Cardiac Biomarkers in ACS — Harrison's Principles of Internal Medicine, 22E (2025)

1. Fundamental Principle

A rise and/or fall in cardiac biomarker values with at least one value above the 99th percentile upper reference limit.

2. Classification of Elevated cTn (Figure 15-3)

3. Biomarkers — Individual Details

A. Cardiac Troponin I (cTnI) and Troponin T (cTnT) ⭐ Preferred

• Structure: cTnT and cTnI have amino-acid sequences that differ from skeletal muscle isoforms, enabling highly specific monoclonal antibody–based assays.
• Measurement: High-sensitivity (hs-cTn) assays are preferred over conventional assays for all suspected ACS.
• Cutoff: >99th percentile of reference population = abnormal.
• Rise in STEMI: cTn rises to 20–50× the upper reference limit in "classic" large MI.
• Temporal profile (STEMI):
  • Detectable: ~2–4 h after onset
  • Peak: ~12–24 h (NSTEMI); earlier peak if reperfusion achieved (washout effect)
  • Elevated for: at least 7–10 days after STEMI
• NSTEMI: Characteristic temporal rise peaking at 12–24 h after symptom onset, then gradually decreasing; direct relationship between degree of elevation and mortality.
• High-sensitivity assays allow:
  • Rapid rule-out protocols using serial testing over 1–2 h
  • In patients >2–3 h after symptom onset: very low hs-cTn at presentation alone may exclude MI (NPV >99%)
  • The 1-h rapid rule-out algorithm (no abnormal elevation of hsTn at 0 or 1 h) recommended by recent practice guidelines
• Measurement timing: At presentation, then repeat at 1–3 h (hs-cTn) or 3–6 h (conventional cTn); further measurements if clinical uncertainty persists.

B. Creatine Kinase-MB (CK-MB)

• Now secondary — not cost-effective to measure alongside cardiac-specific troponin.
• Relative index: CK-MB mass / CK activity ≥2.5 suggests (but is not diagnostic of) a myocardial source.
• Key remaining niche: Because CK-MB declines more rapidly than cTn after AMI onset, it remains useful for detecting early reinfarction during the period when cTn remains elevated from the index event.
• Microinfarction: cTn elevations occur above the upper reference limit in microinfarction even when CK-MB is still within the normal range — an important diagnostic advantage of hs-cTn.

C. Myoglobin

• Released earliest (cytoplasmic pool; small molecular weight).
• Blood levels rise quickly above the cutoff — earliest marker.
• No cardiac specificity — rendered obsolete by troponin assays.

Biomarker Kinetics (Figure 286-4)

4. Other Laboratory Markers

• D-dimer: Useful to exclude pulmonary embolism in the differential of acute chest pain.
• BNP / NT-proBNP: Useful when considered alongside clinical history and examination for the diagnosis of heart failure; multimarker strategies including BNP alongside hsTn are gaining favor for risk stratification in NSTE-ACS.
• WBC: Polymorphonuclear leukocytosis appears within hours, persists 3–7 days, WBC up to 12,000–15,000/μL — nonspecific reaction to myocardial injury.
• ESR: Rises more slowly than WBC, peaks during the first week, may remain elevated 1–2 weeks.

5. Causes of Elevated Cardiac Troponin — Beyond ACS

Myocardial Injury Related to Acute MI

• Atherosclerotic plaque disruption or erosion with thrombosis

Myocardial Ischemia (O₂ Supply/Demand Imbalance — Type 2 MI territory)

Other Cardiac Causes

• Heart failure
• Myocarditis
• Cardiomyopathy (any type)
• Takotsubo syndrome (stress cardiomyopathy)
• Recent coronary revascularization
• Cardiac procedures other than revascularization
• Catheter ablation
• Defibrillator shocks
• Cardiac contusion

Systemic (Non-Cardiac) Causes

• Sepsis
• Chronic kidney disease (reduced clearance + chronic myocardial injury)
• Stroke / subarachnoid hemorrhage (neurogenic myocardial injury)
• Pulmonary embolism
• Infiltrative diseases (e.g., amyloidosis, sarcoidosis)
• Chemotherapeutic agents (cardiotoxicity)
• Critical illness
• Strenuous exercise

Source: Reproduced with permission from K Thygesen et al: Fourth Universal Definition of Myocardial Infarction (2018). Circulation 138:2231, 2018.

6. Critical Clinical Distinctions

Pathophysiology of ACS — Robbins Pathology

Custom Sequential Flowchart

Original Robbins Figure 12.9 (Robbins & Cotran, Pathologic Basis of Disease)

Sequential Steps — Written Summary (Robbins)

① Risk Factors → Endothelial Injury

② Atherosclerotic Plaque Formation

③ Fixed Coronary Obstruction (Chronic)

④ Vulnerable Plaque (the pivot point)

• Large atheromatous lipid core
• Thin fibrous cap
• ↑ Macrophages → metalloprotease secretion → collagen degradation
• ↓ SMCs → reduced collagen synthesis
• Cap thinnest at the shoulder (junction with normal arterial wall) — highest mechanical stress
• External triggers: hypertension, platelet reactivity, vasoconstriction

Robbins key fact: 2/3 of culprit plaques are ≤50% stenotic before rupture; 85% show ≤70% stenosis — i.e., most ACS events arise from previously non-obstructive, asymptomatic plaques.

⑤ Acute Plaque Disruption (Two Mechanisms)

⑥ Exposure of Thrombogenic Contents

⑦ Platelet Adhesion & Activation

⑧ Coagulation Cascade → Stable Thrombus

⑨ Thrombus Outcomes → ACS Spectrum

                    THROMBUS
                       │
        ┌──────────────┼──────────────────┐
        ▼              ▼                  ▼
  Mural / non-     Partial + spasm    Complete occlusion
  occlusive
  ± microemboli
        │              │                  │
        ▼              ▼                  ▼
  • Unstable      Subendocardial     • STEMI
    Angina         infarct            (Transmural MI)
  • NSTEMI       (inner 1/3)        • Sudden
  • Subendo-                          cardiac death
    cardial infarct
        └──────────────┴──────────────────┘
              ▼
     ■ ACUTE CORONARY SYNDROMES ■