Ahmed Elsherif, Suez Canal University; Stanley Oiseth, Chief Medical Editor, Lecturio

Ischemic heart disease (IHD), also termed coronary artery disease (CAD), describes a wide range of clinical conditions in which there is an imbalance between oxygen supply and the myocardial demands resulting in ischemia to a portion of the myocardium.

For further review of this topic, including links to lectures by specialists in the field, follow these links:

This article is not intended to be a substitute for professional medical advice and should not be relied on as health or personal advice. Always seek the guidance of your doctor or other qualified health professional with any questions you may have regarding your health or a medical condition.

Ischemic heart disease

Types of ischemic heart disease. Image by Lecturio.


Ischemic heart disease (IHD), also termed coronary artery disease (CAD), describes a wide range of clinical conditions in which there is an imbalance between oxygen supply and the myocardial demands resulting in ischemia to a portion of the myocardium.

IHD can be classified into stable disease (stable angina) and unstable disease (acute coronary syndrome). 

The major coronary vessels are the right coronary artery (RCA), the left coronary artery (LCA), the left circumflex anterior artery (LCx), and the left anterior descending (LAD) artery.


IHD is the leading cause of death worldwide. It is considered the most common serious chronic illness in the United States, accounting for 42% of all cardiovascular deaths.

Lifetime risk of coronary heart disease:

  • Age 40: 49% in men and 32% in women
  • Age 75: 35% in men and 24% in women

Risk Factors

The most common risk factor of coronary heart disease is atherosclerosis of epicardial coronary arteries, resulting in partial or complete obstruction with subsequent inadequate perfusion of the myocardium supplied by the involved coronary artery.

Many risk factors have been involved in the pathophysiology of coronary heart disease. Among the main risk factors (in addition to an increase of LDL cholesterol or a decrease of HDL cholesterol) include arterial hypertension, diabetes mellitus, and smoking, as well as family history and male gender.

In patients who suffer a heart attack at a younger age (< 30 years), other causes may play a role. These include familial lipid metabolism disorders as well as hypothyroidism and vasculitis. Coronary anomalies, antiphospholipid syndrome, and hyperviscosity syndrome should also be excluded. During history taking, possible drug abuse should be ascertained.

Fixed (Non-Modifiable) Risk Factors
Age Risk increases with age and is rare during childhood, except in cases where the patient has familial hyperlipidemia.
Male Sex Men have a higher incidence of coronary artery disease than premenopausal women. The incidence of atherosclerosis in women increases after menopause due to deficiency of estrogen hormone.
Family History Positive family history is defined as development of coronary heart disease in a first-degree relative before the age of 50 years.
Modifiable Risk Factors
Hyperlipidemia High levels of cholesterol, especially increased low-density lipoprotein (LDL) and decreased high-density lipoprotein (HDL), are associated with an increased risk of atherosclerosis.
Hypertension Systolic and diastolic hypertension are associated with an increased risk of coronary heart disease.
Cigarette Smoking Number of cigarettes smoked is directly related to the risk of coronary heart disease. Cessation of smoking reduces the risk by 25%.
Diabetes Mellitus Abnormal glucose tolerance, or diabetes mellitus, increases the risk of IHD and often coexists or contributes to other risk factors, such as dyslipidemia, obesity, and hypertension.
Lack of Exercise The recommendation is to exercise regularly for 30 minutes with moderate intensity for 5 days/week.
Obesity Reduction of body weight by exercise and healthy diet decreases the risk of coronary heart disease and the risk of diabetes and insulin resistance.
Alcohol Moderate intake of alcohol (1 or 2 drinks/day) is associated with a reduced risk of coronary artery disease. At higher levels, the risk is increased.
Coronary Artery Disease

Drawing of a heart demonstrating advanced atherosclerosis of the left anterior coronary artery. Image: “Coronary artery disease” by BruceBlaus, License: CC BY 3.0

Coronary Artery Stenosis

Stenosis of the coronary arteries can lead to an insufficient supply of oxygen to the heart muscle tissue, or decreased coronary flow reserve (“coronary reserve”), which is the ratio of maximum flow to resting flow. With a normal coronary artery, a vasodilatory stimulus results in an approximately fourfold increase in flow rate compared to baseline. With progressive stenosis, baseline flow remains normal until the coronary artery is narrowed by 80–85%. Coronary flow reserve, however, begins to decrease at 40–50% diameter stenosis. Coronary flow reserve decreases to two times baseline at approximately 75% stenosis, which indicates myocardial ischemia.

Coronary Artery Disease

Drawings of a normal artery and an artery with an atherosclerotic plaque, as typically seen in atherosclerotic coronary artery disease. The atherosclerotic plaque usually has an irregular morphology and may not involve the entire circumference of the artery, as depicted here. Image: “Coronary artery disease” by BruceBlaus. License: CC BY 3.0

Myocardial Oxygen Demand

4 major factors determine the oxygen demand of the myocardium:

  1. Heart rate
  2. Systolic blood pressure (after-load)
  3. Tension on myocardial wall (preload)
  4. Myocardial contractility

Any clinical condition increasing these factors will also increase the myocardial oxygen demand and can result in ischemia, such as tachycardia, hypertension, and ventricular hypertrophy.

Myocardial Oxygen Supply

The capacity of the blood to carry oxygen to the myocardium is affected by different factors such as the hemoglobin level, oxygen tension, and the amount of extracted oxygen from hemoglobin to the tissue, which is related to 2,3 diphosphoglycerate levels. Another factor is coronary artery blood flow, which is affected by the following factors:

  • Coronary artery diameter: Coronary atherosclerosis is the most frequent cause of narrowing and obstructing the coronary artery.
  • Coronary artery tone: Coronary vasospasm, as in variant or Prinzmetal’s angina, reduces the oxygen supply without significant underlying atherosclerotic changes.
  • Perfusion pressure: determined by the pressure gradient from the aorta to the coronary artery.
  • Heart rate: Coronary artery flow occurs mainly during diastole, therefore extreme tachycardia will decrease the duration of diastole, thereby decreasing the blood flow into the coronary arteries.

