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CHRONIC STABLE ANGINA—MEDICAL MANAGEMENT
Chronic stable angina is a clinicalsyndrome resulting from an imbalance
in myocardial oxygen supply and demand. The supply–demand
imbalance is typically a result of coronary atherosclerosis.
The modification of cardiovascular disease (CVD) risk factors and
adoption of healthy lifestyles is a key strategy in both the primary
prevention of coronary artery disease (CAD) and slowing the
progression of established CAD.
Standard therapy for all patients with chronic stable angina includes
sublingual nitroglycerin, antiplatelet therapy, and an anti-ischemic agent
that either restores the appropriate balance of myocardial oxygen supply
and demand (β-blockers, calcium-channel blockers, and long-acting
nitrates), and/or interrupts the negative consequences of myocardial
ischemia on myocardial energy consumption (ranolazine).
β-Blockers are the preferred initial agents for prevention of ischemic
symptoms, especially in patients who have a history of myocardial
infarction (MI) or heart failure.
Although effective as monotherapy, long-acting calcium-channel
blockers are typically added on to β-blocker therapy if additional control
of ischemic symptoms is needed.
Long-acting nitrates should never be used as monotherapy but can be
used as add-on therapy to other anti-ischemic options in chronic stable
Although ranolazine can be used as initial therapy for chronic stable
angina, it is typically reserved as a second-line option. It is especially
useful in patients who cannot tolerate further decreases in heart rate
and blood pressure secondary to the use of traditional antianginal
CHRONIC STABLE ANGINA—REVASCULARIZATION
Myocardial revascularization can be accomplished either through
percutaneous coronary intervention (PCI) or coronary artery bypass
surgery (CABG). In most patients, both are equally effective in
Certain patients who are at high risk for morbidity and mortality from
CAD derive a mortality benefit with CABG as compared to PCI or
In patients not at high risk, optimal medical management is as good as
PCI in the long-term management of chronic stable angina, including the
Patients who undergo myocardial revascularization either with PCI or
CABG should still receive optimal pharmacotherapy for chronic stable
Appropriate pharmacotherapy for patients undergoing elective PCI plus
myocardialstent implantation should include dual antiplatelet therapy
antagonist, in most cases clopidogrel therapy,
for a minimum of 1 month (bare-metalstent) and ideally up to 1 year
(bare-metal and drug-eluting stents).
Antiplatelet nonresponsiveness has been demonstrated to be associated
with an increased risk for cardiovascular events such as MI and death.
An understanding of various testing modalities for antiplatelet response,
as well as potential drug–drug interactions that may lead to reduced
antiplatelet activity will facilitate optimal pharmacotherapy in each
PRINZMETAL ANGINA/CARDIAC SYNDROME X
Patients with Prinzmetal angina and cardiac syndrome X typically
present with severe chest pain despite having coronary arteries that are
Vasodilators are the primary mode of therapy for patients with
Prinzmetal angina, while standard anti-ischemic options should be used
Coronary heart disease (CHD) includes heart failure (HF), arrhythmias, sudden
cardiac death, and ischemic heart disease (IHD) such as myocardial infarction (MI)
as well as unstable and stable angina pectoris. Because angina is a marker for
underlying heart disease, its management is of great importance. Typical angina
pectoris is characterized by substernal chest, jaw, shoulder, back, or arm pain
triggered by exertion or stress, and it is relieved by rest or nitroglycerin (NTG);
however, its presentation is variable.
Patients who have a reproducible pattern of angina that is associated with a certain
level of physical activity have chronic stable angina or exertional angina. In contrast,
patients with unstable angina experience new-onset angina or a change in their angina
intensity, frequency, or duration.
3 Both chronic stable angina and unstable angina
often reflect underlying atherosclerotic narrowing of coronary arteries on coronary
angiography. In contrast, Prinzmetal variant angina is associated with normal findings
on coronary angiography and is thought to be caused by a spasm of the coronary
artery that decreases myocardial blood flow. The presence of atherosclerosis also
may lead to impairment of the normal vasodilatory function of the coronary arteries.
As such, coronary artery disease (CAD) patients who experience ischemia produced
by an increase in myocardial oxygen demand (increased exertion) may also
experience vasospasm at the site of atherosclerosis, further worsening the ischemic
state. As such, patients with CAD likely experience angina due to both increased
demand (exertion) and decreased supply (vasospasm), a phenomenon known as
Silent (asymptomatic) myocardial ischemia can result in transient changes in
myocardial perfusion, function, or electrical activity, and is detected on an
3 The patient, however, does not experience chest pain or
other signs of angina during these episodes.
