Coronary artery disease

Coronary artery disease (CAD) is an ischemic heart disease that is most commonly caused by atherosclerosis and the subsequent reduction of blood supply to the myocardium, resulting in a mismatch between myocardial oxygen supply and demand. Acute retrosternal chest pain (angina) is the cardinal symptom of CAD. Other symptoms include dyspnea, dizziness, anxiety, and nausea. Severe ischemia may lead to myocardial infarction (MI). CAD is diagnosed using cardiac stress testing and/or coronary catheterization. Management of CAD involves primary and secondary prevention of atherosclerosis (e.g., weight reduction), antianginal treatment (e.g., beta blockers) and, in severe cases, revascularization (e.g., percutaneous transluminal coronary angioplasty).

This article provides a basic overview of coronary artery disease and stable angina. “Atherosclerosis” and “Acute coronary syndrome” (including myocardial infarction) are discussed in separate articles.

• Coronary artery disease (CAD): ischemic heart disease due to narrowing or blockage of coronary arteries, most commonly due to atherosclerosis, resulting in a mismatch between myocardial oxygen supply and demand
• Angina: chest pain caused by myocardial ischemia (necrosis of myocytes has not yet occurred) due to narrowing (e.g., thrombus) or spasm (e.g., Prinzmetal angina) of the coronary artery
• Stable angina: a type of angina that occurs upon exertion, mental stress, and/or exposure to cold and usually subsides within 20 minutes of rest or after administration of nitroglycerin

• CAD is the leading cause of death in the US and worldwide. ^[1]
• The lifetime risk of coronary artery disease at age 50 is approx. 50% for men and 40% for women. ^[2]

Epidemiological data refers to the US, unless otherwise specified.

• Atherosclerosis is the most common cause (see “Risk factors for atherosclerosis”).

Plaque formation and coronary artery stenosis ^[3][4]

• For plaque formation, see “Pathogenesis of atherosclerosis.”
• Stable atherosclerotic plaque → vascular stenosis → increased resistance to blood flow in the coronary arteries → decreased myocardial blood flow → oxygen supply-demand mismatch → myocardial ischemia
• The extent of coronary stenosis determines the severity of the oxygen supply-demand mismatch and, thus, the severity of myocardial ischemia.
• Severe ischemia results in myocardial infarction (see “Acute coronary syndrome”).
• Coronary flow reserve (CFR): the difference between maximum coronary blood flow and coronary flow at rest (a measure of the ability of the coronary capillaries to dilate and increase blood flow to the myocardium).
  • In healthy individuals, the CFR can be up to 4 times higher on exertion than at rest.
  • CFR is reduced in individuals with CAD due to vascular stenosis and reduced vascular compliance.

Myocardial oxygen supply-demand mismatch ^[5]

• Definition: mismatch between the amount of oxygen the myocardium receives and the amount it requires
• Factors reducing oxygen supply
  • Coronary atherosclerosis and sequelae, including:
    • Rupture of an unstable atherosclerotic plaque (most common cause)
    • Thrombosis
    • Stenosis
  • Vasospasms
  • ↑ Heart rate
  • Anemia
• Factors increasing oxygen demand
  • ↑ Heart rate
  • ↑ Afterload
  • Anemia

An increased heart rate reduces oxygen supply and increases oxygen demand.

Effect of vascular stenosis on resistance to blood flow ^[6]

• The resistance to blood flow within the coronary arteries is calculated using the Poiseuille equation: R = 8Lη/(πr⁴), where R = resistance to flow, L = length of the vessel, η = viscosity of blood, and r = radius of the vessel.
• Provided the length of the vessel and viscosity of blood remain constant, the degree of resistance can be calculated using the simplified formula: R ≈ 1/r⁴

Vascular stenosis increases vascular resistance significantly. For example, a 50% reduction in radius results in a 16-fold increase in resistance: R ≈ 1/(0.5 x r)⁴ = [1/(0.5 x r)]⁴ = (2/r)⁴ = 16/r⁴.

