• Age: risk increases with age (men > 45, women > 55)
• Male sex: men have earlier and higher rates of CAD; women catch up post-menopause
• Family history of premature CVD: first-degree relative with CVD at age < 55 (male) or < 65 (female) ^[5]
  • Note: the definition of "early death" for family history differs slightly between papers, but the commonly used cut-offs are male < 55, female < 65 ^[5]

• Hypertension — chronic pressure injury to endothelium accelerates atherosclerosis ^[6]
• Diabetes mellitus — hyperglycaemia causes endothelial dysfunction, promotes oxidative stress, accelerates atheroma formation; also leads to a pro-thrombotic state
• Hyperlipidaemia (↑LDL, ↓HDL, ↑triglycerides) — LDL is the primary substrate that accumulates in the arterial intima to form the atherosclerotic plaque ^[7]
• Cigarette smoking — damages endothelium, promotes platelet aggregation, ↑CO levels reducing O₂ carrying capacity, ↑sympathetic tone
• Obesity / abdominal obesity — associated with insulin resistance, dyslipidaemia, pro-inflammatory state
• Sedentary lifestyle / lack of exercise
• Chronic kidney disease — accelerated atherosclerosis, pro-thrombotic milieu, disordered calcium-phosphate metabolism ^[6]

Predisposing factors that might trigger AMI (and by extension, UA/ACS) in an individual: ^[8]

• Unusual heavy exercise
• Emotional stress
• Progression from unstable angina (to MI)
• Surgical procedures
• Infection e.g. pneumonia
• Circadian Periodicity — Peak incidence between 0600–1200 ^[8]

The "4 E's" mnemonic for triggers of angina: ^[8][9]

• Exercise
• Emotion
• Environment (cold/hot)
• Eating (post-prandial — blood is diverted to splanchnic circulation, reducing coronary perfusion relative to demand)

Mortality: 1 vessel disease < 2 vessel disease < 3 vessel disease < left main stem disease ^[7]

• Right dominant (~85%): RCA gives rise to the posterior descending artery (PDA)
• Left dominant (~8%): LCx gives rise to PDA
• Co-dominant (~7%): both RCA and LCx contribute

• Coronary arteries fill primarily during diastole (especially the LV subendocardium), because during systole the contracting myocardium compresses intramural vessels. This is why tachycardia (shortened diastole) worsens angina — less filling time.
• The subendocardium is the most vulnerable zone to ischaemia because it has the highest wall tension and is furthest from the epicardial supply.

Atherosclerosis of coronary artery is by far the most common aetiology of IHD ^[4][7]

The pathogenesis involves:

1. Accumulation of LDL in arterial intima which induces innate inflammatory reaction ^[7]
2. Recruits macrophages which engulf LDL and become foam cells ^[7]
3. Formation of fibroatheroma with accumulation of macrophage foam cells along with cellular necrosis which causes further inflammation and distortion of intima ^[7]

The progression of atherosclerotic lesions: ^[2]

• Fatty streaks: slightly raised yellow deposits — earliest lesion, even found in teenagers
• Atheromatous plaque: fibrous cap + necrotic lipid-rich centre
• Unstable (vulnerable) plaque: thinner fibrous cap + growing necrotic core, which is prone to:
  • Plaque rupture → thrombus formation → occlusion ← This is the key event in UA/NSTEMI/STEMI
  • Aneurysm: pressure atrophy of tunica media
  • Atheroembolism

Significant CAD is usually defined as stenosis ≥ 50% on invasive coronary angiography ^[7]

Stenosis < 70% are typically not flow-limiting and are rarely the cause of angina or ischaemia and thus do not require revascularisation ^[7]

However, in UA, a plaque that was previously only 40–50% stenotic can rupture and suddenly cause near-total occlusion via superimposed thrombus — this is why many patients with ACS have lesions that were not previously "significant" on angiography.