It is estimated that 85.6 million adults in the United States have cardiovascular
1 and 15.5 million of these adults have CHD.
is the first clinical sign of CHD in approximately 50% of patients.
indicate 8.2 million American adults have angina pectoris, although the prevalence of
angina is likely underestimated due to limited population-based data and because it is
often unrecognized in patients.
CVD is the leading cause of death in the United States responsible for one of every
4 Although CHD accounts for one of every seven deaths in the United
States, individual mortality varies according to the patient’s age, sex, cardiovascular
risk profile, myocardial contractility, coronary anatomy, and specific anginal
In addition to the high morbidity and mortality associated with CHD, the economic
cost to the US health care system is substantial. Total direct and indirect costs
associated with CHD were estimated to be $204.4 billion in 2010, and direct
medical costs for CHD are expected to increase by 100% between 2013 and 2030.
A brief review of coronary anatomy will facilitate a thorough understanding of the
pathophysiology of chronic stable angina. Figure 12-1 illustrates the normal
distribution of the major coronary arteries, although variation is common between
Angina pectoris typically occurs from myocardial ischemia. Ischemia in the
myocardium develops when there is a mismatch between myocardial oxygen supply
and demand. The underlying pathologic condition of this mismatch invariably is the
presence of atherosclerosis in one or more of the coronary arteries.
MYOCARDIAL OXYGEN SUPPLY AND DEMAND
The oxygen demand of the heart is determined by its workload. The major
determinants of myocardial oxygen consumption are heart rate, contractility, and
intramyocardial wall tension during systole (Fig. 12-2).
tension, the force the heart is required to develop and sustain during contraction, is
affected primarily by changes in ventricular pressures and volume. Both enlargement
of the ventricle and increased pressure within the ventricle increase the systolic wall
force and consequently myocardial oxygen demand. Increases in contractility and
heart rate also increase oxygen demand.
6 Pharmacologic control of angina is directed
toward decreasing the myocardial oxygen demand by decreasing heart rate,
myocardial contractility, or ventricular volume and pressures.
Figure 12-2 Determinants of myocardial oxygen supply and demand.
Oxygen supply to the heart is impacted by many factors including coronary blood
flow and oxygen extraction (Fig. 12-2). Oxygen extraction by heart cells is high
(~70%–75%) even at rest. When extra demand is placed on the heart, myocardial
oxygen extraction increases slightly and plateaus at approximately 80%. Because
oxygen extraction is increased only modestly when the heart is stressed, high oxygen
demands must be met by increases in coronary blood flow.
arterial blood also is important. Therefore, the hematocrit (Hct), hemoglobin (Hgb),
and arterial blood gases should be monitored. In a similar fashion to targeting
determinants of myocardial oxygen demand, pharmacologic control of angina
is directed at improving oxygen supply through vasodilation of the epicardial
ATHEROSCLEROTIC VASCULAR DISEASE
Although understanding the determinants of myocardial oxygen supply and demand is
important in treating CHD, of equal importance is understanding how atherosclerotic
plaques develop because the underlying pathologic condition of this mismatch
invariably is the presence of atherosclerosis in one or more of the coronary arteries.
Understanding how the process of atherosclerosis unfolds, as well as the primary
pharmacologic and non-pharmacologic interventions that help prevent progression of
atherosclerosis, is an important piece in treating a patient with chronic stable angina
(Fig. 12-3). (See Chapter 8, Dyslipidemias, Atherosclerosis, and Coronary Heart
If an atherosclerotic plaque occludes less than 50% of the diameter of the vessel,
coronary blood flow can be augmented sufficiently during exertion by the
intramyocardial arterioles (resistance vessels), and the patient is pain free. In
patients with chronic stable angina, most coronary artery stenoses are greater than
Traditional risk factors, such as smoking, hypertension, hyperlipidemia, diabetes,
and obesity, are linked to the process of atherosclerosis by producing oxidative
stress within the vasculature. Increased oxidative stress leads to progressive
decreases in nitric oxide (NO) levels and endothelial dysfunction, enhancing
In addition, diets typically seen in western
industrialized countries have been linked to increased oxidative stress within the
vasculature. This may partially explain the link between diet and atherosclerosis.