Myocardial ischemia ^[5]

• Reversible ischemia: Tissue is ischemic but not irreversibly dead and, therefore, still potentially salvageable.
  • Myocardial stunning: acutely ischemic myocardial segments with transiently impaired but completely reversible contractility
  • Hibernating myocardium: a state in which myocardial tissue has persistently impaired contractility due to repetitive or persistent ischemia
    • Partially or completely reversible when adequate oxygen supply is restored (e.g., after angioplasty or coronary artery bypass grafting)
    • Seen in angina pectoris, left ventricular dysfunction, and/or heart failure
• Irreversible ischemia: tissue necrosis (myocardial scars)

Coronary steal syndrome

• Definition: a phenomenon of vasodilator-induced alteration of coronary blood flow in patients with coronary atherosclerosis resulting in myocardial ischemia and symptoms of angina
• Pathomechanism
  • Long-standing CAD requires maximal coronary arterial dilation distal to the stenosis to maintain normal myocardial function.
  • In CAD, the affected coronary artery is maximally dilated distal to the stenosis to compensate for the reduced blood flow .
  • If a vasodilator (e.g., dipyridamole) is administered, the subsequent vasodilation of healthy vessels causes these to “steal” blood from the stenotic blood vessels, resulting in poststenotic myocardial ischemia.
• Clinical relevance
  • Coronary steal is the underlying mechanism of pharmacological stress testing.
  • Administration of vasodilators (e.g., dipyridamole) → coronary vasodilation → decreased hydrostatic pressure in the normal coronary arteries → blood shunting back to well-perfused myocardium → decreased flow to the ischemic myocardium → myocardial ischemia downstream to the pathologically dilated vessels → angina pectoris and/or ECG changes

Coronary steal syndrome should not be confused with coronary-subclavian steal syndrome.

Chronic ischemic heart disease

• Definition: progressive heart failure that occurs after many years of chronic ischemic damage to the myocardium

Angina

Angina is the cardinal symptom of CAD. Patients with CAD usually become symptomatic when the degree of coronary stenosis reaches ≥ 70%.

• Typically retrosternal chest pain or pressure
  • Pain may radiate to the left arm, neck, jaw, epigastric region, or back.
  • Pain is not affected by body position or respiration.
  • No chest wall tenderness
  • May gradually increase in intensity
  • May present as gastrointestinal discomfort
  • May be absent, especially in geriatric and diabetic patients. ^[7]
• Dyspnea
• Dizzinesss, palpitations
• Restlessness, anxiety
• Autonomic symptoms (e.g., diaphoresis, nausea, vomiting, syncope)

Stable angina

• Symptoms are reproducible/predictable
• Symptoms often subside within minutes with rest or after administration of nitroglycerin
• Common triggers include mental/physical stress or exposure to cold

Vasospastic angina

• Description
  • Angina caused by transient coronary spasms (usually due to spasms occurring close to areas of coronary stenosis)
  • Not affected by exertion (may also occur at rest)
  • Typically occurs early in the morning ^[8]
• Epidemiology ^[9]
  • Highest prevalence in Japanese population (especially young women)
  • Average age of onset: 50 years
• Etiology
  • Cigarette smoking; use of stimulants (e.g., cocaine, amphetamines), alcohol, or triptans
  • Stress, hyperventilation, exposure to cold
  • Associated with other vasospastic disorders (e.g., Raynaud phenomenon, migraine headaches) ^[10]
  • Common atherosclerotic risk factors (except smoking) do not apply to vasospastic angina.
• Diagnostics
  • Reversible ST elevation on ECG
  • No troponin I or troponin T elevations on serial measurements
  • Coronary spasms on angiography confirm the diagnosis.
• Treatment
  • Lifestyle modification (especially smoking cessation)
  • Calcium channel blockers (CCBs): first-line agents for acute attacks and prophylaxis
  • Long-acting nitrates
  • Avoid beta-blockers
• Prognosis
  • The 5-year survival rate is > 90% (with treatment). ^[11]
  • Persistence of symptoms is common.

Patient history and physical exam

• History of recurrent angina episodes
• Signs of atherosclerotic vascular disease (e.g., absent foot pulses, carotid bruit)

Pretest probability of CAD

• Clinical assessment of symptomatic patients to predict the probability of CAD, used to:
  • Help determine the need for further diagnostic tests
  • Guide the selection of best initial diagnostic test

Factors used to estimate the probability of CAD ^[12]

• The pretest probability takes into consideration:
  • Patient's age and sex
  • Type of chest pain
    • Typical angina meets all of the following criteria:
      • Retrosternal chest pain of typical quality and duration (e.g., transient retrosternal pain)
      • Provoked by exertion or emotional stress
      • Relieved by rest and/or nitroglycerin
    • Atypical angina: meets only 2 of the aforementioned criteria
    • Noncardiac chest pain: meets one or none of the aforementioned criteria

Resting ECG

• Best initial test for all types of chest pain
• Usually normal in stable angina
• ST segment depression or T wave inversion/flattening indicates previous MI or unstable angina and requires further workup (see “Diagnosis of ACS”).