Non-atherosclerotic CAD: ^[7]

• Spasm = Prinzmetal's variant angina / Cocaine-induced — Prinzmetal angina is a vasospastic angina that classically causes transient ST elevation and occurs at rest, often in the early morning
• Dissection = Aortic dissection (Type A) with retrograde extension / Connective tissue disease (Marfan's syndrome / Ehlers-Danlos syndrome) — spontaneous coronary artery dissection (SCAD) is an increasingly recognised cause, especially in young women
• Embolism = AF / Atrial myxoma
• Vasculitis = Takayasu arteritis (large-vessel) / Polyarteritis nodosa (medium-vessel) / Kawasaki disease (medium-vessel) / EGPA (small-vessel)

Ischaemia without plaque rupture (imbalance between blood supply and demand): ^[7]

• Anaemia — reduced O₂ carrying capacity
• Hypertension — increased afterload → increased myocardial O₂ demand
• Aortic stenosis — LV pressure overload → LVH → increased O₂ demand with compromised subendocardial perfusion
• Thyrotoxicosis — ↑metabolic rate, ↑HR → ↑O₂ demand

The causes of imbalance between blood supply and demand include: ^[9]

• Coronary artery stenosis
• Coronary spasm
• Anaemia, thyrotoxicosis
• Aortic stenosis, hypertension

1. Vulnerable plaque rupture or erosion: The thin fibrous cap of a lipid-rich plaque cracks (rupture) or endothelial cells are denuded (erosion). Inflammatory cells (especially macrophages) within the plaque secrete matrix metalloproteinases (MMPs) that degrade collagen in the fibrous cap, weakening it.

2. Thrombogenic core exposure: The lipid-rich necrotic core contains high concentrations of tissue factor (a potent activator of the extrinsic coagulation cascade). Subendothelial collagen is also exposed, which activates platelets via von Willebrand factor (vWF) binding to platelet GPIb receptors.

3. Platelet activation and aggregation: Activated platelets release ADP and thromboxane A₂ (TXA₂), recruiting more platelets. Platelet aggregation occurs via cross-linking of GPIIb/IIIa receptors by fibrinogen. This forms a "white thrombus" (platelet-rich).

4. Partial/dynamic obstruction: In UA, the thrombus does NOT completely occlude the artery (or if it does, it lyses spontaneously or rapidly). This creates intermittent or partial flow reduction, explaining:

   • Why pain comes and goes
   • Why troponin remains normal (no irreversible necrosis — ischaemia is transient)
   • Why ECG may show transient ST depression or T-wave changes that resolve

5. Additional vasospasm: Thrombus and activated platelets release serotonin and TXA₂, which cause local vasoconstriction, further reducing blood flow. This is why the obstruction is "dynamic" — it fluctuates.

6. Myocardial ischaemia: Reduced coronary flow → O₂ supply < demand → anaerobic metabolism → accumulation of lactic acid, adenosine, bradykinin and other metabolites → stimulation of cardiac sympathetic afferent nerve fibres (travelling with C7–T4 nerve roots) → perception of chest pain (angina).

The cardiac sympathetic afferent fibres enter the spinal cord at C7–T4 levels, sharing pathways with somatic afferents from the chest wall, left arm (especially ulnar aspect), jaw, and shoulder. The brain cannot always distinguish the source — this is referred pain (viscerosomatic convergence). This is why angina typically radiates to the jaw, left arm, or shoulder.

ACS is classified into: ^[1]

• NSTE-ACS
  • Unstable angina (normal troponin)
  • NSTEMI (elevated troponin)
• STE-ACS
  • STEMI (ST elevation + elevated troponin)

Four categories of patients presenting with angina in ACS: ^[1]

• Rest angina — pain at rest, typically > 20 minutes
• New-onset angina — recent onset (within ~2 months) with at least CCS Class III severity
• Increasing (crescendo) angina — previously stable angina that has become more frequent, more severe, longer in duration, or provoked by less exertion
• Post-MI angina — recurrence of angina within 2 weeks of MI

The Braunwald Classification is used to risk stratify patients with unstable angina ^[1][10]

The Braunwald Classification uses the following parameters to stratify patients with unstable angina: History, Character of Pain, Clinical Findings, ECG, and Cardiac Markers ^[1]

^[10]

This classification grades the functional severity of angina (used for both stable and unstable angina to describe the threshold):

^[7]

^[2][11][14]

UA is diagnosed when a patient presents with anginal pain with at least one of the following features: ^[1]

• Is of new onset and severe (at least CCS Class III — markedly limits normal activity)
• Occurs at rest or with minimal exertion (resting angina > 20 minutes)
• Pain is worsening in the severity and length of each episode (crescendo/increasing angina)

AND:

• Troponin / CK-MB: negative ^[7]
• ECG: NO ST elevation ± ST depression ± T-wave inversion ^[7]

