What are the causes of false‑positive cardiac troponin I results?

False Positive Troponin I: Causes and Clinical Approach

True false-positive troponin I results are rare and primarily caused by analytical interferences including heterophile antibodies, macrotroponin complexes (IgG-troponin), fibrin interference, and biotin supplementation in certain assay formats. 1

Primary Analytical Interferences

Heterophile Antibodies

• Heterophile antibodies represent one of the most common causes of false-positive troponin I, producing persistently elevated results that remain at a stable "plateau" level rather than showing the dynamic rise-and-fall pattern of true myocardial injury. 2
• These endogenous antibodies react with the murine monoclonal antibodies used in troponin immunoassays, creating spurious elevation. 1
• Suspect heterophile interference when troponin remains chronically elevated without clinical correlation, ECG changes, or imaging evidence of cardiac disease. 2, 3

Macrotroponin Complexes

• Macrotroponin consists of IgG antibodies bound to troponin I fragments, creating a high molecular weight complex that is detected by certain assays but not others. 4
• This interference is assay-specific—a sample may show marked elevation on one manufacturer's platform (e.g., Abbott Architect) while being undetectable on alternative assays. 4
• Polyethylene glycol (PEG) precipitation and gel filtration chromatography can confirm the presence of these macrocomplexes. 4

Biotin Interference

• Over-the-counter biotin supplements interfere with biotin-streptavidin based immunoassays, potentially causing either false-positive or false-negative results depending on the assay format (competitive vs. sandwich method). 1

Fibrin Strands

• Fibrin interference in inadequately anticoagulated samples can produce false-positive troponin I results through interaction with immunoassay reagents. 1

Skeletal Muscle Disease: A Critical Distinction

• High-sensitivity troponin T (hs-cTnT) is elevated in up to two-thirds of patients with skeletal myopathies due to re-expression of fetal cardiac isoforms that cross-react with cardiac troponin T assays. 5
• High-sensitivity troponin I (hs-cTnI) remains largely unaffected in skeletal muscle disease, making it the preferred biomarker when myopathy is suspected. 5
• Re-expression of fetal troponin isoforms in skeletal muscle pathologies (muscular dystrophy, polymyositis) can cross-react with monoclonal antibodies designed to detect cardiac troponin. 1

Diagnostic Algorithm for Suspected False-Positive Troponin I

Step 1: Exclude Life-Threatening Mimics First

• Aortic dissection causes true troponin elevation in 23-27% of cases through coronary ostial involvement, hemodynamic stress, or tamponade—not analytical interference. 6
• Look for tearing/ripping chest pain radiating to back, blood pressure differential between arms, new aortic regurgitation murmur, pulse deficits, or neurological deficits. 6
• Pulmonary embolism also produces true troponin elevation and must be excluded before attributing elevation to analytical interference. 1, 6

Step 2: Establish the Temporal Pattern

• Obtain serial troponin measurements at 0 and 6-12 hours. 7, 6
• A dynamic rise-and-fall pattern indicates acute coronary syndrome, while persistently stable elevations at a "plateau" level suggest chronic injury or analytical interference. 6, 2
• Remember that 10-15% of patients with true myocardial injury have normal initial troponin, requiring repeat testing. 7, 6

Step 3: Verify Preanalytical Factors

• Exclude sample mislabeling, fibrin clots, hemolysis, or improper specimen handling before pursuing interference testing. 5
• Repeat the measurement to confirm reproducibility. 5

Step 4: Test on Alternative Assay Platform

• If results remain incongruent with clinical presentation, measure troponin using a different manufacturer's assay—ideally high-sensitivity troponin I if the initial test was troponin T, or vice versa. 5, 4
• Macrotroponin and heterophile antibodies are often assay-specific; a negative result on an alternative platform strongly suggests analytical interference. 4

Step 5: Laboratory Confirmation of Interference

• Add heterophile-blocking reagents to the sample and remeasure. 5
• Perform PEG precipitation to screen for macro-analytes (macrotroponin). 5, 4
• If available, use gel filtration chromatography or immunoglobulin depletion (protein A/G) for definitive confirmation. 5, 4
• Addition of mouse serum can help identify heterophile antibodies in some cases. 4

Conditions That Cause TRUE Troponin Elevation (Not False-Positives)

Renal Dysfunction

• Elevated troponin in renal failure originates from the myocardium, not skeletal muscle, reflecting impaired clearance and ongoing subclinical damage from volume overload, hypertension, or left ventricular hypertrophy. 7, 6
• This represents true myocardial injury, not analytical interference. 1

Non-Ischemic Cardiac Conditions

• Myocarditis, severe heart failure, Takotsubo syndrome, tachyarrhythmias, and hypertensive emergencies all cause true troponin elevation. 1, 7
• These should not be labeled as false-positive results but rather reflect the sensitivity of the marker for detecting any form of myocardial injury. 1

Type 2 Myocardial Injury

• Demand ischemia from hypotension, anemia, hypoxemia, tachycardia, or severe systemic illness produces true troponin elevation through supply-demand mismatch. 8

Critical Pitfalls to Avoid

• Do not assume false-positive troponin simply because coronary angiography is normal—consider MINOCA (myocardial infarction with non-obstructive coronary arteries), myocarditis, Takotsubo syndrome, or microvascular dysfunction. 1
• Do not pursue invasive coronary angiography based solely on persistently elevated troponin without dynamic changes or ischemic ECG findings, especially when the elevation remains at a stable plateau level. 2
• Current assays have largely overcome historical false-positive issues, making true analytical interference uncommon in modern practice. 1
• Document confirmed analytical interference clearly in the medical record to prevent future misdiagnosis and guide which assays are reliable for that patient. 5

When to Suspect False-Positive vs. True Elevation

Suspect analytical interference when:

• Troponin remains chronically elevated at a stable "plateau" without dynamic changes 2
• Clinical presentation, ECG, and imaging are entirely normal 2, 3
• Elevation persists beyond 10-14 days without explanation 7
• Patient has known skeletal myopathy and hs-cTnT is elevated but hs-cTnI is normal 5

Recognize true elevation when:

• Serial measurements show rising or falling pattern 6
• Ischemic ECG changes are present 1, 7
• Clinical context includes chest pain, hemodynamic instability, or systemic illness 7, 6
• Imaging demonstrates new wall motion abnormalities or myocardial edema 1