Any clinical condition affecting these factors will reduce the myocardial oxygen supply and can result in ischemia.


Patients with coronary heart disease (CAD) can present with either:

  1. Chronic disease, which most commonly presents as stable angina.
  2. Acute coronary syndromes (ACSs), which are almost always associated with rupture of an atherosclerotic plaque, followed quickly by partial or complete thrombosis of the infarct-related artery. ACS is a term that encompasses:
    • Unstable Angina (UA)
    • Myocardial infarction, divided into:
      • ST-segment elevation myocardial infarction (STEMI)
      • Non-ST-segment elevation myocardial infarction (NSTEMI)
  3. Sudden cardiac death (SCD) is an unexpected death due to cardiac causes occurring in a short time period (generally within 1 hr of symptom onset) in a person with known or unknown cardiac disease. 
    • SCD represents the first expression of CAD in many individuals who experience out-of-hospital cardiac arrest
    • Most cases of SCD are related to cardiac arrhythmias. 
    • ~ 50% of all cardiac deaths


When occurring for the first time, angina pectoris is considered unstable!

Special Forms

Variant (Prinzmetal) Angina: caused by a vasospasm occurring at rest. 

Silent Myocardial Ischemia 

  • Silent ischemia occurs when typical symptoms are missing. It occurs frequently in diabetics (due to neuropathy), patients with renal insufficiency, women, and elderly patients. 
  • The atypical symptoms can be very non-specific. Dizziness and nausea, as well as shortness of breath, generalized weakness, malaise, and epigastric pain, are the most common atypical symptoms.
  • 10-40% of acute myocardial infarctions are not associated with chest pain, most commonly in the elderly, women, diabetics, and often associated with non ST-segment-elevation myocardial infarctions. They are associated with more complications and significantly higher short-term mortality compared with patients presenting with chest pain.

Post-infarction Angina: may occur within 2 weeks after a myocardial infarction.


Several prognostic indicators determine the outcome of coronary heart disease (IHD):

  • Function of the left ventricle: Increased left ventricular end-diastolic pressure, increased ventricular volume and reduced ejection fraction are associated with poor prognosis.
  • Location and severity of coronary artery stenosis: Stenosis of the main left anterior descending coronary artery (“the widow-maker”) is associated with greater risk and poor prognosis.
  • Number and severity of risk factors: Large number of risk factors for atherosclerosis are associated with increased risk of myocardial infarction with a worse prognosis.

Stable angina is defined as substernal discomfort or pressure (the more commonly used descriptor) precipitated by exertion or other stress, with radiation to the shoulder, jaw, or inner aspect of the arm relieved by rest or nitroglycerin in less than 10 minutes. It is typically triggered by physical exertion, psychological stress, or exposure to the cold. The same type and degree of exertion or stress (e.g., walking up 2 flights of stairs) produces the same symptoms. It usually subsides within <10 minutes after rest or after administration of nitrates. Suspect ACS in angina lasting longer than 20 minutes.

Note: Stable anginal pain is always of similar intensity and quality.

Unstable angina (UA) is defined as myocardial ischemia at rest or with minimal exertion in the absence of acute myocardial injury/necrosis. It may be characterized by: prolonged (>20 minutes) angina at rest; new onset of angina; angina that is increasing in frequency, duration, trigger threshold, or that which occurs after a recent episode of myocardial infarction. Many previously diagnosed UAs were probably NSTEMIs, which are diagnosed now with sensitive (troponin) markers of necrosis.



Diagram of discomfort caused by coronary artery disease

Image: “Diagram of discomfort caused by coronary artery disease. Pressure, fullness, squeezing or pain in the center of the chest. Can also feel discomfort in the neck, jaw, shoulder, back or arm.” By lan Furst. License: CC BY-SA 3.0

Onset, Course, and Duration 

The pain starts gradually, with the intensity increasing and decreasing (crescendo-decrescendo in nature) within minutes and typically lasts for 2–5 minutes. It generally does not last for >20 minutes

Site of Pain

Coronary pain is usually described as central substernal discomfort in which the patient can’t exactly localize but typically places his palm or clenched fist over the sternum.


The pain radiates to any dermatome from C8 to T4, most often to the left shoulder and left arm (especially the ulnar surface). It can also radiate to the interscapular region, back, epigastrium, and lower jaw.

Precipitating and Relieving Factors

Episodes of angina are provoked by physical exertion and intense emotion and relieved within minutes by rest and sublingual nitroglycerin.

Associated Symptoms

Angina is usually associated with shortness of breath, diaphoresis, dizziness, light-headedness, and fatigue.


Physical examination is usually unremarkable in patients with stable angina when they are asymptomatic; however, clinicians should search for:

  • Important risk factors such as hypertension and diabetes mellitus
  • Evidence of atherosclerosis at other sites, as carotid bruits and peripheral vascular disease
  • Evidence of valvular diseases and left ventricular dysfunction


Resting ECG

It is normal between attacks and may show evidence of previous myocardial infarction. During the pain, reversible ST-segment depression (injury pattern) or elevation, with or without T-wave inversion, is suggestive of myocardial ischemia.

Resting ECG. Image by Lecturio.

Exercise ECG


Image: “Stress-ECG with ST-segment-depression (arrow) in columns C and D” by J. Heuser. License: CC BY-SA 3.0

Ischemia that is not present at rest is detected by provoking chest pain using a treadmill. Planar or downsloping ST-segment depression of 1 mm or more is indicative of ischemia.

Isotope Scanning

Thallium scan can show areas of diminished uptake of radioactive isotope by coronary myocardium at rest or during exercise.


It visualizes the location, number, and severity of coronary artery stenosis, and is indicated when coronary revascularization is being considered.


General Measures

  1. Lifestyle modification and control of the previously mentioned risk factors.
  2. Assessment of the extent and severity of atherosclerosis affecting different body organs.