Cardiac stress test ^[14]

• Best test for assessing patients with an intermediate pretest probability of CAD.

Provocation methods

• Cardiac exercise stress test: test of choice (preferred over pharmacological testing because exercise can achieve a higher level of strain)
  • The patient exercises until the target heart rate is achieved (e.g., on a treadmill).
    • Maximum heart rate = 220 – age (in years)
    • Target heart rate = 85% of the maximum heart rate
  • Contraindications ^[15][16]
    • Acute myocardial infarction with elevated troponin levels and/or ST elevations (within the past 2 days)
    • Unstable angina pectoris or ST depressions at rest
    • Decompensated heart failure or severe symptomatic stenosis of one or more heart valves
    • Acute endocarditis, myocarditis, or pericarditis
    • Hemodynamically significant arrhythmias
    • Acute thromboembolic disease
    • Acute aortic dissection
    • Mental or physical impairment to exercise
• Cardiac pharmacological stress test: performed if the patient is unable to exercise or has contraindications for exercising
  • Positive inotropic/chronotropic substances (e.g., dobutamine) or vasodilators (e.g., dipyridamole or adenosine) are administered to simulate the effect of exercise on the myocardium.
  • Contraindications
    • For adenosine, dipyridamole
      • Active bronchospasm or reactive airway disease
      • First-degree heart block
      • Low systolic blood pressure (< 90 mm Hg)
      • Methylxanthines
    • For dobutamine
      • Myocardial infarction within the last week
      • Unstable angina
      • Obstructive cardiomyopathy, aortic stenosis
      • Tachyarrhythmias
      • Left bundle branch block
      • Untreated hypertension
      • Thoracic aortic aneurysm

Preparation

• If cardiac stress test is performed for primary diagnosis, withhold the following:
  • Beta blockers, CCBs, nitrates (48 hours)
  • Methylxanthines (especially if a pharmacological cardiac stress test is considered); : caffeine (12 hours); , aminophylline; (24 hours), dipyridamole (48 hours)
• If a cardiac stress test is performed for treatment evaluation, medication can be continued.

Findings in stress-induced ischemia ^[17]

• Clinical findings
  • The following findings should prompt immediate interruption of stress testing:
    • New onset/intensification of chest pain
    • Severe dyspnea, cyanosis, pallor, ataxia, or altered mental status
    • Decrease in systolic BP below the resting BP ^[12]
    • Systolic BP > 250 mm Hg or diastolic BP > 120 mm Hg ^[18]
• ECG (detection method of choice)
  • Downsloping or horizontal ST depressions of ≥ 0.1 mV in the limb leads and ≥ 0.2 mV in the precordial leads
  • ST elevations ≥ 0.1 mV (requires immediate test termination)
  • Excessive or delayed increase in heart rate
  • New-onset ventricular arrhythmia
• Imaging: (echocardiography, myocardial perfusion imaging)
  • Used if the patient's resting ECG cannot be interpreted
  • Helps distinguish between reversible ischemia and irreversible ischemia
  • Echocardiography
    • To detect wall motion abnormalities
    • Simultaneous evaluation of ventricular size and functional parameters (e.g., EF) and detection of valvular disorders is possible.
  • Radionuclide myocardial perfusion imaging (PET or SPECT): to visualize perfusion ^[19]

Patients with new-onset chest pain, ST-depression, hypotension, or arrhythmias should undergo cardiac catheterization.

