Myocardial Injury Versus Infarction: Interpreting Troponin Elevation

Definition and Pathophysiology

Myocardial injury

Myocardial injury is a biochemical diagnosis defined by at least one cardiac troponin value above the assay-specific 99th-percentile upper reference limit. It is classified as acute when serial measurements demonstrate a rise and/or fall. A stable elevation indicates chronic myocardial injury.

Myocardial injury is not synonymous with myocardial infarction. Cardiac troponin identifies injury to myocardial cells, but infarction requires additional clinical evidence that the injury resulted from acute myocardial ischaemia. Thus, a patient may have acute myocardial injury without having an infarction.

The degree of troponin elevation does not by itself establish the mechanism. Increased concentrations may result from acute coronary atherothrombosis, oxygen supply–demand imbalance, direct myocardial injury, systemic illness, structural heart disease, or several mechanisms acting simultaneously.

Acute myocardial infarction

Acute myocardial infarction requires:

• Acute myocardial injury, demonstrated by a rise and/or fall in cardiac troponin with at least one value above the 99th-percentile upper reference limit; and

• Clinical evidence of acute myocardial ischaemia.

At least one of the following provides the required evidence of ischaemia:

• Symptoms compatible with myocardial ischaemia

• New ischaemic ECG changes

• Development of pathological Q waves

• Imaging evidence of new loss of viable myocardium or a new regional wall-motion abnormality in an ischaemic distribution

• Identification of a coronary thrombus by angiography or autopsy, where applicable to the relevant infarction category

Myocardial infarction results from an imbalance between myocardial oxygen supply and demand. The universal classification distinguishes infarction according to its mechanism:

• Type 1 myocardial infarction: acute atherosclerotic plaque disruption or erosion with coronary thrombosis.

• Type 2 myocardial infarction: acute myocardial ischaemia caused by oxygen supply–demand imbalance unrelated to acute coronary atherothrombosis.

• Type 3 myocardial infarction: presumed fatal myocardial infarction in which death occurs before biomarkers can be obtained or become abnormal, in the presence of symptoms suggestive of ischaemia and presumed new ischaemic ECG changes.

The distinction between myocardial injury and type 2 infarction is particularly important. Type 2 infarction requires clinical evidence of ischaemia; an elevated and dynamically changing troponin concentration without evidence of ischaemia should instead be classified as acute myocardial injury.

Mechanisms of troponin release

Troponin I and troponin T are components of the myocardial contractile apparatus and are expressed predominantly in cardiac muscle. Troponin I is highly specific for myocardial injury. Interpretation of troponin T is more complex because injured skeletal muscle may express proteins detected by some troponin T assays.

Troponin can enter the circulation through mechanisms that do not necessarily involve established pathological necrosis. Brief ischaemia, transient pressure overload, increased sarcolemmal permeability, apoptosis, and release from an early cytosolic pool have all been associated with detectable troponin. High-sensitivity assays may therefore identify a continuum of myocardial injury ranging from minor or reversible injury to extensive necrosis.

Causes of myocardial injury

Important causes include:

Clinical Presentation and Symptoms

Troponin elevation has no characteristic symptom profile because it represents a laboratory finding rather than a single disease. Symptoms must therefore be interpreted in relation to the suspected underlying mechanism.

When acute myocardial ischaemia is present, symptoms may include chest discomfort or other symptoms compatible with myocardial ischaemia. In acutely decompensated heart failure, breathlessness may represent an ischaemic equivalent, although dyspnoea alone does not establish a coronary mechanism.

Clinical features suggesting an acute coronary syndrome become more persuasive when accompanied by:

• A dynamic troponin rise and/or fall

• New ischaemic ECG changes

• New loss of myocardial function or a regional wall-motion abnormality

• A coronary thrombus or other evidence of an acute coronary mechanism

Conversely, troponin elevation in the setting of sepsis, pulmonary embolism, tachyarrhythmia, severe anaemia, shock, renal disease, myocarditis or another systemic disorder should not automatically be labelled myocardial infarction.

In athletes, troponin may increase after prolonged endurance exercise or even after brief intense treadmill exercise. These post-exertional increases generally resolve more rapidly than those associated with pathological acute myocardial injury. In such circumstances, symptoms, ECG findings and echocardiography are important for determining whether clinically significant myocardial injury has occurred.