In other words, the diagnosis is made by demonstrating:

1. A clinical presentation consistent with acute myocardial ischaemia
2. No ST elevation on ECG (otherwise → STEMI)
3. No elevation of cardiac biomarkers on serial testing (otherwise → NSTEMI)

Understanding the MI definition helps you understand precisely where UA sits:

Criteria for acute myocardial infarction: ^[7][20]

(1) Detection of a rise and/or fall of cardiac biomarker values, preferably cardiac troponin (cTn), with at least one value above the 99th percentile upper reference limit (URL)

(+ At least one of the following): (2) Symptoms of ischaemia (3) Investigations:

• New or presumed new significant ST-segment–T wave (ST–T) changes
• New left bundle branch block (LBBB)
• Development of pathological Q waves in the ECG
• New loss of viable myocardium or new regional wall motion abnormality on imaging
• Identification of an intracoronary thrombus by angiography or autopsy

The critical point: criterion (1) — troponin elevation — is mandatory for the diagnosis of MI. If troponin is normal on serial testing but the patient has ischaemic symptoms and/or ECG changes, the diagnosis is unstable angina, not MI.

The 3rd/4th Universal Definition classifies MI into 5 types: ^[14]

^[14][20]

Why does this matter for UA? Because some patients presenting with "unstable angina" actually have Type 2 MI (supply-demand mismatch from anaemia, sepsis, tachyarrhythmia) — the troponin may be elevated but the mechanism is not plaque rupture. The management differs fundamentally: you treat the underlying cause (transfuse for anaemia, rate-control for tachycardia) rather than rushing to the cath lab.

The Braunwald Classification is used to risk stratify patients with unstable angina ^[1][10]

Parameters: History, Character of Pain, Clinical Findings, ECG, Cardiac Markers ^[1]

^[10]

The GRACE score uses 9 factors for prognostication ^[5]. It is the preferred risk stratification tool in current ESC guidelines for NSTE-ACS:

The GRACE score stratifies patients into:

• Low risk (GRACE score < 109): 6-month mortality < 3%
• Intermediate risk (GRACE 109–140): 6-month mortality 3–8%
• High risk (GRACE > 140): 6-month mortality > 8% → early invasive strategy recommended

Why is ECG the first investigation? Because it is fast (available in minutes), non-invasive, cheap, and provides the single most important piece of information for triaging ACS: is there ST elevation?

Timing: Perform 12-lead ECG as soon as possible ^[14] — ideally within 10 minutes of first medical contact (ESC guidelines).

What to look for in UA/NSTE-ACS:

STEMI diagnostic criteria: ST elevation in two contiguous leads, with specific thresholds of 2 mm in V1–V3 for men and 1.5 mm for women ^[21]. If these criteria are met → it is STEMI, not UA.

ECG findings for key differentials:

• Concave upward ST elevation + PR depression → benign early repolarisation or acute pericarditis; ST/T ratio > 0.25 suggests acute pericarditis ^[22]
• Pathological Q waves: indicate old/previous MI — any Q wave in V2–V3 ≥ 0.02 seconds is abnormal; Q wave ≥ 0.03 seconds and ≥ 0.1 mV deep or QS complex in any two contiguous leads ^[8]

For ST depression, there is a lower threshold for V2–V3 than for other leads ^[22]

Why troponin? Cardiac troponins (cTnT and cTnI) are structural proteins of the sarcomere — they are released into the bloodstream when cardiomyocytes undergo necrosis. They are the most sensitive and specific markers of myocardial injury.

Rationale behind biochemical markers: Cellular contents of damaged cells (e.g. intracellular enzymes) are leaked into the ECF and plasma directly or via lymphatics in cellular necrosis ^[20]

In unstable angina: troponin is NORMAL — because by definition, there is ischaemia without necrosis.

