Stable Angina

Angina pectoris can manifest as chest pain, chest pressure, or a heavy feeling or squeezing sensation. Angina is a symptom of myocardial ischemia. Stable angina is caused by a mismatch between coronary blood supply and myocardial oxygen demand. The latter is determined by several factors, including heart rate and left ventricular wall stress and contractility (Braunwald, 2000). Coronary supply is determined by oxygen transport capacity and delivery and conditions that regulate the coronary circulatory system (e.g., nitric oxide, endothelin), autonomic nervous system, metabolic activity, neural control, and perfusion pressure. Several pharmacologic interventions also affect the coronary circulation, including adrenergic receptor activation or blockade, adenosine, and acetylcholine. Most coronary flow occurs during systole, whereas only 25% of flow occurs in diastole (Feigl, 1998; Yada et al., 1999).

In stable angina, blood flow cannot meet myocardial oxygen demands because of an obstructive atherosclerotic plaque in one or more coronary arteries (Fig. 27-8). It typically occurs predictably with exertion and resolves within minutes of initiating rest. This stable angina pattern does not usually occur at rest. Nonatherosclerotic obstructive CAD can also cause angina. Although infrequent, it could be mediated by myocardial bridging, vasculitis, or congenital malformation of the coronary arteries. In addition, conditions without obstructive CAD (e.g., cardiomyopathies, valve disease) can trigger angina (Lee, 2000).

Symptoms of stable angina differ among patients. Angina can be perceived as a pressure, tightness, squeezing, or heaviness in the chest. This could radiate to the arm, jaw, shoulders, back, or abdomen. The pain can be associated with an increase in shortness of breath, a feeling of nausea, diaphoresis, or occasional vomiting. Lightheadedness and anxiety might accompany those symptoms. Patients might describe one or more of these symptoms, which can be very atypical in female and diabetic patients. Finally, as observed in patients with long-standing DM, myocardial ischemia can be silent with no angina reported. Dyspnea without chest pain can be an "anginal equivalent." Ischemia can induce stiffness in the myocardium and reduces ventricular relaxility, which in return raises left ventricular end-diastolic pressure and leads to dyspnea. Angina or anginal-equivalent symptoms typically resolve with rest or nitroglycerin.

Noncardiac chest pain typically occurs with certain maneuvers, such as taking a deep breath (e.g., sharp pleuritic pain), palpation of the chest wall (as in musculoskeletal pain, costochondritis), or after certain types of food ingestion (e.g., esophageal pain from refluxed acid). If chest pain is noncardiac in origin or the cause of pain cannot be easily identified, it is important to rule out pulmonary embolism (Lee, 2002) or aortic dissection (Collins, 2004) because these etiologies

Figure 27-8 Glacov remodeling of the coronary lumen in response to early plaque formation.

can be fatal if missed. Pulmonary hypertension and pericarditis are also part of the differential diagnosis.

Several signs may be noted on examination in a patient with angina. Paradoxical splitting of the second heart sound (S2), systolic murmurs, and S3 or S4 can be appreciated during an anginal episode. Findings of cardiomyopathy or valvular disorders may help establish the diagnosis of a noncoronary cause of chest pain. Patients can also be hypertensive, have signs of hyperlipidemia (arcus cornea or xanthelasmas), or findings of diabetes (neuropathy or diabetic retinopathy).

Noninvasive Testing

Electrocardiogram

The electrocardiogram (ECG) often does not show ischemic changes in patients with stable angina who are at rest and have no symptoms. The resting ECG, however, might show nonspecific ST-segment and T-wave abnormalities in a patient with known severe CAD. False-positive results are common in patients with left ventricular hypertrophy (LVH), digoxin intake, electrolyte imbalances, or electrical conduction anomalies such as bundle branch blocks (BBBs) or preexcitation syndromes.

The ECGs need to be compared to previous readings. Frequently, new Q-wave abnormalities or the emergence of conduction disturbances might indicate an interval change in the patient's cardiac status. The ECG can be helpful during an episode of chest pain, when more than 50% of patients with normal resting ECG show new changes. Typically, these changes include the presence of ST-segment depression or elevation in two contiguous leads, new T-wave inversions or pseudonormalization of already-inverted T waves.