Evaluation and Physical Examination

Evaluation begins with assessment of the clinical syndrome and the probability of acute myocardial ischaemia. Troponin results should not be interpreted in isolation. The history, physical examination, ECG and, where appropriate, cardiac imaging determine whether an elevated value represents infarction, acute non-ischaemic injury or chronic injury.

The examination should seek evidence of the underlying precipitant and of haemodynamic consequences. Relevant clinical contexts include:

• Hypotension or shock

• Respiratory failure

• Sustained tachyarrhythmia or bradyarrhythmia

• Severe hypertension

• Acute decompensated heart failure

• Pulmonary embolism or pulmonary hypertension

• Sepsis or multiorgan critical illness

• Severe anaemia

• Aortic dissection

• Recent cardioversion, defibrillation, pacing, ablation or other cardiac procedure

In critically ill patients, troponin elevation is common and is associated with adverse prognosis irrespective of the primary illness. The same patient may have type 1 infarction, type 2 infarction, or non-ischaemic myocardial injury. Clinical judgement is therefore required during the acute illness and again after recovery to determine whether further assessment for coronary artery disease or structural heart disease is appropriate.

Diagnostics

Electrocardiography

A 12-lead ECG is central to the evaluation of suspected acute coronary syndrome and should be interpreted alongside the troponin pattern.

New ischaemic ECG changes satisfy one of the criteria required to diagnose acute myocardial infarction when accompanied by acute myocardial injury. The ECG also helps identify the STEMI and non-STEMI pathways in suspected acute coronary syndrome.

In anterior infarction, the total magnitude of ST-segment elevation across the precordial leads correlates with the extent of myocardial injury. A greater number of leads showing ST-segment elevation is associated with higher mortality. New ECG findings may also support recognition of reinfarction when interpreted with the clinical presentation and serial troponin measurements.

An ECG may be non-diagnostic despite clinically important myocardial injury. Conversely, abnormalities may occur in conditions other than type 1 infarction. The ECG must therefore be integrated with symptoms, serial biomarkers and imaging.

Echocardiography and other imaging

Imaging can establish evidence required for an infarction diagnosis by demonstrating:

• New loss of viable myocardium

• A new regional wall-motion abnormality in a pattern consistent with ischaemia

Echocardiography is also useful when troponin is elevated in acute heart failure. An abnormal troponin result should prompt consideration of the cause, particularly when accompanied by a change in ventricular function.

In critically ill patients with sepsis, marked reduction in ejection fraction may occur with subsequent complete recovery after treatment of the sepsis. This illustrates why reduced ventricular function and troponin elevation do not necessarily indicate coronary thrombosis.

Cardiac magnetic resonance imaging may provide additional information when the mechanism of myocardial injury remains uncertain. Myocardial perfusion studies and coronary angiography may also be required, depending on the clinical context. In patients with abnormal troponin or natriuretic peptide concentrations suggestive of structural disease, echocardiography is reasonable, especially when biomarker levels increase over time.

In patients with low-level troponin elevation, no typical symptoms or ECG changes, and an intermediate clinical risk, normal radionuclide perfusion imaging is associated with very low short-term cardiac mortality. An abnormal perfusion study identifies a higher-risk group, and the extent of inducible ischaemia can help determine the need for coronary angiography and revascularisation. Quantitative stress positron-emission tomography may offer particular value in intermediate- to high-risk patients with low-level troponin elevation and no obstructive coronary disease, because impaired global myocardial flow reserve may indicate chronic microvascular ischaemia.

Coronary angiography

Angiography can identify a coronary thrombus and establish a coronary mechanism in appropriate cases. It is also relevant when a patient with suspected infarction requires revascularisation.

However, coronary anatomy alone does not determine whether an elevated troponin represents type 1 infarction. Patients with stable coronary disease may develop type 2 infarction from hypotension, vasospasm, anaemia or increased demand. Conversely, troponin elevation may be unrelated to ischaemia despite the presence of coronary disease.

Electrophysiology and rhythm assessment

The source material does not describe a specific electrophysiological testing strategy for myocardial injury. Sustained tachyarrhythmia and bradyarrhythmia are recognised causes of myocardial injury related to oxygen supply–demand imbalance and should be considered when interpreting troponin elevation.

Biomarkers and Laboratory Findings

Cardiac troponin

Cardiac troponin I and T are the preferred biomarkers for myocardial injury, and high-sensitivity assays are recommended for routine use. Creatine kinase-MB is less sensitive and less specific; routinely measuring both troponin and CK-MB is unnecessary in suspected STEMI.