Medical Treatment

  1. Antiplatelet therapy: Low-dose aspirin or clopidogrel (if aspirin- intolerant) should be prescribed for all patients.
  2. Antianginal therapy:
  • Nitrates:
    • Causes venous and arterial dilatation, thus lowering myocardial oxygen demand by reducing the preload and afterload on the heart
    • Sublingual glyceryl trinitrate (GTN) should be taken during attack, relieves the pain within 2–3 minutes
    • Taken prophylactically before strenuous exercise
  • Beta-blockers:
    • Lower myocardial oxygen demand by reducing heart rate and force of contraction
    • Aim of therapy: relieve angina and ischemia, and reduce mortality and re-infarction rates after myocardial infarction
  • Calcium channel antagonists:
    • Lower myocardial oxygen demand by reducing blood pressure and myocardial contractility

Coronary Revascularization


Image: “A coronary angiogram” by Bleiglass. License: CC BY-SA 3.0

It’s more appropriate to start treatment of stable angina with medical treatment. Coronary revascularization should be considered in:

  • Low exercise capacity or ischemia at low workload
  • Large area of coronary myocardium
  • Impaired LV function with ejection fraction <40%

Percutaneous coronary intervention is mainly used in patients with single-vessel or 2-vessel disease with suitable anatomy, whereas coronary artery bypass grafting (CABG) is mainly used in patients with 3-vessel or left main stem disease.

Vasospastic Angina


A sudden coronary artery spasm that leads to a reduction in coronary blood flow, thus causing severe chest pain (angina) at rest, is called vasospastic angina. It was formerly called Prinzmetal’s angina or variant angina. This type of angina occurs at rest, rather than with exertion or any other initiating factors, and is promptly relieved by short-acting nitrates. This chest pain usually lasts less than 15–30 minutes. Myocardial ischemia in variant angina is due to transient vasospasm with or without any underlying pathology. 


Vasospastic angina is an uncommon cause of myocardial ischemia, responsible for approximately 5% of angina cases. Patients are generally younger (< 50 years of age) than those with stable or unstable angina secondary to coronary artery atherosclerosis.

This syndrome has a higher incidence in Japan compared to Western countries, with a higher prevalence in women. The overall incidence has decreased significantly over the past thirty years. It is believed that this decline is due to increased use of calcium antagonists to treat hypertension.


Causes of Vasospastic Angina

Coronary artery spasm can occur as a result of various risk factors such as stress, smoking, cocaine use, insulin resistance, and medications that have the effect of constricting blood vessels, such as triptans.

Rarely, coronary artery vasospasm may be triggered after coronary artery bypass surgery or near a drug-eluting stent. Generally, the specific trigger is unknown. Many patients don’t usually display the classical coronary risk factors, apart from heavy smoking.

Variant angina is associated with systemic vasomotor disorders such as migraine and Raynaud’s phenomenon. This suggests the presence of a general vascular disorder.


The underlying mechanism causing vasospasm in vasospastic angina is debatable, and many theories have been put forward in recent years. Vasospasm occurs in response to local vasoconstrictor stimuli in the coronary segment. Impaired regulation of myofibril contraction in smooth muscle cells of coronary vessels causes smooth muscle hyperactivity, resulting in vasospasm.

Other abnormalities of the endothelium such as a defect in the enzyme endothelial nitric oxide synthase can lead to reduced levels of nitric oxide. Nitric oxide is a natural vasodilator, and its decreased synthesis can lead to vasoconstriction. Current studies also show that coronary artery vasospasm can result from impairment of K+ ATP-dependent channels and hyperactivity of an intracellular enzyme rho-kinase.

Sudden vasoconstriction resulting from any of the aforementioned phenomena leads to decreased coronary blood flow which causes myocardial hypoxia which triggers angina.

In vasospastic angina, focal coronary artery spasm occurs and significantly reduces the diameter of the coronary artery lumen, causing temporary occlusion and leading to myocardial ischemia. This vasospasm can occur in normal-appearing arteries as well as in arteries affected by atherosclerosis. The right coronary artery is most commonly affected, but more than one artery may be involved, which is a negative prognostic factor.

Coronary Circulation

Image: “Coronary Circulation” by PhilSchatz. License: CC BY 4.0

The exact mechanisms that cause coronary artery spasm are not completely understood. Some theories that have been proposed relate to endothelial dysfunction and increased contractility of vascular smooth muscle. With endothelial dysfunction, there is an imbalance between relaxing and contracting factors that are produced by the endothelium.

An important mechanism is related to decreased nitric oxide (NO) production by the dysfunctional endothelium, which is normally made from L-arginine by endothelial NO synthase. As NO has potent smooth muscle relaxation and vasodilator effects, reduced levels can contribute to vasoconstriction. Increased activity of phospholipase C (PLC) has also been reported, which is an enzyme that mobilizes intracellular calcium and may cause smooth muscle contraction.

Rho-kinase is also believed to play a role in the pathogenesis of this condition, involved in regulating vascular smooth muscle contractility.

Other factors that have been suggested to contribute to the pathogenesis of coronary artery spasm include autonomic nervous system dysfunction, magnesium deficiency, chronic low-grade inflammation, and increased oxidative stress (with smoking). Genetic factors may be involved, as there is a 3-fold greater incidence in Japanese people, compared to Caucasians. It is possible that certain genetic mutations predispose to coronary artery spasm, such as those affecting the endothelial NOS gene.

Clinical Features

Symptoms of Vasospastic Angina

Patients experience very severe central chest pain, which is the same type of pain as classic angina. These attacks tend to happen at rest or during normal activity. Some patients may also experience these attacks during or after exercise, including those who have co-existing fixed coronary artery stenosis. Other symptoms include shortness of breath and palpitations. Patients typically experience attacks of angina in clusters, from midnight to early morning. 

Patients with variant coronary syndrome often have asymptomatic ischemic episodes. If coronary artery spasm causes a prolonged disturbance in coronary blood flow, it can cause a myocardial infarction.

Syncope may also occur if there are disturbances to the heart rhythm such as asystole, atrioventricular block, or ventricular tachyarrhythmias. Fatal arrhythmias and sudden cardiac death can also occur.