Exercise Treadmill Stress Testing

Exercise treadmill testing can be performed in patients who are able to exercise on a treadmill. Using different protocols (Bruce, Modified Bruce, Naughton), the patient exercises at

Mpi Myocaridal
Figure 27-9 Myocardial perfusion scan shows reversible ischemia in the anterior wall, apex, and inferior wall.

different inclines and speeds until achieving 85% of peak predicted heart rate for age ([220 - age] x 85%). The test provides information about the presence of ischemic ST-segment changes, reproducibility of chest pain, arrhythmias, and changes in BP, heart rate, and functional capacity. Patients with good functional capacity generally have a good prognosis. An early positive stress test (in first two stages of exercise) can indicate a worse prognosis. The mean sensitivity of this test is 68% and specificity 77% (Gibbons et al., 2002). Some studies indicate that, when selection bias is removed, the sensitivity can be as low as 40% to 50%, but specificity as high as 85% to 90% (Detrano et al., 1989; Gianrossi et al., 1989).

The test specificity is reduced when baseline ECGs are abnormal with LVH, preexcitation syndrome, or BBB, or if the patient is taking digoxin (Sketch et al., 1981; Sundqvist et al., 1986) or has electrolyte abnormalities (Gibbons et al., 2002; Froelicher et al., 1999). Also, if a patient cannot reach target heart rate, the diagnostic accuracy of the test is diminished. If a patient experiences chest pain and 1 mm ST-segment depression during exercise, the test can be 90% predictive of the presence of CAD. A 2 mm ST depression accompanied by chest pain is almost pathognomonic of the presence of obstructive CAD. It should be noted that the presence of anti-ischemic agents (nitrates, p-blockers, calcium channel blockers) can reduce the sensitivity of the test and should be withheld for 2 to 3 days before the procedure for long-acting drugs and 24 hours for short-acting drugs, if the intent from the test is to diagnose the presence of obstructive disease (Gibbons et al., 2002).

A treadmill stress test can be a first choice test to diagnose CAD by the family physician, in both male and female patients, assuming the patient can exercise on a treadmill, the baseline ECG has no indication of LVH or conduction abnormalities, and the patient has no electrolyte disturbances and is not taking digoxin (Melin et al., 1985). When adjusting for the pretest probability of disease, female patients have only a slightly reduced specificity on a regular stress than male patients. A baseline borderline ST-segment depression less than 1 mm is not an exclusionary criterion to perform a treadmill stress test.

The absolute contraindications to stress testing are decom-pensated CHF, symptomatic severe aortic valve stenosis, ongoing rest chest pain, a recent MI (in past week), severe hypertension, and intractable arrhythmias. When patients have conditions that reduce the specificity of a stress test, an imaging stress test (nuclear or echocardiography) can more accurately evaluate for CAD.

Stress Myocardial Perfusion Imaging

Myocardial perfusion imaging (99mTc-sestamibi, 99mTc-tetrofosmin, or thallium-201) provides a more accurate modality to diagnose the presence of obstructive CAD than a treadmill ECG alone (Fig. 27-9). The sensitivity and specificity of this test have been reported to be 88% and 72%, respectively. When referral bias is accounted for, the specificity of this test is as high as 90%. In addition to myocardial perfusion, the test provides information about ejection fraction and wall motion abnormalities and is very valuable to predict a patient's prognosis (Klocke et al., 2003).

Nuclear stress testing is expensive, so regular treadmill testing is considered as the first diagnostic modality when possible. Nuclear stress testing is useful in patients with the likelihood of a low-specificity treadmill ECG. Nuclear imaging can provide information about prognosis and myocar-dial viability in regions of wall motion abnormalities, as well as help localize the area of myocardium in jeopardy. As with most stress tests, these are best ordered in patients with an intermediate likelihood of obstructive CAD.

Myocardial perfusion imaging can be also performed with the induction of pharmacologic stress, usually with adenosine or dobutamine. Adenosine is a vasodilator and stresses the heart by a "steal phenomenon." Adenosine and dipyridamole dilate normal coronaries, shunting blood from abnormal regions of the myocardium and creating a discrepancy in perfusion between normal and abnormal regions. Dobutamine increases heart rate and contractility and therefore increases myocardial oxygen demand.

