| Physical Examination
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Coronary artery disease occurs when atherosclerosis affects the coronary arteries that deliver blood flow to the myocardium. This can result in symptoms presenting as stable angina, reviewed here, or an acute coronary syndrome, reviewed in the Unstable Angina/Non-STEMI Topic Review and STEMI Topic Review, when restriction of blood flow to the myocardium occurs.
Coronary artery disease is the most common cause of death in the United States. The atherosclerotic process in the coronary arteries may be silent or lead to the development of symptoms from decreased oxygen supply to the myocardium. These symptoms are termed angina pectoris, from the Latin term meaning “a strangling feeling in the chest.”
The same factors that contribute to the atherosclerotic process increase the risk for coronary artery disease. These include diabetes, tobacco use, hypertension, lipid disorders and genetic factors (family history of ischemic heart disease) and are discussed further in the Atherosclerosis Topic Review.
Atherosclerosis of an artery restricting blood flow.
Pathophysiology – CAD - Stable Angina
The term ischemic heart disease is used when there is an oxygen supply/demand mismatch that can result in symptoms. The most common cause of this mismatch is atherosclerotic narrowing of the coronary artery, resulting in decreased flow. Angina may also be caused by reduced oxygen supply during profound anemia/hypotension or during a period of increased oxygen demand such as during tachyarrhythmias, hypertensive emergencies or severe aortic valve stenosis.
Three main factors determine myocardial oxygen demand.
Left ventricular wall stress: This is the force acting against the myocardial cells. It is directly proportional to the LV pressure and radius. Wall stress is indirectly proportional to two times wall thickness. This is described with the Law of LaPlace — quite important in understanding which disease states can alter oxygen demand, resulting in angina, and which therapies can relieve angina.
Left ventricular pressure increases with states that increase “afterload” of the heart including systemic hypertension and aortic valve stenosis.
Left ventricular radius increases in valvular heart disease (especially aortic regurgitation) or cardiomyopathies that cause systolic heart failure.
Left ventricular wall thickness increases in chronic hypertension or aortic valve stenosis as a compensatory mechanism to decrease wall stress, making it inversely proportional to wall stress, and thus decreasing oxygen demand, as the stress is distributed over a larger mass. Hypertrophic obstructive cardiomyopathy, or HOCM, similarly increases wall thickness. After myocardial infarction, the wall thins during remodeling, thereby increasing wall stress.
Contractility: Also known as inotropy, contractility is the force of contraction that occurs with each heartbeat, independent of heart rate. Sympathetic nervous system activation increases contractility as occurs during physical exertion or exercise. Beta-blocker therapy, which blocks the sympathetic nervous system, will decrease contractility; this, in turn, decreases oxygen demand and relieves symptoms of angina.
Heart rate: Also known as chronotropy, the heart rate influences the oxygen demand. The greater the number of ventricular contractions per minute, the greater the oxygen requirements. States of tachycardia increase oxygen demand significantly. which explains why anginal symptoms are frequently exertional. Conversely, beta-blocker therapy slows the heart rate and significantly decreases oxygen demand, which explains the efficacy of beta-blockers to treat angina.
Etiology – CAD - Stable Angina
Atherosclerosis of the coronary arteries is the most common cause of ischemic heart disease. The five major risk factors for atherosclerotic heart disease include diabetes, tobacco use, hypertension, lipid disorders and genetic factors (family history of ischemic heart disease), as mentioned previously. States of increased oxygen demand or decreased supply, as described in Pathophysiology, may cause angina. Other rare causes of angina include coronary spasm, congenital coronary anomalies, vasculitis, increased blood viscosity, coronary aneurysms, severe myocardial bridging, coronary emboli, external compression, coronary fistulas, syndrome X and anxiety states such as Da Costa’s syndrome (not true angina). These are discussed in Special Situations.
In general, stable anginal symptoms will not develop unless there is greater than 70% stenosis of a major epicardial coronary vessel (left anterior descending, circumflex, or right coronary artery). Multiple tandem stenosis can, at times, cause angina, even if the obstruction is less than 50%. Stenosis of the left main coronary artery can cause symptoms when only 50% blockage is present. Below is an angiographic example of a hemodynamically significant coronary stenosis.
Physical Examination – CAD - Stable Angina
Physical examination findings are relatively non-specific and usually only present during the anginal episode, making this a less helpful means of diagnosis. When examined during an anginal attack, the heart rate and blood pressure may be elevated due to increased sympathetic tone. A S4 heart sound may be present during myocardial ischemia due to the lack of adenosine triphosphate production impairing LV relaxation. Recall that myocardial relaxation is an active process requiring ATP — reduced during ischemia — and a S4 heart sound occurs when a non-compliant, stiffened left ventricle receives blood after atrial contraction.