Definitive vasospastic angina is diagnosed if the angina responds to nitrates and there are transient ischemic ECG changes during the spontaneous episodes or coronary artery arteriography documents >90% spasmodic constriction during a spontaneous or induced episode. Suspected vasospastic angina is diagnosed if nitrate-responsive angina is present but no definite ECG changes or coronary spasm can be documented.


Electrocardiography is one of the essential keys to diagnosing vasospastic angina. ECG changes demonstrate transient ST-segment elevation (≥ 0.1 mV), ST segment depression (≥ 0.1 mV), and no new negative U waves. These changes must be in at least two contiguous leads, be evident during the attack of chest pain, and resolve when the pain dissipates. An episode can often be induced by having the patient hyperventilate.

Arrhythmias may occur during an episode of variant angina, and may manifest as ventricular tachycardia, atrioventricular block, and bradyarrhythmia.

If silent episodes of coronary spasm or arrhythmias are suspected, then an ambulatory 24-hour Holter ECG should be utilized. This is also helpful for recording ECG changes during symptomatic episodes.

Image: Episode of variant angina showing a 2:1 sinus bradycardia with a prolonged PR interval, as well as significant ST elevations (5–6 mm) in the inferior leads with ST depressions (2–3 mm) anteriorly. By: Ruisi M, Ruisi P, Rosero H, Schweitzer P. License: CC BY 3.0

Coronary Angiography

Diagnostic coronary arteriography is recommended if vasospastic angina is suspected by the history and ECG findings. It may either confirm the diagnosis and/or detect a high-grade fixed coronary obstruction. Provocative tests using acetylcholine or ergonovine (not available in the US) may be used by experienced operators.

Image: Coronary angiography in a patient with vasospastic angina
A: Coronary angiography demonstrates 95% stenosis in the proximal left anterior descending (arrow in A) after administering intravenous ergonovine, which also provoked typical chest pain
C: After injection of intracoronary nitroglycerin, the stenosis completely resolved (arrow in C). By: Choi W, Kim YN, Kim KH. License: CC BY 4.0, cropped by Lecturio.


With vasospastic angina, blood tests are generally negative for cardiac enzymes, including troponins and CK-MB.

Exercise Testing

Exercise testing with ECG monitoring has variable results. Changes that can be detected in response to exercise include ST elevation, ST depression, or no change. ECG changes may point to fixed artery stenosis, coronary artery spasm, or no problems.


Myocardial infarction and life-threatening arrhythmias, including ventricular tachyarrhythmias or bradyarrhythmias, sinus arrest, or even an AV block from a severe ischemic episode following vasospasm. Sudden cardiac arrest, with or without syncope, can occur due to ischemia-induced ventricular fibrillation. Atherosclerosis can also occur later at the site of vasospasm leading to local coronary thrombosis.


Medical Treatment

  • Sublingual nitroglycerin should be used to relieve an attack of vasospastic angina. 
  • The main drug used to treat variant coronary syndrome is a calcium channel blocker (CCB), such as diltiazem or amlodipine. Calcium channel blockers are very effective in the prevention of ischemia. 
  • A long-acting nitrate (e.g., isosorbide mononitrate) is added if a CCB is not sufficient to control the episodes.
  • Importantly, documentation of suppression of both symptomatic and (the more commonly occurring) asymptomatic episodes by ambulatory electrocardiographic monitoring is needed.
  • Statins: effective in preventing coronary artery spasm, possibly by their effects on vascular smooth muscle or by enhancing production of endothelial nitric oxide 

Implantable cardioverter-defibrillator (ICD): recommended for patient with documented ventricular arrhythmia,

Lifestyle Factors

  • Smoking cessation
  • Eat a healthy balanced diet and exercise regularly
  • Report any change in the pattern or severity of chest pains to healthcare provider immediately

Regular follow-up investigations include:

  • Blood tests
  • ECG: Holter monitor to assess control of asymptomatic episodes, which occur much more commonly than symptomatic ones.


Drugs to avoid:

  • Non-selective beta-blockers, e.g., propanol, because they can worsen vasospasm
  • Aspirin at high doses because it inhibits prostacyclin production, but low dose aspirin is permitted
  • Sumatriptan (used to treat acute migraine headache) and other drugs in the triptan class because of their ability to cause vasospasm
  • Fluorouracil (5-fluorouracil) may cause coronary artery spasm.


Average survival is 89 to 97% at 5 years, and the risk increases if: more than one artery is affected; both vasospastic angina and atherosclerotic coronary artery obstruction are present; the fixed obstruction is higher grade. Myocardial infarction and life-threatening arrhythmias occur in approximately 25% of untreated patients. Therapy appears to decrease the frequency of life-threatening events. If the condition is controlled from early on, it can have a favorable prognosis. Complications, such as acute myocardial infarction, and cardiac death typically occur early on after the onset of angina. Patients who have coronary spasm in multiple arteries are prone to having fatal arrhythmias.

Overall survival rates for vasospastic angina are over 90% at 5 and 10 years. Individuals who do not have co-existing coronary artery stenosis generally have a more benign prognosis and better survival than those who do have severely diseased arteries and coronary artery vasospasm.