Adenosine is typically infused over 4 or 6 minutes, depending on the protocol used. The infusion rate of 140 \ig/kg/ min starts with ECG monitoring. Usually halfway through the infusion, sestamibi (Myoview) or thallium is injected. Adenosine causes flushing, shortness of breath, nausea, chest pain, and a "strange" feeling in most patients that does not reflect the presence of CAD. Adenosine can also cause bradycardia and a high-degree atrioventricular (AV) block. Patients should not take any caffeinated beverages for at least 12 to 24 hours before the test. Also, adenosine can precipitate asthma and should not be used in patients with hyperreac-tive airway disease. Adenosine is an excellent choice for a test in patients who cannot exercise on a treadmill or those with a left BBB or a pacemaker rhythm. The sensitivity and specificity of adenosine stress imaging are 90% and 82%, respectively (Klocke et al., 2003).

Dobutamine is infrequently used and is reserved for patients who cannot exercise on a treadmill and have a contraindication to taking adenosine. Dobutamine is infused at 10 ng/kg/min for 3 minutes and then increased by increments of 10 ^/kg/min every 3 minutes to a maximum of 50 \ig/kg/ min, or if target heart rate has been achieved. If despite this high dose of dobutamine, target heart rate is not achieved, atropine is administered to a maximum of 1 to 2 mg. Car-diolite is injected typically at target heart rate, and the infusion is then terminated. Patients are generally observed for at least 10 minutes post-test or until the heart rate is below 100 beats/min. Dobutamine can cause a shaky feeling, nausea and arrhythmias. In general, it is well tolerated.

Although pharmacologic nuclear stress imaging provides similar diagnostic accuracy to treadmill nuclear stress testing, patients are best exercised on a treadmill. More information can be obtained from the treadmill test, including functional capacity, presence of arrhythmias with exercise, and hemodynamic response to physical exertion.

Stress Echocardiography

Stress echocardiography is an alternative imaging stress test to a nuclear stress test (Cheitlin et al., 2003). However, the sensitivity is slightly lower with an increase in specificity, making the overall accuracy of this test similar to stress nuclear imaging. Stress echocardiography is performed by obtaining an initial resting echocardiogram to assess a patient's left ventricular ejection fraction, wall motion characteristics, and cavity size. In about 25% of patients, it may be difficult to obtain optimal echocardiographic images for adequate interpretation of the test, and therefore an alternative stress testing is needed. This is particularly true in patients with severe chronic obstructive pulmonary disease (COPD) and patients with severe obesity. Patients are then exercised on a treadmill using a symptom-limited protocol. Patients need to achieve the minimum target heart rate for age (85% of maximum predicted) but preferably a higher rate to allow ample time for the sonographer to obtain immediate post-stress echo-cardiographic images while the heart rate is still over target. Typically, the sonographer needs about 20 to 30 seconds to obtain these images. In patients who cannot exercise, dobutamine can be used as previously described to achieve the target heart rate, and then the infusion is discontinued when all echocardiography images are acquired.

Regardless of the modality of stress testing, a test should be terminated when a patient displays significant arrhythmias, lightheadedness, a symptomatic drop in BP, or significant ischemic changes on the ECG, particularly if associated with anginal symptoms. Also, a stress test should not be performed in patients with unstable rest symptoms, frequent arrhythmia, known severe left main disease, severe symptomatic valvular disease, or decompensated CHF. The test needs to be closely monitored at all times by the technician, and a physician must always be nearby and frequently checking ECG changes and assessing the patient's symptoms and progress.

Computed Tomography of Heart

Multidetector computed tomography (MDCT) of the heart has recently emerged as an imaging modality for the diagnosis of coronary artery disease. As with the majority of noninvasive testing, MDCT is helpful in identifying CAD in patients with an intermediate pretest probability for CAD. Very-high-risk patients are not appropriate for this test and should undergo an invasive angiographic assessment. A negative MDCT result for CAD is helpful to exclude CAD, given the very high specificity of this test and thus low false-positive rate. Patients with equivocal noninvasive stress testing are ideal candidates, and if negative, MDCT can add to the reassurance of lack of significant obstructive CAD. CT angiography is not a screening tool in asymptomatic patients. Furthermore, MDCT is a reliable tool to evaluate bypass grafts and is an excellent test for identifying coronary anomalies (Cury et al., 2007). The test is not risk free, and the patient needs to be counseled on the risk of radiation exposure and contrast dye reactions.