During inferior ischemia, posteromedial papillary muscle dysfunction can cause mitral regurgitation, resulting in a holosystolic murmur at the cardiac apex radiating to the axilla; see Heart Murmurs Topic Review.
This rarely occurs during anterior or lateral ischemia, as the anterolateral papillary muscle has dual supply from the left anterior descending and circumflex coronary artery.
When the left ventricular end-diastolic pressure, or LVEDP, increases during myocardial ischemia, that pressure can be transmitted backward to the pulmonary veins and into the pulmonary vasculature, causing transient pulmonary edema that results in dyspnea and rales on lung examination.
Symptoms – CAD - Stable Angina
The symptoms of occlusive CAD manifest as chronic stable angina pectoris. Substernal chest pressure upon physical exertion with radiation to the medial portion of the left arm or left jaw is the classic description. Emotional upset/stress or other hemodynamic stresses (i.e. hypertensive emergency) as described above well known to cause anginal symptoms as well.
Angina can be described as a “tightness,” “discomfort, not pain,” “squeezing,” “indigestion,” “heaviness,” or an “elephant sitting on my chest.” Levine sign is when a patient places his or her fist in the center of the chest to describe the sensations of squeezing and tightness with angina. Pain from angina is gradual in onset and must last for at least 5 minutes. Also, the pain is diffuse and difficult to localize to one part of the chest; the description of a large vs. small area of pain can help distinguish from musculoskeletal issues.
Less common presentations include only shoulder pain, pain down both arms, left wrist pain, right-sided chest or jaw pain, radiation to the right arm, mid-thoracic pain and only dyspnea without chest pains. Rarely, the pain of angina is described as sharp.
Some associated symptoms that occur simultaneously with the classic anginal symptoms above include dyspnea, diaphoresis (cold sweats), fatigue/weakness, nausea and dizziness. Women, elderly patients and patients with diabetes tend to have more atypical presentations of angina.
Many non-cardiac disease states can cause chest pain, as well. Important features that would suggest non-cardiac causes of chest pain include the worsening with inspiration (pleuritic pain), the duration of the pain (< 5 minutes), a small pinpoint area of pain (angina is more diffuse) and no relief with nitroglycerine. Note that esophageal spasm — a relatively uncommon cause of chest pain — can be relieved with nitroglycerine, causing it to mimic symptoms of angina. Sharp, shooting chest pains lasting a few seconds to a minute are common and usually musculoskeletal-related.
When an atherosclerotic plaque ulcerates and thrombosis occurs, an acute coronary syndrome develops and the above-mentioned anginal symptoms can occur at rest. In this setting, the pain is frequently more severe and has a longer duration; see Acute Coronary Syndromes Topic Review.
Diagnosis – CAD - Stable Angina
Diagnosing coronary disease in the absence of an ACS can be difficult as the clinical presentation varies and, as previously mentioned, physical examination is non-specific.
When potential anginal symptoms such as chest pains or dyspnea are present, cardiac stress testing can be performed to detect hemodynamically significant stenosis in a coronary artery (> 70% stenosis). Coronary computed tomographic angiography, or CTA, is being utilized more frequently as the technology advances. Coronary calcium scoring can be helpful in identifying calcified atherosclerotic plaque in intermediate-risk patients without symptoms. The gold standard for diagnosis of coronary disease is invasive coronary angiography.
The difference between stable angina pectoris, unstable angina pectoris, a non-ST segment elevation myocardial infarction, or non-STEMI, and a ST segment elevation myocardial infarction, or STEMI, are below. The later three are considered ACS and are reviewed in detail elsewhere.
Stable Angina Pectoris
Symptoms of angina with a consistent amount of physical exertion that is relieved with rest that has been present for a long duration.
Unstable Angina Pectoris
Three different presentations of unstable angina exist.
- Exertional angina of new onset (even if relieved with rest and requiring a consistent amount of exertion to produce symptoms, angina is considered unstable when it first occurs)
- Exertional angina that was previously stable and now occurs with less physical exertion
- Anginal symptoms at rest without physical exertion
In unstable angina, the cardiac enzymes remain normal or are only very minimally elevated.
Non-ST Segment Elevation Myocardial Infarction
Anginal symptoms at rest that result in myocardial necrosis, as identified by elevated cardiac biomarkers (see Cardiac Enzymes Topic Review) with no ST segment elevation on the 12-lead ECG.