Key principles:

Roles of biochemical markers of ACS: ^[20]

• Risk prediction and prognosis — categorise patients into high and low-risk groups
• Selection of site of care: Coronary care unit / Out-patient settings
• Selection of therapeutic intervention: Aggressive / Conservative therapy
• ACS evaluation — any troponin level > URL = myocardial damage
• Detection of reinfarction
• Assessment of reperfusion
• Estimation of infarct size — magnitude and temporal course of markers

Baseline evaluation blood tests: ^[14][4]

CXR is usually non-diagnostic in ACS — look for other causes (e.g. aortic dissection, PE, pneumonia, or pneumothorax) ^[14]

Specifically in UA/ACS, CXR may show:

• Pulmonary oedema (upper lobe venous diversion, Kerley B lines, peribronchial cuffing, pleural effusions) — if present, indicates LV failure = high-risk feature
• Widened mediastinum → raise suspicion for aortic dissection (but widened mediastinum is not specific — a lot of patients above age 70 have this due to fat accumulation ^[16])
• Normal — most common finding in UA
• Cardiomegaly (CT ratio > 0.5) — suggests pre-existing cardiac disease; does not specify which heart compartment is enlarged ^[23]

Baseline echocardiography recommended for all patients ^[14]

Stress testing is used when the diagnosis of CAD is uncertain — it is more relevant to stable angina workup than to acute UA, but may be performed after stabilisation in intermediate/low-risk UA patients to guide further management.

Non-invasive investigation algorithm for patients with chest pain: ^[3]

^[3]

Choices of Stress Testing — Comparison: ^[3]

^[3]

Exercise Treadmill Test (ETT) details:

• Bruce protocol: 7-stage test with treadmill increasing speed and grade ^[2]
• Exercise until target HR reached (HR = (220 − age) × 0.8), symptomatic, or ST-T changes ^[2]
• Positive finding: Ischaemic: planar / downsloping ST depression ^[2]
• Duke treadmill score: based on exercise time, presence of angina, max net ST segment changes ^[2]
• Stop antihypertensive on the day of test ^[2]

After doing pharmacological stress test, you can either do cardiac MRI or SPECT ^[12]

Pharmacological stress agents:

• Dobutamine (β₁ agonist → ↑HR, ↑contractility → ↑O₂ demand) — C/I: recent MI ^[2]
• Adenosine / regadenoson (coronary vasodilator → "steals" blood from ischaemic territory) — C/I: asthma (adenosine can cause bronchospasm) ^[2]

Stress testing risk stratification for prognosis: ^[14]

• High risk = area of ischaemia > 10% (> 10% for SPECT, ≥ 3 LV segments for echo)
• Intermediate risk = area of ischaemia 1–10%
• Low risk = no ischaemia

• Non-invasive anatomical assessment of coronary arteries
• Excellent negative predictive value — very good at ruling out significant CAD
• Calcium score (non-contrast CT): draw circles around areas of calcium; good for prognostication ^[16]
• Issue: calcified plaques create false positives ^[16] — heavily calcified arteries can obscure the lumen, making stenosis appear worse than it is
• Most useful for patients with low-to-intermediate pre-test probability where you want to rule out CAD non-invasively

The gold standard for defining coronary anatomy. A catheter is inserted (usually via radial or femoral artery) and contrast is injected directly into the coronary ostia under fluoroscopy.

Indications for invasive coronary angiogram: ^[3][4]

• Unacceptable angina despite medical therapy (for consideration of revascularisation)
• Non-invasive testing results with high-risk features
• Angina or risk factors for CAD in the setting of depressed LVEF
• For diagnostic purposes, in the individual in whom the results of non-invasive testing are unclear

In the context of NSTE-ACS (including UA):

• If stable, then determine high-risk features → if yes, proceed to invasive procedures ^[5]
• This patient has T-wave changes, no high risk features → are we really thinking of unstable angina? Yes, since symptoms and signs are compatible → so still go with invasive procedures ^[5]

Key findings on angiography:

• Degree and location of stenosis (1-vessel, 2-vessel, 3-vessel, left main stem disease)
• Mortality: 1 vessel disease < 2 vessel disease < 3 vessel disease < left main stem disease ^[14]
• Significant CAD: stenosis ≥ 50% on invasive coronary angiography ^[7]
• Thrombus burden, culprit lesion identification
• Can proceed directly to PCI if indicated

• Assesses both structure and function
• Late gadolinium enhancement (LGE): identifies areas of fibrosis/scar (infarction) vs viable myocardium
  • Subepicardial LGE → myocarditis pattern ^[16]
  • Subendocardial or transmural LGE → infarction pattern
• Stress perfusion MRI: identifies ischaemic territories with high sensitivity and specificity
• Particularly useful in MINOCA (MI with No Obstructive Coronary Atherosclerosis) ^[14] — helps differentiate myocarditis, takotsubo, microvascular disease from true atherosclerotic ACS
• No late GDE in certain patients → may need further workup ^[16]

D-dimer is a fibrin/blood clot degradation product. It is not very specific (cannot rule in) but is quite sensitive (can rule out) ^[24]

Used only to exclude pulmonary embolism as a differential, NOT for diagnosing UA. Only for patients who are haemodynamically stable ^[23]. Many conditions cause elevated D-dimer (VTE, DIC, surgery, cancer, pregnancy, infection, chronic inflammation, liver/renal disease) ^[24].

