Acute Coronary Syndromes — Part 2: Cardiac Biomarkers & Risk Stratification

1. Cardiac Troponin — The Biomarker of Myocardial Necrosis

1.1 Biology of Cardiac Troponin

Cardiac troponins are structural proteins of the sarcomere that regulate calcium-mediated contraction of cardiac myocytes. The troponin complex consists of three subunits:¹

• Troponin C (TnC): Binds calcium; identical isoform in cardiac and skeletal muscle — not used as a cardiac biomarker
• Troponin I (cTnI): Inhibits actin-myosin interaction; cardiac-specific isoform distinct from skeletal muscle
• Troponin T (cTnT): Binds the troponin complex to tropomyosin; cardiac-specific isoform distinct from skeletal muscle

Both cTnI and cTnT are preferred biomarkers for the detection of myocardial injury. Following myocardial necrosis:^{1 2}

1.2 Conventional vs. High-Sensitivity Troponin Assays

1.3 Commonly Used High-Sensitivity Troponin Assays and Thresholds

Critical note: Assay-specific thresholds must be used. Values are NOT interchangeable between platforms. Clinicians must know which assay their laboratory uses.^{2 3}

1.4 Sex-Specific Thresholds

The international expert consensus panel and the European cardiology guidelines committee both recommend the use of sex-specific 99th percentile thresholds for high-sensitivity troponin assays. Women have lower circulating troponin levels than men; using a single (overall) threshold may result in underdiagnosis of MI in women. Sex-specific thresholds increase the diagnosis of MI in women by approximately 40-60% in registry studies, with improved long-term outcomes when appropriately treated.^{3 4}

2. Rapid Rule-Out and Rule-In Algorithms

2.1 The 0/1-Hour Algorithm (European Cardiology Guidelines Committee)

The 0/1-hour (0h/1h) algorithm is recommended as the preferred rapid assessment pathway by the international cardiology guidelines committee, using high-sensitivity cardiac troponin (hs-cTn) measured at presentation (0h) and at 1 hour (1h).³

Prerequisites for using the 0/1h algorithm:

• High-sensitivity troponin assay (not conventional assay)
• Chest pain onset > 3 hours before presentation (if < 3 hours, a 3-hour re-test is recommended if 0/1h is negative)
• Assay-specific validated cutoffs must be used

0/1-Hour Algorithm for hs-cTnT (Roche Elecsys)

0/1-Hour Algorithm for hs-cTnI (Abbott ARCHITECT)

0/1-Hour Algorithm for hs-cTnI (Siemens Atellica/ADVIA Centaur)

2.2 The 0/3-Hour Algorithm

For institutions not validated on the 0/1h pathway or using conventional troponin assays, a 0/3-hour protocol is an acceptable alternative:^{3 5}

2.3 Key Principles of Troponin Interpretation

1. Rise and/or fall pattern: A single elevated troponin value indicates myocardial injury but does not distinguish acute from chronic injury. The dynamic change (rise and/or fall) is essential for diagnosing acute myocardial injury.¹
2. Clinical context is paramount: An elevated troponin requires clinical correlation. The differential diagnosis of elevated troponin extends far beyond Type 1 MI.
3. Delta values: The absolute change (delta) between serial measurements is more clinically useful than relative (percentage) change, particularly with hs-cTn assays.³

2.4 Common Causes of Elevated Troponin Beyond Type 1 MI

3. Other Cardiac Biomarkers

3.1 CK-MB

Creatine kinase-MB isoenzyme is no longer recommended as the primary biomarker for MI diagnosis but retains a role in specific clinical scenarios:¹

• Detecting reinfarction: CK-MB rises and falls more rapidly than troponin (returns to baseline within 48-72 hours), making it useful for detecting reinfarction in the setting of an already-elevated troponin from a recent MI
• Periprocedural MI: Some protocols still use CK-MB for diagnosing periprocedural MI after PCI or CABG
• Timing of MI: A rising CK-MB with elevated troponin suggests acute (< 48 hour) MI; an elevated troponin with normal CK-MB suggests the MI occurred > 48-72 hours prior

3.2 BNP / NT-proBNP

B-type natriuretic peptide and its N-terminal fragment are not diagnostic for MI but provide prognostic information in ACS:²

• Elevated BNP or NT-proBNP at presentation is associated with higher risk of death and heart failure in ACS
• Useful for assessing LV dysfunction and volume status
• May help differentiate dyspnea due to HF vs. ACS vs. pulmonary causes

3.3 High-Sensitivity C-Reactive Protein (hs-CRP)

• Inflammatory biomarker associated with plaque instability
• Elevated hs-CRP (> 2 mg/L) in ACS is associated with worse outcomes
• Not recommended for acute diagnosis; may have role in risk stratification for secondary prevention decisions²

4. Risk Stratification Scores

4.1 HEART Score

The HEART score was specifically developed and validated for risk stratification of undifferentiated chest pain patients in the emergency department. It has been validated in multiple large multicenter studies and is recommended by the chest pain evaluation guidelines committee.^{5 6}

Complete HEART Score Table

Total score range: 0-10

HEART Score Risk Categories and Recommended Disposition

4.2 HEART Pathway

The HEART Pathway integrates the HEART score with serial high-sensitivity troponin testing to create a structured decision protocol:⁶