ST Segment Elevation Myocardial Infarction
Anginal symptoms at rest that result in myocardial necrosis, as identified by elevated cardiac biomarkers (see Cardiac Enzymes Topic Review) with ST segment elevation on the 12-lead ECG.
Treatment – CAD - Stable Angina
Treatment of CAD consists of reducing the risk for disease progression, preventing acute coronary syndromes/cardiovascular death and treating symptoms of stable angina. The treatment of ACS is discussed elsewhere.
Reducing Disease Progression Risk
Once a CAD diagnosis is made, treatment directed at the known CV risk factors should be aggressively undertaken to prevent progression of disease. This includes lipid management, smoking cessation, BP management, weight loss and dietary/exercise counseling. Aside from the above and regardless of LDL cholesterol levels, all patients with CAD should be taking a HMG-CoA reductase inhibitor, or statin, proven to reduce progression of disease. Two small trials actually showed regression of atherosclerotic plaque in a moderate percentage of patients who were taking high-dose atorvastatin or rosuvastatin.
Preventing Acute Coronary Syndromes
All patients with CAD, regardless of the above risk factors, should be treated with antiplatelet therapy and HMG-CoA reductase, or statin, therapy to reduce the risk for acute coronary syndromes/CV death. Certainly, controlling hypertension, lipid management and smoking cessation have been shown not only to prevent disease progression, but also prevent ACS.
Usually given in the form of aspirin, all patients with documented CAD should be taking antiplatelet therapy for the prevention of ACS. Low-dose aspirin (75 mg-150 mg) has been shown to be equally effective as medium-dose aspirin (162 mg-325 mg) with less gastrointestinal bleeding complications. Clopidogrel (Plavix) has been shown in small studies to be slightly more effective at reducing ACS and CV death; however, cost concerns have precluded its use in the general population for this purpose, especially with aspirin being inexpensive and effective.
HMG-CoA Reductase Inhibitors
“Statins” have played a pivotal role in reducing CV events and mortality; see HMG-CoA Reductase Inhibitors Topic Review. Every patient with coronary disease should be treated with these agents, regardless of their LDL cholesterol level. Significant mortality benefits and reduction of ACS have been demonstrated in multiple trials, even in patients with coronary disease and normal LDL levels. The “pleiotropic effects” of statins are an intense topic of research. Statins seem to have anti-inflammatory properties and plaque stabilization capabilities independent of LDL lowering. The 2013 American College of Cardiology/American Heart Association guidelines for cholesterol therapy recommend high-intensity statin therapy (defined as > 50% LDL reduction from baseline) in patients aged younger than 75 years with clinical vascular disease such as stable angina. For those aged older than 75 years, moderate-intensity statin therapy (defined as a 30-50% LDL reduction from baseline) is recommended. There are no longer target LDL levels that must be achieved as was the case in the older ATP III cholesterol guidelines.
Managing Stable Angina Symptoms
When stable anginal symptoms develop, treatment is aimed at increasing myocardial oxygen supply and reducing myocardial oxygen demand, as discussed in Pathophysiology. This can be accomplished with nitrates, beta-blockers, calcium channel blockers, ranolazine and external counterpulsation. As these therapies are discussed, recall that wall stress, heart rate and contractility determine oxygen demand.
Nitroglycerin forms the free radical nitric oxide, which has many beneficial properties in the presence of myocardial ischemia. Venodilation, the predominant mechanism, results in decreased preload, in turn reducing LV pressure and LV volume (decreases radius). Some arterial vasodilation from smooth muscle relaxation occurs as well, increasing oxygen supply and reducing vasospasm. It is important to note that nitrates have never been proven in clinical trials to improve survival or reduce the risk for ACS.
Nitroglycerine is available as a sublingual tablet or spray for acute angina attacks on an as-needed basis. When an anginal spell occurs, one tablet/spray is used and relief should be noted within 1 to 3 minutes. If no relief is seen, a second tablet/spray can be taken and, at this point (according to ACC/AHA guidelines), that patient should dial 911 as an ACS may be present. Long-acting nitrates are available in a pill form — isosorbide mononitrate and isosorbide dinitrate — and as a patch to prevent angina from occurring.
Significant headaches can occur, and this limits higher doses of nitrates. Hypotension is common, especially in patients who are “preload dependent” such as during right ventricular infarction. This hypotension can cause a reflex tachycardia, which is not ideal because increased heart rate will increase oxygen demand. Tachyphylaxis, or tolerance resulting in decreased efficacy, occurs with nitrates — requiring drug-free intervals for best results. For example, nitroglycerine patches must be applied in the morning and removed in the evening; when left on all day, tolerance quickly develops, and the clinical benefits decrease significantly.
