal imaging stress test, studies have shown a direct correlation between the amount of coronary calcification and the probability that a 70% stenosis is present.
Multidetector computed tomography (MDCT) scanners can reli- ably perform coronary angiography with the use of intravenous con- trast agents and specifically timed imaging protocols. This can provide insight into coronary anatomy that stress testing cannot. When this technique is coupled with newer techniques such as CT fractional flow reserve (FFR), it can provide a functional assessment as well. The PLATFORM trial demonstrated that in patients with stable chest pain, CTA + FFR guiding the need for invasive coronary angiography (ICA) resulted in similar outcomes but with lower costs compared to stan- dard of care. A negative study carries a high negative predictive value for the occurrence of coronary events and thus is useful in patients
with low-intermediate pretest probability for coronary artery disease.
MDCT is also valuable in defining coronary anomalies.
Invasive coronary angiography (ICA) has been considered the
“gold standard” for detecting the extent and severity of underlying CAD. This approach carries a small risk of MI, stroke, or death, so it must not be taken lightly. In the case of patients with positive stress tests, particularly those with high-risk features, coronary angiography adds more discrete information regarding the underlying disease and guides the potential use of revascularization techniques (i.e., percuta- neous coronary intervention or coronary artery bypass surgery) ver- sus medical therapy to treat CAD (Table 8.3). Additional tools, such as pressure wires used to perform FFR, add to the diagnostic power of invasive catheterization by allowing one to discriminate between physiologically significant lesions and those not likely to cause isch- emia. Revascularization is not indicated for lesions that do not cause ischemia.
The physician must also be cognizant of the fact that not all chest discomfort is related to CAD. Other causes of chest discomfort include esophageal disease (esophageal reflux may mimic typical angina pec- toris), chest wall–related pain, pulmonary embolism, pneumonia, and trauma. The clinical presentation of the patient usually points in one direction or another, but patients with chest discomfort commonly undergo an evaluation for CAD, typically with the use of stress test- ing. Once CAD is reliably ruled out, the physician needs to consider alternative causes of the symptom. In the acute setting of severe chest discomfort, particularly in a hemodynamically unstable patient, the differential diagnosis includes acute MI, pulmonary embolism, and aortic dissection. Prompt and accurate diagnostic evaluation, com- monly with the use of invasive or CT angiography, can be lifesaving in this situation.
Treatment
Medical management of stable angina. The treatment of CAD and angina pectoris is multifaceted. The presence of CAD with or without angina requires the physician to recommend risk factor modification, frequently associated with lifestyle changes. For Submaximal exercise
Maximal exercise
6 min of recovery
10 min of recovery
II V2 II V2
Standing at rest 1 min 30 sec of recovery 138/90
HR: 58
162/94 HR: 115 Mild chest pain 164/94 HR: 127 Moderate chest pain
166/94 HR: 98 Moderate chest pain 108/90 HR: 82 Chest pain resolved
104/90 HR: 87
Fig. 8.3 Treadmill exercise test demonstrates a markedly ischemic electrocardiogram (ECG) response. The resting ECG is normal. The test was stopped when the patient developed angina at a relatively low work- load, accompanied by ST-segment depression in lead II and ST-segment elevation in lead V2. These changes worsened early in recovery and resolved after administration of sublingual nitroglycerin. Only leads II and V2 are shown; however, ischemic changes were seen in 10 of the 12 recorded leads. Severe atherosclerotic disease of all three coronary arteries was documented at subsequent cardiac catheterization.
angina pectoris, pharmacologic therapy is typically used to control symptoms, allowing for maintenance of reasonable exercise tolerance.
Revascularization is commonly used to control symptoms to a degree better than what can be achieved with medications alone, but only a small group of patients with CAD benefit from revascularization in terms of increased longevity.
Other medical conditions can lower the threshold for angina, caus- ing worsening symptoms and affecting quality of life. Anemia is a com- mon medical problem that, when addressed, can significantly reduce the frequency of angina pectoris. Hyperthyroidism, with its increased metabolic demand and tachycardia, can increase the frequency of angina pectoris. Uncompensated congestive heart failure lowers the anginal threshold through the effects of LV dilation and filling pressure elevation on myocardial oxygen demand. Chronic obstructive pulmo- nary disease (COPD) and obstructive sleep apnea leading to hypox- emia can trigger angina pectoris. The use of illicit substances such as cocaine can also lead to angina through increased metabolic demand as well as coronary vasospasm.
