What are the causes of elevated high sensitivity troponin (hs-troponin) levels?

Causes of Elevated High-Sensitivity Troponin

Elevated high-sensitivity troponin (hs-cTn) results from myocardial injury with a broad differential diagnosis that extends well beyond acute coronary syndromes, encompassing cardiac, vascular, pulmonary, renal, infectious, and critical illness etiologies. 1

Cardiac Causes

Acute Coronary Syndromes

• Myocardial infarction remains the most common cause of troponin elevation, reflecting myocardial cellular damage from coronary artery occlusion and distal embolization of platelet-rich thrombi 1, 2
• Elevations beyond 5-fold the upper reference limit have high (>90%) positive predictive value for acute type 1 MI 1, 2
• Elevations up to 3-fold the upper reference limit have only limited (50-60%) positive predictive value for acute MI and may be associated with a broad spectrum of conditions 1

Arrhythmias

• Tachyarrhythmias cause myocardial stress through demand ischemia, leading to troponin elevation without coronary occlusion 1, 3, 2
• Bradyarrhythmias similarly cause supply-demand mismatch, representing type 2 myocardial infarction 3

Structural and Functional Cardiac Disease

• Heart failure (both acute and chronic) causes wall stress and myocyte damage, resulting in troponin elevation 1, 3, 2
• Valvular heart disease, especially aortic stenosis, increases wall stress leading to troponin elevation 1, 3
• Hypertensive emergencies increase afterload, causing myocardial strain and troponin elevation 1, 3

Inflammatory and Infiltrative Conditions

• Myocarditis causes inflammatory damage to cardiac myocytes, producing troponin elevation 1, 3, 2
• Takotsubo syndrome results in catecholamine-mediated injury with troponin elevation 1, 3
• Infiltrative diseases (amyloidosis, hemochromatosis, sarcoidosis, scleroderma) cause troponin elevation 1, 3

Iatrogenic Causes

• Cardiac procedures including CABG, PCI, ablation, pacing, cardioversion, or endomyocardial biopsy cause troponin elevation 1, 3
• Cardiac contusion from trauma elevates troponin 1, 3

Non-Cardiac Causes

Pulmonary Conditions

• Pulmonary embolism causes right ventricular strain, leading to troponin elevation 1, 3, 2
• Pulmonary hypertension causes chronic right heart strain with troponin elevation 1, 3, 2
• Respiratory failure causes hypoxemia leading to myocardial injury and troponin elevation 3, 2

Vascular Conditions

• Aortic dissection can involve coronary arteries or cause hemodynamic compromise, leading to troponin elevation 1, 3

Renal Disease

• Renal dysfunction (both acute and chronic) reduces troponin clearance and associates with cardiac disease, causing troponin elevation 1, 3, 2
• Most often in elderly patients with renal dysfunction, elevations should not be primarily attributed to impaired clearance and considered harmless, as cardiac conditions such as chronic coronary syndromes or hypertensive heart disease are the most important contributors 1

Critical Illness and Systemic Conditions

• Critical illness (shock, sepsis, burns) causes troponin elevation through inflammatory mediators and demand ischemia 1, 3, 2
• Acute neurological events (stroke, subarachnoid hemorrhage) cause troponin elevation 1, 3

Endocrine Disorders

• Hypo- and hyperthyroidism cause troponin elevation 1, 3

Toxic and Drug-Related

• Myocardial drug toxicity or poisoning (doxorubicin, 5-fluorouracil, herceptin, snake venoms) elevates troponin 1
• Rhabdomyolysis can cause troponin elevation 1

Extreme Physical Stress

• Extreme endurance efforts cause troponin elevation 1

Interpretation of Troponin Elevations

Distinguishing Acute from Chronic Injury

• Rising and/or falling cardiac troponin levels differentiate acute (as in MI) from chronic cardiomyocyte damage (the more pronounced the change, the higher the likelihood of acute MI) 1, 3, 2
• Stable elevations indicate chronic myocardial injury 3, 2

Magnitude of Elevation

• Elevations beyond 5-fold the upper reference limit have high (>90%) positive predictive value for acute type 1 MI 1, 2
• Elevations up to 3-fold the upper reference limit have only limited (50-60%) positive predictive value for acute MI 1
• Mild elevations (<2-3 times upper limit of normal) in patients with non-cardiac conditions generally do not require workup for type 1 MI unless strongly suggested by clinical symptoms or ECG changes 3

High-Sensitivity Assay Considerations

• It is common to detect circulating levels of cardiac troponin in healthy individuals with high-sensitivity assays 1
• High-sensitivity assays can detect troponin in most healthy individuals, making serial changes more important than absolute values 3, 2

Clinical Approach to Elevated Troponin

Serial Measurements

• Serial measurements at 3-6 hour intervals (or 0h/1h or 0h/2h with hs-cTn) are essential to identify rising/falling patterns characteristic of acute myocardial injury—a single elevated value is insufficient for diagnosis 1, 3, 2
• For diagnosis of acute myocardial necrosis, evidence of a rising and/or falling pattern with at least one value above the 99th percentile is required 3, 2
• A serial increase or decrease ≥20% is required if the initial value is elevated 3, 2

Clinical Context Assessment

• Interpret troponin in clinical context, considering chest pain, ECG changes, or new wall motion abnormalities, which suggest MI 1, 3, 2
• Without clinical evidence of acute coronary syndrome, consider non-coronary causes of troponin elevation 3

Common Pitfalls

• Point-of-care troponin tests have substantially lower sensitivity than central laboratory methods and may not accurately quantify values 3
• Troponin may remain elevated for up to 2 weeks after myocardial injury, complicating detection of reinfarction 3
• In patients with end-stage renal disease, troponin elevations are common even without clinical evidence of ACS 3

Prognostic Significance

• Even minor elevations carry prognostic significance, with elevated troponin associating with increased short- and long-term mortality risk independent of the underlying cause 3, 4
• The 5-year mortality rate for myocardial injury without overt ischemia is approximately 70%, with a major adverse cardiovascular event rate of 30% 4