Step 1: Calculate HEART score at presentation Step 2: Obtain initial troponin

• If HEART score 0-3 AND initial troponin negative → low risk
  • If using hs-cTn: consider single-draw discharge if hs-cTn below limit of detection and symptom onset > 3 hours
  • If using conventional troponin: obtain repeat troponin at 3-6 hours
• If HEART score 0-3 AND troponin positive → reclassify as intermediate/high risk
• If HEART score 4-6 → intermediate risk pathway (observation, serial troponins, stress testing or CTA)
• If HEART score 7-10 → high risk (invasive strategy)

Step 3: Serial troponin (if indicated)

• If both troponins negative AND HEART 0-3 → discharge with follow-up
• If troponin rises above threshold → manage as NSTEMI

Validation data: The HEART Pathway has been shown to safely identify approximately 40% of ED chest pain patients as low risk for early discharge, with a 30-day MACE miss rate of < 1%.⁶

4.3 TIMI Risk Score for NSTEMI/UA

The TIMI risk score for NSTEMI/UA was derived from clinical trial data and predicts 14-day risk of death, MI, or urgent revascularization.⁷

Total score range: 0-7

4.4 TIMI Risk Score for STEMI

The TIMI risk score for STEMI predicts 30-day mortality in patients with STEMI treated with fibrinolytic therapy. It was derived from the InTIME-II trial.⁸

Total score range: 0-14

4.5 GRACE Score

The Global Registry of Acute Coronary Events (GRACE) score is the most extensively validated risk prediction tool for in-hospital and 6-month mortality across the entire ACS spectrum. It is recommended by the international cardiology guidelines committee as the preferred risk assessment tool for guiding timing of invasive strategy in NSTE-ACS.^{3 9}

GRACE Score Components

Note: The GRACE score is typically calculated using an online calculator or app (www.gracescore.org) because the individual variable points follow non-linear curves. A simplified GRACE risk calculator (GRACE 2.0) is also available.

GRACE Score Risk Categories

4.6 Comparison of Risk Scores

5. Chest Pain Observation and Disposition Pathways

5.1 Who Can Be Safely Discharged from the ED?

Based on the 2021 chest pain evaluation guidelines and contemporary evidence, patients may be considered for early discharge from the ED if ALL of the following criteria are met:⁵

1. HEART score 0-3 (low risk)
2. Normal or non-ischemic ECG (no ST changes, no new conduction abnormalities)
3. Negative serial troponin (two negative hs-cTn values using a validated protocol — 0/1h or 0/3h — OR a single hs-cTn below the limit of detection with symptom onset > 3 hours)
4. No ongoing symptoms at time of proposed discharge
5. No hemodynamic instability during ED stay
6. Reliable follow-up can be arranged within 72 hours

5.2 Observation Unit / Chest Pain Unit Pathways

For patients not meeting criteria for immediate discharge or high-risk admission, an observation pathway is appropriate:⁵

5.3 Coronary CT Angiography (CCTA) in the Chest Pain Pathway

The 2021 chest pain guidelines provide a Class I recommendation for CCTA as an alternative to functional stress testing for low-to-intermediate risk patients with acute chest pain:⁵

• Advantages: High sensitivity (95-99%) and negative predictive value (97-100%) for obstructive CAD; rapid (< 30 minutes); provides anatomic information
• Best candidates: Young to middle-aged patients, no known CAD, low-intermediate pretest probability, able to hold breath, heart rate controllable to < 65 bpm (beta-blocker premedication)
• Limitations: Radiation exposure, contrast administration, limited in heavy calcification (calcium score > 400), post-stent/post-CABG evaluation limited, less useful in known CAD

5.4 Stress Testing Options for the Chest Pain Pathway

6. Approach to Troponin Elevation in Specific Clinical Scenarios

6.1 Chronic Kidney Disease

Patients with CKD (particularly stages 4-5 and dialysis) frequently have chronically elevated troponin levels, especially hs-cTnT. This reflects chronic myocardial injury (from LVH, microvascular disease, volume overload) rather than acute MI.^{1 3}

Key principles:

• The 99th percentile URL remains the diagnostic threshold; do NOT use a higher threshold for CKD patients
• The dynamic change (rise and/or fall) is the critical distinction between chronic elevation and acute MI
• A delta of ≥ 20% (some guidelines suggest ≥ 50% for hs-cTnT in advanced CKD) from baseline to 3-6 hour repeat is suggestive of acute MI
• hs-cTnI may be less affected by renal function than hs-cTnT, though both can be chronically elevated in CKD
• Clinical context and ECG remain essential

6.2 Heart Failure

Patients with acute and chronic heart failure frequently have elevated troponin, reflecting ongoing myocardial stress and injury. A stable chronically elevated troponin in a heart failure patient carries prognostic significance (higher mortality) but does not indicate acute MI. The same rise/fall criteria apply for diagnosing superimposed acute MI.¹

6.3 Very Early Presentation (< 1-2 Hours from Symptom Onset)

• Initial troponin may be negative even with true MI if measured very early
• A single negative hs-cTn below the limit of detection (< 5 ng/L for most assays) with symptom onset > 3 hours has > 99% NPV for MI and may be sufficient for rule-out in low-risk patients
• If symptom onset < 3 hours, a repeat troponin at 1 hour (0/1h algorithm) or 3 hours (0/3h algorithm) is mandatory regardless of the initial result³

6.4 Late Presentation (> 12-24 Hours)

• Troponin may have already peaked and may be declining
• A single elevated troponin above the 99th percentile URL in the appropriate clinical context suggests acute MI, but additional testing (repeat troponin to demonstrate fall, imaging for wall motion abnormalities) may be needed to confirm the diagnosis and timing

References