Phosphodiesterase inhibitors (sildenafil, vardenafil, tadalafil), used to treat erectile dysfunction, enhance nitric oxide production and can cause potentially fatal hypotension when used in combination with nitrates. These two drugs should not be used together within 24 hours (sildenafil) or 48 hours (vardenafil, tadalafil) due to this interaction. Interestingly, it was during investigations of phosphodiesterase inhibitors for the treatment of stable angina when researchers noted the improvement of erectile dysfunction, and thus redirected their efforts.
These drugs block the actions of the sympathetic nervous system, reducing heart rate, contractility and BP, and thereby significantly decreasing oxygen demand; see Beta-Blockers Topic Review. Titration to achieve a heart rate of about 60 beats per minute is frequently required for optimal relief of angina. The commonly-used beta-blockers are metoprolol, atenolol, propranolol and carvedilol.
Although quite effective in relieving angina symptoms, beta-blockers have a number of potential side effects and contraindications. Significant bradycardia can occur, leading to fatigue, hypotension and dizziness. Asthma can be exacerbated, especially with non-cardioselective beta-blockers that antagonize beta-2 receptors. Beta-blocker overdose is treated with glucagon.
Calcium Channel Blockers
There are two types of calcium channel blockers. Dihydropyridine calcium channel blockers (amlodipine, nifedipine) act on peripheral calcium channels to cause smooth muscle relaxation and arterial vasodilation. This increases oxygen supply when the coronary arteries are vasodilated, decreasing afterload (BP) and thus LV pressure, which reduces oxygen demand. Vasodilation of coronary arteries also reduces vasospasm. Non-dihydropyridine calcium channel blockers (diltiazem, verapamil) act on the myocardium to decrease heart rate and contractility, thus reducing myocardial oxygen demand.
Sublingual dihydropyridine calcium channel blockers (nifedipine) were historically used for angina and hypertensive emergencies; however, they have been shown to increase stroke — likely due to sudden severe drop in BP — as well as myocardial infarction and death. Their use has been abandoned except in autonomic dysreflexia in spinal cord injury.
A novel agent to treat angina, the drug ranolazine does not change any hemodynamic parameters (BP, heart rate, vascular tone). The exact mechanism is somewhat controversial; however, it likely inhibits sodium channels, eventually reducing the intracardiac calcium causing reduced oxygen consumption. Initially, ranolazine was thought to shift the main energy substrate of myocytes from lipid metabolism to glucose metabolism, but this has not been definitively proven at normal doses. Ranolazine is considered for patients with angina who fail nitrates, beta-blockers and calcium channel blockers. Although side effects are relatively uncommon, ranolazine can prolong the QT interval, increasing the risk for polymorphic ventricular tachycardia (Torsades de Pointes).
Enhanced external counterpulsation, or EECP, is used in the outpatient setting in patients who are refractory to medical therapy. Compression cuffs are applied to the lower extremities and compressed air is applied during diastole — based on the ECG recording — to improve backward flow to the coronary arteries. This is similar to how an intra-aortic balloon pump works hemodynamically. Significant anginal relief has been shown in small studies, including the including the Multicenter Study of Enhanced External Counterpulsation (MUST-EECP) trial.
Percutaneous Coronary Intervention (PCI)
Percutaneous coronary intervention, known as PCI or stenting, can relieve angina almost instantly in a large majority of patients with hemodynamically significant stenosis (> 70%) in a major epicardial coronary vessel, but has not been definitely shown to improve outcomes. The Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial investigated medical management vs. PCI for patients with CAD and stable angina. Patients were randomized to optimal medical therapy vs. coronary revascularization. There was no mortality benefit, and medical therapy was frequently able to relieve the angina adequately. This is a controversial trial and further investigation is underway.
Coronary Artery Bypass Grafting (CABG)
Surgical revascularization of coronary stenosis with coronary artery bypass grafting is ideal for certain patients. Those with three-vessel CAD have historically been treated with this approach, although some trials question whether multi-vessel stenting may be safer instead; see the Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multi-vessel disease (FREEDOM) trial. Patients with diabetes or those with severe LV systolic dysfunction have improved outcomes with surgical revascularization compared with PCI. Also, when the left main coronary artery or a left main equivalent (proximal left anterior descending and proximal circumflex) is involved, CABG is recommended.