Review Questions

  1. A young boy of 18 years visits the emergency department with severe chest pain radiating to the back. ST-elevation is seen on the ECG but his cardiac enzymes are normal. The anxious parents insisted on coronary artery catheterization which reveals a normal study. What is your most probable diagnosis?
    1. Stable angina
    2. Unstable angina
    3. Ludwig’s angina
    4. Vasospastic angina
    5. Vincent’s angina
  2. A Japanese woman comes to the clinic complaining of chest pain. For the last three years, she has had intermittent chest pain, mostly at night, that lasts up to 10 minutes. It awakens her from sleep and is associated with nausea and sweating. An electrocardiogram is unremarkable. What would be the most likely finding on a Holter monitor during an episode of chest pain?
    1. Normal ECG
    2. PR segment depression in most leads
    3. Prolonged QT interval
    4. Transient ST-segment elevation in the inferior leads
    5. Bradycardia with no other ECG changes
  3. A 56-year-old man who has been diagnosed with vasospastic angina, comes to the emergency department with an acute episode of chest pain. Which of the following would be the initial drug of choice for this patient?
    1. Nitroglycerin patch
    2. Sublingual nitroglycerin
    3. Oral nitroglycerin
    4. Verapamil
    5. Amlodipine

Answers: 1D, 2D, 3B

Acute Coronary Syndrome (ACS)


Clinical presentation and classification of ACS. Image: “Abbreviations used for ACS (Acute coronary syndrome)” by J. Heuser. License: CC BY-SA 3.0


The term acute coronary syndrome (ACS) refers to patients in whom there is a suspicion or confirmation of acute myocardial ischemia or infarction, associated with symptoms of precordial discomfort or pressure, with or without dyspnea, nausea, and diaphoresis. The three traditional types of ACS are non-ST-elevation myocardial infarction (NSTEMI), ST-elevation MI (STEMI), and unstable angina (UA). Since the advent of high-sensitivity troponin testing, most patients who would have been diagnosed with UA in the past are now diagnosed as having NSTEMI. The most common cause of acute coronary syndromes is an acute thrombus in an atherosclerotic coronary artery, with lesser causes being coronary artery embolism, coronary spasm, and coronary artery dissection.
70% of ACSs are NSTEMIs.
Unstable angina and NSTEMI are also both known together as “Non-ST elevation acute coronary syndromes (NSTEACS).”


It is often difficult to distinguish between these ACS entities based on clinical symptoms alone.

Diagnosis Clinical features ECG findings Laboratory findings
Unstable angina Ischemic chest pain that occurs at rest or with previously tolerated levels of exertion None, or ST-segment depressions None
Non-ST-elevation myocardial infarction (NSTEMI) Ischemic chest pain in any setting None or ST-segment depressions Elevated troponin
ST-elevation myocardial infarction (STEMI) Ischemic chest pain in any setting ST-segment elevations Elevated troponin


ACS is a subcategory of ischemic heart disease, which is the leading cause of death worldwide. 

  • Mean age at onset: 68 (IQR 56—79)
  • Male to Female ratio: 3:2
  • 70% of ACSs are NSTEMIs


In about 95% of the cases, a ruptured plaque, which has formed inside the coronary arteries within the context of atherosclerosis, is responsible for the symptoms of the acute coronary syndrome. Coronary spasm, coronary artery dissection, vasculitis, endocarditis, cocaine use, or emboli from heart valve prostheses are rare causes. 

Plaque Rupture

Image: Heart showing irregular dark brown area indicating irreversibly damaged (dead/necrotic) muscle caused by acute myocardial infarction. Figure B is a longitudinal cross-section of the coronary artery with plaque buildup and an occlusive thrombus (blood clot) resulting from plaque rupture. By: National Heart Lung and Blood Institute (NIH). License: Public Domain


The pathology of ACS can be traced back to the lack of blood flow to the heart tissue. When ACS is due to full-thickness or ST-elevation myocardial infarction (STEMI), the perfused region has received less than 25% of the normal flow, causing irreversible tissue damage. After 6–12 hours, the damage can be seen by light microscope in the form of loss of cross-striations and contraction bands. This is followed 24–72 hours later by pyknotic then lost nuclei and heavy neutrophilic infiltrates. Grossly, the center of the infarct is yellow-tan. At 3–7 days, dead myofibers are starting to be phagocytosed by macrophages at the infarct borders. At 7–10 days, granulation tissue (= new vessels and fibroblasts) is seen at the margins. At 10–14 days, there is well-established (“organizing”) granulation tissue with prominent new blood vessels and collagen deposition. From 2 to 8 weeks, there is decreased cellularity and collagen deposition continues, so that after 2 months, a dense collagenous scar is formed.

Images showing the temporal evolution of pathological changes in STEMI are shown below.

Clinical Features

There is often sudden, severe pain, which typically radiates into the left shoulder and left arm (Note: Can radiate to the right side of the body, or anywhere from the umbilicus up to the jaw). It often occurs without previous exertion, improves only slightly or not at all by administration of nitroglycerin or rest, and lasts longer than 15 minutes.

The pain can be described as an unbearable, cramp-like tightness in the chest. In addition, dyspnea and fear of death, as well as accompanying weakness, nausea, and sweating are typical. Radiation into the upper abdomen, spine, or neck can also occur. A drop in blood pressure and tachycardia, accompanied by cold sweating, can be signs of early cardiogenic shock. Infarcts often occur during the early hours of the morning.


In addition to the medical history and physical examination, a 12-lead ECG, and the determination of the cardiac enzymes CK, CK-MB (specific for myocardial infarction) and especially the troponins I and T, are of crucial importance.

Laboratory Tests

Assessment of cardiac enzymes (CK, CK-MB, and troponin) is important to differentiate between different entities of ACS.

  • Unstable angina (UA) is characterized by a lack of increase in troponin levels. 
  • NSTEMI and STEMI are characterized by destruction of cardiac muscle tissue, which results in elevated cardiac enzymes in the blood.


Even if there is no direct increase in troponin, an infarct cannot immediately be excluded and testing must be repeated every 4–6 hours.

The classification of the heart’s enzymes provides information about the presence and extent of myocardial damage. The determination of troponin I or T is considered the gold standard. Troponin as a cardiac marker is specific to the myocardial tissue.

It increases shortly after the infarction. About 70% of patients show an increase 3 hours after the incident and that number rises to 90% six hours after the event. This timeline stresses the necessity to measure cardiac enzymes again at a later time even when the initial result was negative.