Pharmacologic Management

Patients with stable angina have an imbalance between coronary blood supply and demand. Also, they are at increased risk of MI and arrhythmias. Medical therapies therefore should focus on alleviating angina, reducing plaque progression and rupture, and restoring a patient's functional capacity. Some reversible causes of angina need to be evaluated, such as conditions that increase myocardial oxygen demand. These include fever, thyrotoxicosis, anemia, and cardiac stimulants such as cocaine or amphetamines. Severe valvular dysfunction and CHF might also be precipitating factors.

Nitrate Therapy

Nitrate therapy reduces myocardial oxygen demand by increasing venous capacitance and therefore reducing venous return and ventricular wall stress. Also, nitrates increase coronary blood supply by dilating the coronary arteries (Parker and Parker, 1998). Administering nitrates to patients with stable angina increases their symptom-free walking distance and reduces the frequency and severity of their anginal episodes. Nitrates are not known to reduce risk for MI significantly or to prolong survival. On a chronic basis, nitrates can be administered orally or transdermally. Regardless of the mode of administration, it is important to have 8 to 10 hours of a nitrate-free period to avoid tolerance to this drug (Parker et al., 1995). Intravenous nitroglycerin is reserved for the unstable angina patient to reduce anginal pain and intracardiac filling pressures and to improve symptoms of heart failure.

Beta-Adrenergic Blockade

Beta-adrenergic blockers reduce myocardial oxygen demand primarily by reducing heart rate and contractility. Beta blockers are essential in patients with stable angina and a history of prior MI or reduced left ventricular function. In these conditions, p-blockers can prolong survival and should be administered to those patients unless absolutely contraindi-cated (Gottlieb et al., 1998).

It is unclear whether survival or serious arrhythmias are reduced in patients with stable angina and no prior MI or left ventricular dysfunction. Relative or absolute contraindications to beta-blocker therapy include patients with severe hyperreactive airway disease, heart block, severe bradycardia, or severe symptomatic peripheral vascular disease.

Calcium Channel Blockers

Long-acting CCBs are potent anti-ischemic drugs and also can be used to treat the patient with stable angina (Braunwald, 1982). Generally, short-acting CCBs need to be avoided because of the potential to increase adverse events. Dihydropyridines such as amlodipine (Norvasc) or nifedipine (Procardia XL) do not alter heart rate significantly and are primarily vasodilators. Diltiazem reduces heart rate but also increases coronary blood supply, whereas verapamil reduces oxygen demand primarily by reducing heart rate with less vasodilatory effects.

Ranolazine

Ranolazine (Ranexa) inhibits the cardiac late sodium current typically present in patients with ischemia. An increase in the late sodium current leads to excess entry of calcium into cardio-myocytes, which impairs cardiac relaxation. Ranolazine does not increase the rate pressure product, and its exact antianginal mechanism of action is unknown. In the Combination Assessment of Ranolazine in Stable Angina (CARISA) trial, patients were randomized to ranolazine and placebo added to standard antianginal therapy (Chaitman et al., 2004). Ranolazine increased exercise duration time and time to angina onset significantly, which was sustained at 12 weeks of therapy. Furthermore, in the Efficacy of Ranolazine in Chronic Angina (ERICA) RCT, ranolazine versus placebo was administered in patients with at least three anginal attacks per week despite high-dose amlodipine (10 mg/day). Over a 6-week period, ranolazine reduced anginal frequency by 23% and weekly nitroglycerin use by 25% compared to placebo (Stone et al., 2006).

Antiplatelet Agents

In high-risk patients, aspirin (81 mg) reduces vascular events by approximately 35% and is a prime therapy in patients with stable angina (Antiplatelet Trialists Collaboration, 1994). Aspirin is very effective in reducing MI in healthy subjects and elevated serum CRP levels (Ridker et al., 1997).

