Unstable angina

Coronary atherosclerotic disease is the underlying cause in nearly all patients with acute myocardial ischemia. The most common cause of unstable angina (UA) is coronary artery narrowing caused by a thrombus that develops on a disrupted atherosclerotic plaque and is usually nonocclusive.[2]Rao SV, O'Donoghue ML, Ruel M, et al. 2025 ACC/AHA/ACEP/NAEMSP/SCAI guideline for the management of patients with acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Joint Committee on clinical practice guidelines. Circulation. 2025 Apr;151(13):e771-862. https://www.ahajournals.org/doi/10.1161/CIR.0000000000001309 http://www.ncbi.nlm.nih.gov/pubmed/40014670?tool=bestpractice.com

A less common cause is intense vasospasm of a coronary artery (variant or Prinzmetal angina, ischemia and no obstructed arteries [INOCA], or secondary to cocaine use). This intense vasospasm is caused by vascular smooth muscle or by endothelial dysfunction in INOCA.

The initiating lesion in coronary artery disease (CAD) is a fissure in the vessel endothelial lining over an underlying cholesterol plaque, which results in a loss in the integrity of the plaque cap. Plaques that fissure or rupture tend to have a thin fibrous cap, a high lipid content, few smooth muscle cells, and a high proportion of macrophages and monocytes.[17]Libby P. Molecular bases of the acute coronary syndromes. Circulation. 1995 Jun 1;91(11):2844-50. https://www.ahajournals.org/doi/full/10.1161/01.cir.91.11.2844 http://www.ncbi.nlm.nih.gov/pubmed/7758192?tool=bestpractice.com [18]Moreno PR, Falk E, Palacios IF, et al. Macrophage infiltration in acute coronary syndromes: implications for plaque rupture. Circulation. 1994 Aug;90(2):775-8. http://www.ncbi.nlm.nih.gov/pubmed/8044947?tool=bestpractice.com

The fissure or plaque rupture leads to exposure of subendothelial matrix elements (e.g., collagen), stimulating platelet activation and thrombus formation. Release of tissue factor directly activates the coagulation cascade and promotes the formation of fibrin.

If an occlusive thrombus forms, the patient may develop an acute ST-segment elevation myocardial infarction (STEMI) unless the affected myocardium is richly collateralized. If the thrombus formation is not occlusive, the patient may develop non-ST-elevation myocardial infarction (NSTEMI)/UA with nonspecific ST changes on the ECG (ST depression or T-wave changes).

Arterial inflammation caused by or related to infection may cause plaque destabilization and rupture and precipitate acute coronary syndrome (ACS). Activated macrophages and T lymphocytes located at the shoulder of a plaque increase the expression of enzymes such as metalloproteinase that may cause thinning and disruption of the plaque, leading to ACS.[19]Hansson GK, Libby P, Tabas I. Inflammation and plaque vulnerability. J Intern Med. 2015 Nov;278(5):483-93. https://onlinelibrary.wiley.com/doi/full/10.1111/joim.12406 http://www.ncbi.nlm.nih.gov/pubmed/26260307?tool=bestpractice.com

Myocardial supply and demand mismatch may cause ischemia without significant CAD. These include:

• Increased myocardial oxygen requirements such as fever, tachycardia, thyrotoxicosis

• Reduced coronary blood flow: for example, hypotension

• Reduced myocardial oxygen delivery such as anemia or hypoxemia

In patients with prior ACS with coronary stents, stent thrombosis or in-stent restenosis may cause STEMI, NSTEMI, or UA. Both stent thrombosis and restenosis have complex causes, triggers, pathophysiology, and risk factors. Of importance, premature cessation of antiplatelet agents in patients with stents (drug-eluting and bare-metal) may trigger an ACS.[1]Byrne RA, Rossello X, Coughlan JJ, et al. 2023 ESC guidelines for the management of acute coronary syndromes. Eur Heart J. 2023 Oct 12;44(38):3720-826. https://academic.oup.com/eurheartj/article/44/38/3720/7243210 http://www.ncbi.nlm.nih.gov/pubmed/37622654?tool=bestpractice.com [2]Rao SV, O'Donoghue ML, Ruel M, et al. 2025 ACC/AHA/ACEP/NAEMSP/SCAI guideline for the management of patients with acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Joint Committee on clinical practice guidelines. Circulation. 2025 Apr;151(13):e771-862. https://www.ahajournals.org/doi/10.1161/CIR.0000000000001309 http://www.ncbi.nlm.nih.gov/pubmed/40014670?tool=bestpractice.com

Classification of acute coronary syndrome (ACS)[1]Byrne RA, Rossello X, Coughlan JJ, et al. 2023 ESC guidelines for the management of acute coronary syndromes. Eur Heart J. 2023 Oct 12;44(38):3720-826. https://academic.oup.com/eurheartj/article/44/38/3720/7243210 http://www.ncbi.nlm.nih.gov/pubmed/37622654?tool=bestpractice.com ​​[2]Rao SV, O'Donoghue ML, Ruel M, et al. 2025 ACC/AHA/ACEP/NAEMSP/SCAI guideline for the management of patients with acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Joint Committee on clinical practice guidelines. Circulation. 2025 Apr;151(13):e771-862. https://www.ahajournals.org/doi/10.1161/CIR.0000000000001309 http://www.ncbi.nlm.nih.gov/pubmed/40014670?tool=bestpractice.com

The term ACS is used to describe the range of conditions resulting from sudden reduction in coronary blood flow. Symptoms should be present suggestive of angina or anginal equivalent presentation. The presence or absence of ST-segment elevation on presenting ECG indicates STEMI or non-ST-elevation ACS (NSTE-ACS). NSTE-ACS is further subdivided into NSTEMI or unstable angina, depending on elevation of troponin.

1. STEMI: ECG demonstrates ST elevation of >1 mm in ≥2 anatomically contiguous leads, usually associated by location. Repolarization abnormalities often evolve over time from hyperacute T waves to ST elevation to T-wave inversion to the development of Q waves. STEMI patients typically have a rise and fall of serum cardiac biomarkers. While biomarkers are useful for confirmatory and prognostic purposes, they are not required for the diagnosis of STEMI and should not delay treatment. Clinicians must be careful to recognize other causes of ST elevation that mimic a STEMI. These include left ventricular hypertrophy, left bundle-branch block, paced rhythm, benign early repolarization, pericarditis, and hyperkalemia.

2. NSTEMI: ECG does not show persistent ST elevation, but may show ischemic changes such as ST depression or T-wave inversion. The ECG may also be normal. Serum levels of cardiac biomarkers are elevated.

3. Unstable angina pectoris: cardiac biomarkers are normal.