Post-MI reinfarction (PMIR) cannot be diagnosed by means of troponin since the troponin concentration only returns to normal after about 1–2 weeks. In contrast, myoglobin is nonspecific and also increases when damage to skeletal muscles occurs, but goes back to normal after a day at the latest. CK-MB is specific to the infarction, but it only starts to rise 4 hours after the occurrence of ischemia. A CK-MB concentration of between 6–20% of the total CK indicates myocardial damage, if muscle injury is not present, since CK-MB can also be released from skeletal muscle. Within the first 18 hours after an MI, a diagnosis of PMIR can be made if there is a new ST segment elevation on ECG AND at least one other criterion —such as recurrent chest pain or hemodynamic decompensation. For patients more than 18 hours from the initial MI, a biomarker rise and at least one additional criterion are sufficient for the diagnosis of PMIR. Resampling of CK-MB levels can be used to detect early reinfarction because the initial levels would have returned to baseline 36 to 48 hours after infarction; troponin levels would still be elevated from the first MI, but resampling would show another increase, albeit from an abnormal baseline.

LDH can serve as a long-term marker of myocardial damage. It starts to increase only after 6–12 hours, but reaches its maximum after 2–4 days and stays at an increased level for up to 2 weeks following the infarction. GOT, which is actually a marker for liver cells, also exists in the heart muscle and can be used for diagnostics as well. 


Image: “Typical changes in CK-MB and cardiac troponin in Acute Myocardial Infarction” by J. Heuser. License: CC BY-SA 3.0

The following table provides an overview of the various parameters:

Parameter  Beginning of increase Maximum Normal levels
Troponin 3–8 hours 12 hours 1–2 weeks
CK-MB 3–12 hours 24 hours 2–3 days
Myoglobin 1–4 hours 4 hours 1 day
LDH 6–12 hours 2–4 days 1–2 weeks
GOT 4 hours 48 hours 3–6 days


Troponin is not suitable for the diagnosis of re-infarction because it remains elevated for about 2 weeks before the levels return to normal. 

High-yield fact:

It is better to use the CK-MB marker instead of troponin to diagnose post-MI re-infarction. 



  • ECG can be completely normal with no specific ECG changes, so repeat the ECG every 15-30 minutes if suspicion is high or the patient continues to be symptomatic
  • ECG may show ST-segment depression or deep-negative T-waves


The usual sequence of ECG changes in patients with STEMI is as follows:

  • A hyperacute T wave is often the first change. It is tall, peaked, and symmetric in at least two contiguous leads.
  • Elevation of the J point, and the ST segment retains its concave configuration but may become convex or rounded upward. The J point and ST segment elevation are the hallmarks of acute myocardial infarction. 
  • The ST-segment elevation becomes more prominent and its form becomes convex or rounded upward.
  • The ST segment merges with the T wave. This is a “current of injury” or so-called “tombstone” pattern. Reciprocal ST-segment depressions are usually observed in other leads.
  • The ST-segment eventually returns to baseline, an initial Q wave develops, and there is a loss of R wave amplitude. If the ST segment elevation lasts >3 weeks, suspect a ventricular aneurysm in the infarcted region.
  • The T wave becomes inverted and it may remain inverted or return to upright.
  • Over a variable amount of time, the ECG continues to evolve. The R wave amplitude becomes markedly reduced, the Q wave deepens, and the T wave remains inverted or becomes positive. Usually these occur within 2 weeks, but they can occur after several hours.


Echocardiography is a valuable tool that can be used in the diagnostic workup of ACS. The following can be assessed by direct visualization of the heart:

  1. Site/size of segmental wall motion abnormalities
  2. LV systolic function.
  3. Presence of complications (aneurysm, valvular insufficiency, ventricular septal rupture, and pericardial effusion).

Coronary angiography

Coronary computed tomographic angiography (CCTA) is a valuable noninvasive test for the assessment of coronary artery disease (CAD) in selected patients with suspected coronary syndromes. It can determine the exact location and extent of coronary vessel stenosis, and guide further management (e.g., the need for revascularization), and can also completely rule out the presence of CAD.

Risk Assessment

There are multiple risk stratification tools available, such as “HEART” in the table below. Their goal is to predict major adverse cardiac events (MACE).

“HEART” score for chest pain patients

History Highly suspicious 2
Moderately suspicious 1
Slightly suspicious 0
ECG Significant ST depression 2
Non-specific repolarization disturbance 1
Normal 0
Age ≥ 65 years 2
45—65 years 1
≤ 45 years 0
Risk factors ≥ 3 risk factors or history of atherosclerotic disease 2
1 or 2 risk factors 1
No risk factors are known 0
Troponin ≥ 3x normal limit 2
1–3x normal limit 1
≤ normal limit 0

Risk Factors

  • Hypertension
  • Diabetes
  • Hypercholesterolemia
  • Obesity (BMI >30 kg/m2)
  • Positive family history of ACS <65 years of age
  • Known cardiovascular disease (CAD, TIA/stroke, PAD)
  • Smoking
HEART score % patients % MACE Recommended management
0–3 32 1–2 Discharge
4–6 51 12–17 Observe, risk reduction, noninvasive testing
7–10 17 50–65 Admit, medical management, consider early invasive testing

BMI: Body mass index; ACS: Acute coronary syndrome; CAD: Coronary artery disease; TIA: Transient ischemic attack; PAD: Peripheral arterial disease

Treatment of ACS

  • The initial treatment of patients with unstable angina (UA) or acute non-ST elevation myocardial infarction (NSTEMI) is similar to that used in an acute ST elevation myocardial infarction (STEMI) but without fibrinolysis. 
  • An elevation in troponins may not be detectable for hours after presentation

Initial treatment steps for ACS:

  1. Assess airway, breathing, and circulation.
  2. Do a focused history and examination (ask about any contraindications to the use of thrombolytic therapy).
  3. Perform and interpret 12-lead ECG, and attach cardiac monitor.
  4. Bring resuscitation equipment to the patient’s bedside.
  5. Supplemental oxygen if O2 saturation <90% (hyperoxia has a vasoconstrictor effect on the coronary arteries) unless there is respiratory distress. 
  6. Obtain intravenous (IV) access and blood work (basic electrolyte concentrations, renal function studies, and a complete blood count with platelets. Indices of coagulation, INR, aPTT, and cardiac biomarkers, preferably including high-sensitivity troponin)
  7. Dual antiplatelet therapy: Aspirin, 325 mg (unless aortic dissection is a concern), chewed before swallowing, or as rectal suppository; and ticagrelor or clopidogrel
  8. Sublingual nitroglycerin, 0.4 mg, every 5 minutes for 3 doses, unless there are contraindications to nitrates (hypotension, severe aortic stenosis, hypertrophic cardiomyopathy, suspected right ventricular infarct, marked bradycardia or tachycardia, and recent use of a phosphodiesterase 5 inhibitor [e.g., Viagra])
  9. Intravenous morphine sulfate for relief of unacceptable severe chest pain if not relieved by other means. It should not be given routinely because it may be associated with decreased survival, possibly due to its interference with the antiplatelet effect of the P2Y12 receptor blockers (also called “ADP receptor inhibitors,” e.g., clopidogrel). Morphine dosage: initially 2–4 mg, then 2–8 mg, every 5–15 minutes as needed.
  10. High-intensity statin (e.g., atorvastatin 80 mg/d)
  11. Beta-blocker if no contraindications (heart failure, heart block, active asthma)
  12. Anticoagulation: IV unfractionated heparin if catheterization planned; if not, then enoxaparin (adjusted for renal impairment) or fondaparinux (but not if creatinine clearance is < 30 mL/min) 
  13. Consider other diagnoses for chest pain besides cardiac ischemia (the potentially life-threatening conditions are underlined):
    • Cardiovascular but not coronary artery disease: Aortic dissection, aortic aneurysm, myocarditis, stress (takotsubo) cardiomyopathy, pericarditis
    • Pulmonary: Pulmonary embolism, tension pneumothorax, pleuritis, pneumonia
    • Gastrointestinal: Esophageal rupture, perforated peptic ulcer, non-perforated peptic ulcer, esophagitis, esophageal spasm, esophageal reflux, pancreatitis, cholangitis, cholecystitis, choledocholithiasis, biliary colic
    • Chest wall: Costochondritis, rib fracture, cervical disc disease, herpes zoster-before rash, neuropathic pain, fibrositis
    • Psychiatric: Anxiety disorders (panic disorder, hyperventilation), depression, somatic symptom disorder
  14. If STEMI diagnosed ⇒ treat accordingly
  15. If normal biomarkers and normal or the ECG is nondiagnostic ECG, and low to moderate risk: Repeat ECG every 15-30 minutes and second troponin at 3 hours 
    • If second troponin is negative and HEART risk score is ≤ 3 then rule out life-threatening other possible causes and discharge to personal physician <72 hr with diagnosis of “non-specific chest pain.”
    • If second troponin is negative and HEART score > 3 then send for non-invasive or stress imaging ⇒
      • If positive, admit to hospital with cardiologist referral;
      • If negative, and life-threatening alternative diagnoses are ruled out, diagnosis is “non-specific chest pain” and refer to personal physician <72 hr.
      • If indeterminate, cardiologist consultation and usually admit to hospital

Acute Myocardial Infarction: NSTEMI and STEMI

Clinical Features

The typical symptoms include severe retrosternal pain that typically radiates to the left or right arm, neck, or lower jaw and does not improve after nitroglycerin administration. These symptoms are observed in only about 40% of patients.

Painless infarctions (or silent infarctions) especially affect diabetic patients with neuropathy, and also affect women and the elderly.

Infarction pain can also be atypical, manifesting as upper abdominal pain, feeling of faintness combined with vagal symptoms such as sweating, dyspnea, nausea, or vomiting. These painless or atypical presentations occur in about one-third of all cases.


ECG of an ST Elevation Myocardial Infarction (STEMI). Image: HWI akut. By: JHeuser. License: CC BY-SA 3.0


In the case of NSTEMI, the ST-segment may be temporarily depressed and may be accompanied by a negative pre-terminal T-wave. 

The ECG changes of NSTEMI are often atypical, which means that an infarction can only be ruled out through serial cardiac enzyme testing.


In case of a STEMI, the ECG shows typical changes, such as the monophasic ST-segment elevation, which transitions directly into the T-wave, with pathologically enlarged Q-spikes. 

Various other ECG changes are typical depending on the stage of the infarction.

  • Initial stage: Up to 6 hours after the infarction, typically characterized by pointed elevation of the T-wave, which is called a hyperacute T-wave.
  • Acute infarction: Few hours up to days after the infarction, characterized by the typical monophasic ST-elevation.
  • Intermediate stage: The ST-elevation and R-spike decrease, so-called poor R-wave progression occurs, as well as enlargement of the Q-spike, 
  • Final stage: More than 6 months after the infarction, the changes of the QRS complex remain, while the ST-segment and the T-wave return to normal.

Localization of Infarction

The ECG leads depicting the characteristic ST changes in STEMIs provide information about which coronary artery is most likely obstructed and the location of the infarction. They are less useful for localization in NSTEMIs.

Localization of Infarction ECG Changes
Extensive anterior MI I, aVL, V1-6
Anterior MI V1-6
Lateral MI I, aVL, V5-6
Anteroseptal MI V1-V4
Inferior MI II, III, aVF
Posterior MI V7-9, inverse in V1-V2

Imaging Modalities 

  • Echocardiography: A diagnostic tool that helps to detect wall motion abnormalities, determine LV function, and exclude complications, such as cardiac valvular defects.
  • Cardiac catheterization: This is considered the gold standard and should be performed as quickly as possible in case of STEMI.
  • MRI cardioangiography: It serves as another means of detecting wall motion abnormalities and determining the size of infarction scars.