Aspirin resistance has been reported recently and can be present in approximately 25% of patients. Also, aspirin hypersensitivity is common and primarily related to GI side effects. Aspirin's side effects (e.g., bleeding, dyspepsia) can be reduced without compromising its effectiveness with the use of enteric-coated aspirin.

Clopidogrel (Plavix), an ADP-receptor antagonist, is a potent irreversible antiplatelet drug. In the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events study (CAPRIE Steering Committee, 1996), Clopidogrel was slightly but statistically more effective than aspirin in reducing cardiovascular events in high-risk patients with a history of stroke, MI and peripheral vascular disease (8.7% relative risk [RR] reduction; p = 0.043). The combination of aspirin and clopidogrel in stable angina patients with no recent unstable coronary syndrome is unknown and currently being tested in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial (Bhatt and Topol, 2004). Clopido-grel is an effective alternative to patients who are unable to take aspirin.

In addition to the previous measures, aggressive management of dyslipidemia, hypertension, impaired glucose control, and smoking cessation are essential interventions to reduce future cardiovascular events in the stable angina patient. Cardiac rehabilitation is a critical therapeutic modality in patients with CAD, particularly after revascularization. The initiation of hormone replacement therapy in postmenopausal females is not indicated for cardiovascular risk reduction.

KEY TREATMENT

Beta blockers are recommended as initial therapy in the absence of contraindications in patients with or without prior myocardial infarction.

Aspirin is strongly recommended in patients with stable angina in the absence of contraindications.

SECONDARY PREVENTION, CHRONIC STABLE ANGINA*

1. Comprehensive risk factor management and cardiac rehabilitation are essential in the management of the stable angina patients (SOR: A).

2. Recommended lipid management includes assessment of a fasting lipid profile. LDL-C should be less than 100 mg/dL (SOR: A).

3. Angiotensin-converting enzyme (ACE) inhibitors should be started and continued indefinitely in all patients with left ventricular ejection fraction (LVEF) of 40% or less and in those with hypertension, DM, or chronic kidney disease, unless contraindicated (SOR: A).

4. Angiotensin receptor blockers (ARBs) are recommended for patients who have hypertension, have indications for but are intolerant of ACE inhibitors, have heart failure, or have had an MI with LVEF of 40% or less (SOR: A).

5. Aldosterone blockade is recommended for use in post-MI patients without significant renal dysfunction or hyperkalemia who are already receiving therapeutic doses of an ACE inhibitor and a beta blocker, have LVEF of 40% or less, and have either diabetes or heart failure (SOR: A).

6. It is beneficial to start and continue beta-blocker therapy indefinitely in all patients who have had MI, acute coronary syndrome, or left ventricular dysfunction with or without heart failure symptoms, unless contraindicated (SOR: A).

*ACC/AHA quoted guidelines (Fraker, 2007).

Mechanical and Revascularization Strategies

Coronary Angioplasty and Bypass Surgery

Coronary angioplasty and stenting are currently reserved for patients who (1) are symptomatic and have failed optimal medical therapy with antianginal drugs or (2) have a moderate to large area of ischemia on nuclear scintigraphic imaging, severe proximal left anterior descending artery disease, single- or double-vessel CAD, or three-vessel CAD in nondia-betic patients with preserved left ventricular function.

Coronary artery bypass surgery is reserved for patients with (1) left main disease or severe three-vessel CAD, particularly diabetic patients or those with reduced left ventricular function, or (2) unsuitable anatomy for coronary angioplasty or those with disease in multiple CABGs, especially if the graft to the left anterior descending coronary artery is involved and can be considered for bypass surgery.

Enhanced External Counterpulsation (EECP)

Mechanical interventions such as EECP can be effective in the treatment of the patient with stable angina who is not a candidate for revascularization and has continued chest pain despite medical therapy (Michaels et al., 2005). This therapy requires about 32 sessions of 1-hour duration for 5 days a week. Although its functional mechanism is largely unknown, EECP improves exercise tolerance, reduces exercise-induced myocardial ischemia, and improves left ventricular diastolic filling in patients with CAD (Urano et al., 2001). Future therapies such as gene therapy to stimulate angiogenesis in the coronary arteries are being tested as an alternative to EECP in these patients.

Run for Your Life The Health Benefits Of Treadmills

Run for Your Life The Health Benefits Of Treadmills

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