The role of a healthy lifestyle and diet is crucial in preventing the development or
Figure 12-4 Endothelial function.
Although traditional risk factors have long been appreciated as the underlying
cause for the development of CAD, continuing research efforts have attempted to
identify novel risk factors to refine risk assessment for the development of CAD.
Potential candidates have included highly-sensitive C-reactive protein,
homocysteine, fibrinogen, and lipoprotein (a), among others.
INTERHEART study indicate little may be gained from identifying additional risk
In this large case–control study, nine clinical risk factors were strongly
associated with the development of first-ever MI and accounted for greater than 90%
of the risk for developing CAD (Table 12-1). The results were consistent across sex,
geographic regions, and ethnic groups, suggesting that strategies to reduce the
incidence of CAD can be applied universally. Subsequent studies have verified the
findings of INTERHEART, and many of these potential risk factors may indeed more
accurately reflect the presence of CAD and be considered markers, as opposed to
predicting who will subsequently exhibit CAD.
PLATELET AGGREGATION AND THE FORMATION OF THROMBI
Although coronary atherosclerosis is the underlying mechanism for most patients with
anginal syndromes, thrombotic factors commonly play a key role in the pathogenesis
of myocardial ischemia. Both blood flow turbulence and stasis can cause intermittent
platelet aggregation or intermittent coronary artery thrombosis. Thus, platelet-active
agents are used in the treatment of chronic stable angina.
Risk Factors for First-Time Myocardial Infarction from the INTERHEART
Risk Factor Adjusted Odds Ratio (99% Confidence Interval)
Current smoking 2.87 (2.58–3.19)
Abdominal obesity 1.62 (1.45–1.80)
Moderate alcohol intake 0.91 (0.82–1.02)
Vegetables and fruits daily 0.70 (0.62–0.79)
All combined 129.2 (90.2–185.0)
aRisk of MI increases with increased ratio.
INTRACELLULAR SODIUM AND CALCIUM HANDLING
Recently, an appreciation has emerged for the role of the late sodium current (INa
the development and maintenance of myocardial ischemia. Most sodium enters the
myocardium in phase 0 of the action potential. Under normal conditions, however, a
small amount of sodium will enter the cell during phase 2 (plateau phase) of the
action potential. When ischemia is present, sodium handling is altered such that a
substantial increase occurs in the late INa
. The increase in intracellular sodium
triggers an increase in the influx of calcium through the reverse mode of the sodium–
calcium exchanger. The net result of the alterations in intracellular ion handling is
intracellular calcium overload.
Increases in intracellular calcium impair myocardial
relaxation, increase intramyocardial wall tension, decrease perfusion to the
myocardium owing to compression of the small arterioles feeding the myocardium,
and increase myocardial oxygen demand.
15 Ultimately, these pathologic changes in
sodium and calcium handling perpetuate and worsen ischemia once it develops.
Targeting this pathologic process has led to the development of new antianginal
medications (e.g., ranolazine) with a distinct, novel mechanism of action compared
with traditional antianginal agents (i.e., nitrates, β-blockers, and calcium-channel
A detailed description of chest pain is vital in order for the clinician to determine
whether chest pain represents chronic stable angina, Acute Coronary Syndrome
(ACS), or is noncardiac in origin. Five key components commonly used to
characterize chest pain include the location, duration, severity, and quality of pain, as
well as any factors that provoke and relieve the pain (Table 12-2). Chest pain
stemming from myocardial ischemia is often described as a sensation of pressure or
heavy weight located over the sternum. Patients may also complain of shortness of
breath (SOB), nausea, vomiting, or diaphoresis. Pain may also occur in the neck,
jaw, shoulder, or arm. The precipitation of pain is typically associated with exertion
and rapidly resolves with rest or the administration of NTG. Chest pain that occurs at
rest, prolonged in duration, or increased in severity is likely reflective of unstable
disease and warrants immediate medical attention to prevent complications such as
MI, HF, and death. Importantly, some patients (women, people with diabetes) may
present with atypical symptoms such as indigestion or gastric fullness, or may present
with diaphoresis alone without concomitant chest pain. Last, many episodes of
ischemia are asymptomatic and termed as “silent ischemia.”
Physical findings in patients with chronic stable angina are often absent or
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