Special Situations – CAD - Stable Angina
Da Costa’s Syndrome
Also known as “soldier’s heart” or “cardiac neurosis,” Da Costa’s syndrome was first described during the American Civil War. Symptoms are that of typical stable angina, but no abnormality is detected on stress testing or angiography, and typical anginal therapies are not effective. In modern times, Da Costa’s syndrome is considered part of a generalized anxiety disorder. Similar symptoms are sometimes seen as a part of the mitral valve prolapse syndrome. This is somewhat different than syndrome X, which can indeed show signs of myocardial ischemia, even with normal coronary arteries and no inducible coronary vasospasm.
This occurs when typical angina is present with ST segment depression upon exercise testing despite angiographically normal coronary arteries without inducible coronary vasospasm with ergonovine infusion. This is a controversial topic, as no clear etiology has been seen. Some authorities believe actual myocardial ischemia is present — perhaps in the coronary microvasculature — and others categorize this as a part of an anxiety disorder or “sensitive heart,” similar to Da Costa’s syndrome.
Hibernating myocardium occurs when significantly reduced blood flow affects a segment of the myocardium, causing dysfunction on a chronic basis. If blood flow is restored via PCI or surgical bypass grafting, the function can return to normal. Viability testing can help determine if myocardium is hibernating or completely infarcted. This testing is best performed using magnetic resonance imaging, or MRI, but can also be achieved with positron emission tomography, or PET, scanning, thallium myocardial perfusion imaging and dobutamine stress echocardiography.
Stunning of the myocardium occurs when transient ischemia resulting from total or subtotal coronary occlusion, such as during an ACS, results in segmental myocardial dysfunction. When blood flow is restored via coronary revascularization, the dysfunction persists. Segmental LV dysfunction can remain for days or even weeks after the ischemic insult, but eventually returns to normal.
In the setting of chronic ischemia, collateral circulation may develop to compensate for the reduced blood flow. These consist of small vessels that grow from sub-branches of a neighboring, non-occluded coronary vessel. Collateral circulation can sometimes be extensive and is increased by exercise. Some patients develop more extensive collateral circulation than others, and some therapies are under investigation to enhance the development of coronary collaterals.
This occurs when angina is present with lower level of activity but is relieved when exercise is continued. On treadmill testing, ST segment depression may be seen early on, then completely resolves. It is believed this is due to myocardial ischemia resulting in release of vasodilators, which help open collateral circulatory channels, eventually increasing the flow to the ischemic myocardial segment and relieving the symptoms of angina.
When arterial tone is suddenly increased, coronary vasospasm can occur and result in angina. This is also known as Prinzmetal’s Angina or Variant Angina. Coronary arteries are angiographically normal, but vasospasm can be induced by ergonovine or acetylcholine infusion. The treatment is dihydropyridine calcium channel blockers. Beta-blockers should be avoided, as this leads to “unopposed alpha agonism,” which worsens vasoconstriction. Circulating catecholamines will agonize alpha receptors more easily if the beta-receptors are occupied by a beta-blocker.
The ECG during coronary vasospasm can be markedly abnormal mimicking ischemia or an ST segment elevation myocardial infarction. The ECG changes quickly resolve once the angina and vasospasm are relieved. Coronary vasospasm is most common in middle-aged women.
This occurs when a coronary vessel does not run along the epicardial surface of the heart, but instead dives deeply to run within the myocardial wall itself. During contraction, the coronary vessel can be compressed and is frequently seen on angiography. Exercise exacerbates this due to increased contractility and faster heart rates, resulting in decreased time in diastole; recall that the coronary arteries fill in diastole. On rare occasions, myocardial bridging is thought to cause angina; however, the finding is benign and has no clinical significance a majority of times. Vasospasm has been more commonly found to be in patients with myocardial bridging.
When a coronary arterial wall becomes weakened, it can dilate and form a coronary artery aneurysm. This can occur as post-stenotic dilation during atheroslcerotic coronary disease or can occur as a part of a vasculitis. Kawasaki’s disease — a form of vasculitis — during childhood can lead to coronary aneurysms in adulthood that cause ischemic heart disease and angina when the coronary aneurysms are large, The pathophysiologic mechanism of ischemia is thought to be due to microemboli; thus, anticoagulation with warfarin is frequently utilized, though there is no clinical data to support this therapy.
Congenital Coronary Anomalies
Many types of congenital variations of the coronary arteries exist. Although most are benign, some anomalous coronary arteries can pass between the aorta and the pulmonary artery — known as an interarterial course — and cause compression, myocardial ischemia and angina. Coronary anomalies are the second leading cause of sudden cardiac death in young athletes, after HOCM. Some examples include the left anterior descending originating from the right coronary cusp, the right coronary artery arising from the left main coronary artery, and the circumflex coronary artery arising from the right coronary cusp.
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