Cardiac catheterization

• Indications
  • Persistent symptoms of angina despite appropriate therapy
  • Abnormal results of noninvasive testing
  • Ambiguous results on noninvasive procedures and in high clinical suspicion of CAD
• Advantages
  • Considered the gold standard of CAD diagnosis since it provides:
    • Information on several parameters; (e.g., coronary blood flow; , pressure within heart chambers, cardiac output, oxygen saturation)
    • Direct visualization of coronary arteries (coronary angiography)
    • Opportunity for direct therapeutic intervention using percutaneous coronary intervention (see “Treatment” below)

Additional tests

• Holter monitoring
  • Can detect silent ischemia and arrhythmias
  • May be used to evaluate heart rate variability and pacemaker/ICD function
• Coronary magnetic resonance imaging (CMRI) or coronary computed tomography angiography (CCTA)

See “Differential diagnosis of chest pain.”

The differential diagnoses listed here are not exhaustive.

Approach ^[20]

• All patients: risk factor reduction and antiplatelet drugs (see “Prevention” below)
• Mild CAD: pharmacologic therapy
• Moderate CAD: consider coronary angiography and percutaneous transluminal coronary angioplasty (PTCA)/percutaneous coronary intervention (PCI)
• Severe CAD: coronary angiography and revascularization or coronary artery bypass grafting

Antianginal treatment ^[20]

• Goal: reduction of MVO₂ (myocardial O₂ demand)
  • This can be achieved by altering the following parameters that influence the extent of MVO₂:
    • Blood pressure
    • Heart rate
    • Inotropy (contractility)
    • Ejection time
    • End-diastolic volume
• First-line
  • Beta blockers (except in vasospastic angina)
    • Can reduce the frequency of coronary events
    • Partial beta agonists like pindolol and acebutolol should be used cautiously.
  • Nitrates
    • Can prevent exertional angina
    • Suitable for relief of acute angina or for long-term treatment
• Second-line
  • CCBs: indicated if there are contraindications to beta blockers or in addition to beta blockers (if angina or hypertension persist)
  • Ranolazine: a metabolic modulator that reduces myocardial oxygen demand without altering the heart rate, blood pressure, contractility, and/or end-diastolic volume
    • Indication: stable angina that is refractory to first-line treatment
    • Mechanism of action
      • Inhibition of late inward sodium channels on cardiac myocytes → reduced calcium influx (via sodium-calcium channel pump) → reduced wall stress and oxygen demand
      • Decreased rate of fatty acid beta-oxidation (aerobic process) with a simultaneous increase in glycolysis (anaerobic process) ^[21]
    • Side effects
      • Nausea, constipation
      • Headache, dizziness
• Combination therapy
  • Indicated if angina persists with monotherapy
  • Beta blocker PLUS nitrate
  • CCB (nondihydropyridine) PLUS nitrate (CCBs, such as verapamil, have a similar effect to beta blockers.)
  • Beta blocker PLUS CCB (long-acting dihydropyridine, such as nitrendipine)

Revascularization

• Indications
  • Stable angina, in the presence of:
    • Activity-limiting symptoms despite optimal medical treatment
    • Contraindications to medical therapy
    • Stenosis of critical (e.g., LCA) or multiple coronary arteries
  • Acute coronary syndrome
• Techniques
  • Percutaneous coronary intervention
  • Coronary artery bypass grafting

• Prognostic factors
  • Left ventricular function: increased mortality if EF < 50% ^[22]
  • Involvement of left main coronary artery or involvement of more than one vessel is associated with a worse prognosis
• Stable angina
  • Annual mortality rate: up to 5% ^[23]
  • 25% of patients will develop acute myocardial infarction within the first 5 years. ^[24]
  • High-grade stenosis is associated with an unfavorable prognosis.

Prevention of atherosclerosis

• See “Primary and secondary prevention of atherosclerosis.”

Special considerations in coronary artery disease ^[25][26]

• Antiplatelet drugs
  • For myocardial infarction prevention
  • Aspirin or clopidogrel; (if aspirin/ASA is contraindicated) for all patients with CAD
• Arterial hypertension management
  • Blood pressure targets: < 140/90 mm Hg in cases of low/moderate risk and < 130/80 mm Hg in high-risk patients
  • Beta blockers: first-line therapy
  • ACE-inhibitors: in post-MI patients (especially those with left ventricular systolic dysfunction)
  • CCBs (see “Antianginal treatment” above)
• Diabetes mellitus: maintenance of HbA_1c at < 7% levels
• Lipid levels
  • Lifestyle modifications (e.g., weight loss, diet modification)
  • See “Guidelines for lipid-lowering therapy (ATP III guidelines).”