What percentage of patients with myocarditis have normal cardiac enzymes, such as troponin and creatine kinase (CK)?

Myocarditis with Normal Cardiac Enzymes

Approximately 34-66% of patients with biopsy-proven myocarditis have normal cardiac troponin levels, making normal cardiac enzymes insufficient to rule out myocarditis. 1, 2

Diagnostic Sensitivity of Cardiac Biomarkers

Troponin Sensitivity in Myocarditis

• Troponin I is elevated in only 34% of patients with histologically confirmed acute myocarditis, even in those with an average of 1 month of heart failure symptoms, according to data from the US Myocarditis Treatment Trial 2

• Troponin T demonstrates higher sensitivity at 35% (28 of 80 patients) with clinically suspected myocarditis, compared to creatine kinase (5%) and CK-MB (1.25%) 3

• In immune checkpoint inhibitor-associated myocarditis, troponin T is elevated in 98% of cases within 72 hours of admission, while troponin I is positive in only 88% (P=0.03), and creatine kinase in 75% (P<0.001) 4

• The timing of biomarker measurement is critical: troponin elevations are significantly correlated with ≤1 month duration of heart failure symptoms (P=0.02), suggesting that myocyte necrosis occurs early and the diagnostic window may be brief 2

Creatine Kinase Performance

• Creatine kinase is elevated in the majority of patients with checkpoint inhibitor-related myositis (median 2650 IU/L, range 335-20,270 IU/L), but CK levels are usually within normal range in patients presenting with myalgia alone 1

• CK-MB is elevated in only 5.7% of patients with biopsy-proven myocarditis, making it substantially less sensitive than troponin I (34%, P=0.001) 2

Clinical Implications

When Normal Enzymes Cannot Exclude Myocarditis

Normal cardiac enzymes cannot always rule out the possibility of myocarditis, particularly when clinical syndrome, electrocardiographic changes, or cardiac MRI findings suggest myocardial inflammation 1

Key scenarios where myocarditis may exist despite normal biomarkers:

• Patients presenting beyond the acute phase (>1 month after symptom onset), when the majority of myocyte necrosis has already occurred 2

• Patients with focal or patchy myocardial involvement where the extent of injury is below the detection threshold of current assays 3

• Early presentation within 3-4 hours of symptom onset, before troponin release from the cytosolic pool 5

Diagnostic Algorithm for Suspected Myocarditis

Serial troponin measurements are mandatory: A single normal troponin at presentation is insufficient, as 10-15% of patients may not show troponin deviations initially 5

1. Measure cardiac troponin (I or T) at presentation and repeat at 6-12 hours after symptom onset or hospital admission 5

2. Obtain electrocardiography to assess for PR-segment depression, diffuse ST-segment elevation (suggesting pericarditis), low voltage with thickened LV walls (suggesting myocardial edema), or QRS width >120 ms (predicting higher risk of death or transplantation) 1

3. Perform cardiac MRI when clinical syndrome, elevated troponin, or ECG changes suggest myocarditis, looking for epicardial or midwall delayed gadolinium enhancement (distinct from the endocardial pattern of ischemic injury) 1

4. In checkpoint inhibitor-associated cases, prioritize troponin T over troponin I for both diagnosis and surveillance, as cTnT demonstrates superior sensitivity (98% vs 88% within 72 hours) 4

Common Pitfalls

Troponin Assay Variability

• Troponin I assays are heterogeneous, with different manufacturers using different antibodies and cutoff values, requiring clinicians to know the specific sensitivity of their hospital's assay 1

• Troponin T exists as a single standardized third-generation immunoassay, eliminating inter-assay variability 1

• High-sensitivity troponin assays may detect subclinical myocardial damage in conditions like renal failure, left ventricular hypertrophy, or heart failure, complicating interpretation 5

Timing-Related Diagnostic Errors

• Troponin elevation is delayed 3-4 hours after symptom onset due to initial release from the cytosolic pool, with persistence up to 2 weeks from proteolysis of the contractile apparatus 5

• The prolonged elevation window can complicate detection of recurrent necrosis in patients with recent infarction 5

Differential Diagnosis Considerations

Other life-threatening conditions presenting with chest pain and elevated troponin must always be considered, including aortic dissection and pulmonary embolism 5

• In checkpoint inhibitor-related cases, search systematically for concurrent myositis (dyspnea, palpitations, chest pain, syncope) and myasthenia gravis (ptosis, diplopia, bulbar symptoms), as these frequently coexist and increase mortality risk to approximately 20% 1

• Cardiac evaluation must be systematic for any patient with myositis or suspected myositis, including cardiac troponin (troponin I is more specific than troponin T in skeletal muscle disease), electrocardiography, and cardiac MRI if clinical syndrome or biomarkers are abnormal 1