Attention to the major modifiable risk factors for CAD is a cor- nerstone of therapy. Poorly controlled diabetes mellitus, hyperten- sion, hyperlipidemia, and ongoing smoking all drive the progression of CAD and increase the risk for catastrophic events such as MI or sudden death. The wealth of clinical research on preventing death and disability from CAD has led to the development of evidence-based
guidelines that form the basis of contemporary therapy for CAD (Table 8.4). Complete smoking cessation is a must for patients with CAD regardless of the presence of symptoms. Control of hypertension is also important. The use of statin medications to reduce LDL choles- terol has revolutionized the therapy for CAD and remains the corner- stone of lipid therapy. Statins have been shown to reduce the risk of MI in patients with proven CAD (goal LDL <70 mg/dL) and in those at significant risk (goal to lower LDL levels by >30% in intermediate risk patients and >50% in high-risk patients). If LDL levels do not reach the goal with statin monotherapy, ezetimibe can be utilized as an adjunc- tive agent. A new class of drug, PCSK-9 inhibitors (alirocumab and evolocumab), can have a dramatic impact on a patient’s lipid profile but are somewhat cost-prohibitive. These are considered for second- ary prevention in patients who have refractory hyperlipidemia to sta- tin therapy as well as patients with familial hyperlipidemia syndromes who are at extreme risk for developing clinical ASCVD. There is also interest in low HDL levels, which appear to confer increased risk for coronary events. Exercise increases HDL levels and may confer pro- tective effects through other mechanisms. Pharmacologic strategies to elevate HDL including niacin have not been proven to be beneficial.
Antiplatelet therapy is known to reduce the risk of MI in those who have known CAD. Patients should be instructed to take aspirin, 75 to 162 mg/day (clopidogrel 75 mg/day may be used in those who are aspirin intolerant or allergic). Angiotensin-converting enzyme (ACE) inhibitors reduce the risk of recurrent MI and are also beneficial for patients with diabetes mellitus or reduced LV function. Angiotensin receptor blockers (ARBs) can be substituted in those who experience significant side effects from ACE inhibitors.
Regular aerobic exercise can benefit patients with CAD by reduc- ing their risk for complications related to the disease. Aerobic exercise also increases exercise tolerance and may reduce the frequency of exer- cise-related angina pectoris. Positive benefits also accrue from weight loss related to exercise and improved blood pressure control. In seden- tary individuals, isometric activities such as snow shoveling can trigger MI and should be avoided. There may be some benefits to judicious weight training in patients with CAD.
TABLE 8.3
Indications for Coronary Angiography in Patients With Stable Angina Pectoris
Unacceptable angina despite medical therapy (for consideration of revascularization)
Noninvasive testing results with high-risk features
Angina or risk factors for coronary artery disease in the setting of depressed left ventricular systolic function
For diagnostic purposes, in the individual in whom the results of noninvasive testing are unclear
TABLE 8.4
Goals of Risk Factor Modification
Risk Factor Goal
Dyslipidemia
Elevated LDL-cholesterol level
Patients with CAD or CAD equivalenta LDL <70 mg/dL
Without CAD, ≥2 risk factorsb LDL <130 mg/dL (or <100 mg/dLc) Without CAD, 0-1 risk factorsc LDL <160 mg/dL
Elevated TG TG <200 mg/dL
Reduced HDL-cholesterol level HDL >40 mg/dL
Hypertension Systolic blood pressure <140 mm Hg
Diastolic blood pressure <90 mm Hg
Smoking Complete cessation
Obesity <120% of ideal body weight for height
Sedentary lifestyle 30-60 min moderately intense activity (e.g., walking, jogging, cycling, rowing) five times per week CAD, Coronary artery disease; CRP, C-reactive protein; HDL, high-density lipoprotein; hsCRP, high-sensitivity C-reactive protein; LDL, low-density lipoprotein; TG, triglycerides.
aCAD equivalents include diabetes mellitus, noncoronary atherosclerotic vascular disease, or >20% 10-year risk for a cardiovascular event as pre- dicted by the Framingham risk score.
bRisk factors include cigarette smoking, blood pressure ≥140/90 mm Hg or taking antihypertensive medication, HDL-cholesterol level <40 mg/dL, family history of premature coronary atherosclerosis (male, <45 yr; female, <55 yr).
cTarget of 100 mg/dL should be strongly considered for men ≥60 yr and for individuals with a high burden of subclinical atherosclerosis (coronary calcification >75th percentile for age and sex), hsCRP >3 mg/dL, or metabolic syndrome.