Initial Management of Myocardial infarction 

As outlined above for ACS, plus a reperfusion method is chosen: 

  • Primary percutaneous coronary intervention (PCI: activate the cardiac catheterization team) 
    • Much preferred to fibrinolysis
    • Can be done even >12 hours if symptoms, esp. if high risk patient or ongoing ischemia 
    • PCI is the usual procedure in selected patients, but coronary artery bypass graft (CABG) is recommended for left main disease, or if multiple vessel disease involving the left anterior descending artery with LV dysfunction or diabetes.
    • MI with normal coronary arteries are present in 9-14% of NSTEACS, possibly due to vasospasm, rapid clot lysis, myocarditis, microvascular disease.
  • Fibrinolysis
    • Treat with fibrinolysis if:
      • PCI unavailable < 2 hours of first medical contact
      • Symptoms <12 hours
      • No contraindications.
    • Drugs which may be used: tenectaplase, reteplase, alteplase
  • Timing of dosage (“time is muscle”): 
    • Time from first medical contact (ambulance or ED) to drug administration (“door-to-needle time”) should be <30 min. 
    • Should be delivered <10 min of STEMI confirmation on the ECG (do not wait for troponin levels if clinical presentation is typical)
    • The benefit from thrombolytic therapy is maximal when given < 2 hours of symptom onset.

Initial Management of Unstable Angina and NSTEMI (“Non-ST elevation acute coronary syndromes [NSTEACS]”)

  • As outlined above for ACS, plus immediate coronary arteriography (CA) and revascularization for very high-risk patients with any sign(s) of: obvious heart failure (HF), severe left ventricular dysfunction, recurrent or persistent rest angina despite intensive medical therapy, hemodynamic instability due to acute mitral regurgitation, ventricular septal defect or other structural disorder, or unstable ventricular arrhythmias.
  • Select a method for early and late risk stratification for the other patients, such as the popular 7-item TIMI score, to decide which ones need urgent CA. 
    • One point is given for each of the seven criteria (age ≥65, three or more CAD risk factors, known CAD with > 50% stenosis, aspirin use in the past seven days, severe angina in the preceding 24 hours, elevated cardiac markers, ST deviation >0.5 mm). 
    • Patients with a score of 0–2 have 5-8% chance of death, MI, or urgent revascularization by two weeks and are considered low-risk. 
    • High-risk patients have scores of 5–7, and have a 26-41% risk and the intermediate risk group has scores of 3 or 4, with a 13-20% risk. 
    • All high-risk patients are referred for early (<24 hours) CA, while low- and intermediate-risk patients are referred for noninvasive testing if early CA is not done.
  • Fibrinolytic therapy is not recommended for patients with an NSTEACS.
Absolute Contraindications of Fibrinolytic Therapy
· Previous hemorrhagic stroke at any time.

· Ischemic stroke within 3 months.

· Known intracranial neoplasm.

· Closed head injury within 3 months.

· Active bleeding, or bleeding diathesis.

· Suspected aortic dissection

Relative Contraindications
· Severe uncontrolled hypertension > 180/110

· History of ischemic stroke > 3 months.

· Prolonged CPR > 10 minutes.

· Major surgery < 3 weeks.

· Recent (within 2–4 weeks) internal bleeding.

In the case of non-ST-segment elevation myocardial infarction (NSTEMI), anticoagulants, such as fondaparinux or enoxaparin, should be administered instead as explained above.

Coronary Angiography after Fibrinolysis (Rescue PCI) 

It is indicated in case of:

  • Failure of reperfusion (as evidenced by < 50 % resolution of ST-segment elevation > 90 min after completion of fibrinolytic treatment)
  • Spontaneous recurrent ischemia while in a hospital
  • High-risk features, e.g., extensive ST-segment elevation, signs of heart failure and hypotension (systolic blood pressure < 100 mmHg).

Complications of STEMIs

STEMI complications can be classified into early and late.

Early complications:

  1. Sudden cardiac death (SCD).
  2. AV block and ventricular tachyarrhythmias, which could be fatal.
  3. Acute left heart failure (pulmonary edema) that results from acute pump failure of heart or acute mitral valve insufficiency secondary to papillary muscle dysfunction.
  4. Cardiogenic shock is the worst complication besides SCD, with mortality rates exceeding 50%.

Late complications of STEMI:

  1. Pericarditis—further classified into:
    • Early infarct-associated pericarditis which occurs within the first week of MI
    • Dressler syndrome (post-cardiac injury syndrome):a noninfectious pericarditis that occurs 2–20 weeks post-MI secondary to deposition of anticardiac antibody immune complexes in the pericardium, pleura, and lungs, eliciting an inflammatory response. 
  2. Congestive heart failure
  3. Re-infarction due to an unstable plaque
  4. Atrial and ventricular aneurysms which may precipitate:
    • Thrombus formation and increased risk of thromboembolism
    • Cardiac arrhythmia
    • Rupture leading to pericardial effusion and cardiac tamponade 

The following table shows complications of myocardial infarction:

Time Complications
0–24 h Ventricular arrhythmia, HF, Cardiogenic shock
1–3 days Postinfarction fibrinous pericarditis
3–14 days Free wall rupture with tamponade, papillary muscle rupture with mitral regurgitation, Interventricular septal rupture due to macrophage-mediated structural degradation, LV pseudoaneurysm (risk of rupture)
2 weeks to several months Dressler syndrome, HF, arrhythmias, true ventricular aneurysm (risk of mural thrombus)


Since 95% of the cases of acute coronary syndrome are manifestations of coronary heart disease, the goal is prevention by eliminating or decreasing the impact of the main risk factors of high cholesterol, arterial hypertension, diabetes mellitus, and smoking. The approaches are predominantly concerned with the patient’s behavior such as food choices and choice of physical activity. These approaches can also be assisted by medication.

Review Questions

  1. What does a typical STEMI-ECG look like?
    1. ST-segment depression with direct transition into a T-wave
    2. ST-segment elevation with negative preterminal T-wave
    3. A pointed depression of the T-wave, the so-called anoxic T
    4. Q-wave
    5. A monophasic ST-segment elevation with direct transition into a T-wave
  2. What is the best laboratory test for acute MI?
    1. LDH
    2. Troponin I/T
    3. CK-MB
    4. Myoglobin
    5. GOT
  3. Which medication is contraindicated when a patient has also taken sildenafil?
    1. ASS
    2. P2Y12 inhibitors
    3. Nitroglycerin
    4. Heparin
    5. Oxygen

Answers: 1E, 2B, 3C

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