For very high risk angina patients, add rivaroxaban/Factor Xa inhibitor 2.5 mg twice daily on top of low-dose aspirin (81–100 mg daily) ^[4] — the COMPASS trial showed benefit in stable high-risk CAD/PAD patients.

General measures: ^[14]

• Lifestyle: stop smoking, regular exercise (but not beyond point of discomfort)

• Treat precipitating factors: thyrotoxicosis, anaemia

• Manage risk factors:

  • DM: aim HbA1c < 7%, consider SGLT2i or GLP-1a — SGLT2i (empagliflozin, dapagliflozin) and GLP-1 agonists (liraglutide, semaglutide) have proven cardiovascular benefits independent of glucose lowering
  • HTN: aim < 140/90, use BB if indicated
  • Lipids: ↓LDL to < 1.8 mmol/L with lifestyle and drug

• Cardiac rehabilitation: structured exercise programme, psychological support, education

• Weight management: aim BMI < 25 kg/m²; waist circumference targets

• Diet: Mediterranean diet; reduce salt intake, saturated fats, refined sugars

• Alcohol: moderate consumption only

• Influenza and pneumococcal vaccination: reduce risk of infection-triggered ACS

These are mechanical complications of MI — they are devastating but fortunately rare in pure UA (since they require myocardial necrosis). However, if UA progresses to MI, these must be on your radar:

Post-MI mechanical complications are indications for CABG: ^[2]

• Ventricular septal rupture (VSR)
• LV free wall rupture / aneurysm

Ventricular aneurysm diagnosis: ^[14]

• Paradoxical impulse on chest wall (outward when systole)
• ECG: persistent ↑ST and Q despite reperfusion
• CXR: unusual bulge from cardiac silhouette
• Echo: diagnostic

Ventricular aneurysm management: ^[14]

• Oral anticoagulation if documented mural thrombus
• Aneurysmectomy + CABG if intractable VAs or heart failure refractory to medical therapy

Transient ischaemia can trigger the same arrhythmogenic mechanisms (re-entry, enhanced automaticity) described above, albeit usually more transiently. Patients with UA can develop:

• Ventricular ectopic beats
• Non-sustained VT
• Supraventricular tachycardia / AF (new-onset AF during ACS is a sign of poor prognosis)
• Bradycardia (especially if inferior territory ischaemia → vagal activation via Bezold-Jarisch reflex)

This is precisely why continuous ECG monitoring is mandated for all ACS patients ^[25].

Ischaemic myocardium becomes "stunned" — it is viable but temporarily non-contractile. This can cause:

• Transient regional wall motion abnormalities (RWMA) on echocardiography
• Reduced LVEF during ischaemic episodes
• Acute pulmonary oedema if ischaemia is severe or prolonged
• These features are reversible once ischaemia resolves (unlike infarction)

Refractory angina is listed as a high-risk complication ^[2]. Despite maximal medical therapy (DAPT + heparin + nitrates + beta-blockers), some patients continue to have:

• Recurrent chest pain
• Dynamic ECG changes
• These patients need urgent coronary angiography and revascularisation ^[25]

Post-ACS ischaemia is indicated by symptoms/ECG changes + new rise in cTn > 20% or to > 5× ULN ^[14]

The most feared treatment complication. The combination of DAPT + anticoagulation creates a significant bleeding risk.

Main side effect of antiplatelet: GI upset (aspirin), bleeding ^[4]

Prevention:

• Add PPI when using 2 or more antithrombotics ^[26]
• Use radial access for PCI (lower bleeding risk than femoral — radial artery is paired with ulnar artery and can be compressed easily against the radius) ^[2]
• Monitor aPTT if on UFH
• Adjust LMWH dose for renal impairment

Complications of PCI: overall mortality < 0.5% ^[2][14]