A troponin concentration above the assay-specific 99th-percentile upper reference limit establishes myocardial injury. A rise and/or fall defines the injury as acute. The magnitude of change must be interpreted using the assay-specific characteristics and in relation to the clinical presentation.

A single initial troponin measurement may be normal early in the course of STEMI because biomarker release takes time. For suspected acute coronary syndrome:

• High-sensitivity troponin should be measured at presentation and repeated after 1–3 hours.

• Conventional troponin should be repeated after 3–6 hours.

• Further testing may be required when clinical suspicion remains high or diagnostic uncertainty persists.

• In patients presenting more than 2–3 hours after symptom onset, a very low high-sensitivity troponin concentration at presentation may exclude infarction with a negative predictive value greater than 99%, in the appropriate clinical setting.

High-sensitivity assays permit detection of small absolute changes over short intervals and may support rapid rule-out or rule-in pathways. Their interpretation requires knowledge of the assay’s 99th-percentile limit at the local institution.

Persistent and chronic elevation

Troponin may remain elevated for weeks after STEMI because of ongoing release from degenerating contractile proteins. Reperfusion alters release kinetics and can produce an earlier, more pronounced peak. The peak troponin concentration correlates approximately with infarct size, although late measurements are less reliable for estimating infarct size because they may reflect delayed release from the myofilament-bound pool.

Stable elevations occur in chronic conditions such as:

• Chronic kidney disease or renal dysfunction

• Heart failure with reduced or preserved ejection fraction

• Left ventricular hypertrophy

• Chronic myocardial disease

In stable myocardial injury, progressively higher high-sensitivity troponin concentrations are associated with increasing risk of cardiovascular death and heart failure in patients with stable ischaemic heart disease. This prognostic relationship does not, by itself, establish an acute infarction or define a specific treatment.

Troponin in pulmonary embolism

Troponin elevation may reflect right-ventricular strain in acute pulmonary embolism and can aid prognostic assessment when combined with clinical and imaging findings. On its own, it has limited specificity and positive predictive value for early mortality in normotensive patients.

High-sensitivity troponin T below 14 pg/mL had a negative predictive value of 98% for excluding an adverse in-hospital outcome in one prospective cohort of normotensive patients with pulmonary embolism. Age-adjusted thresholds of at least 14 pg/mL in patients younger than 75 years and at least 45 pg/mL in those older than 75 years may improve negative predictive value.

Troponin in heart failure

Detectable troponin is common in heart failure, particularly when measured with high-sensitivity assays. A substantial proportion of patients exceed the 99th-percentile upper reference limit, especially during acute decompensation.

Mechanisms include:

• Type 1 or type 2 infarction

• Increased transmural pressure

• Small-vessel coronary obstruction

• Endothelial dysfunction

• Anaemia or hypotension

• Cardiomyocyte apoptosis and autophagy related to wall stretch

• Inflammatory, neurohormonal or infiltrative cellular toxicity

• Release from an early cytosolic troponin pool

In acute decompensated heart failure, troponin should be measured promptly and an ECG recorded to identify or exclude ischaemia as the precipitant. A significant rise and/or fall, particularly with ischaemic symptoms, new ischaemic ECG changes or new loss of myocardial function, should increase suspicion for type 1 infarction.

Other biomarkers

B-type natriuretic peptide and N-terminal pro-B-type natriuretic peptide are not sufficiently specific to diagnose stable ischaemic heart disease, but higher concentrations are associated with major cardiovascular events and structural cardiac abnormalities. They are useful when interpreted with the clinical history and examination, particularly in suspected heart failure.

In patients with stable ischaemic heart disease, higher concentrations of high-sensitivity troponin and natriuretic peptides are associated with graded increases in cardiovascular risk. Serial measurements may provide additional prognostic information. Growth differentiation factor-15, soluble suppression of tumorigenicity 2, fibroblast growth factor-23 and galectin-3 have also been associated with outcomes, but their incremental value beyond high-sensitivity troponin and natriuretic peptides is insufficiently established.

D-dimer may be used to assist evaluation for pulmonary embolism, and B-type natriuretic peptide may support assessment of heart failure when considered with the clinical findings.

Treatment and Management

General principles

Management is directed at the underlying cause, not at the troponin concentration alone. The initial task is to determine whether the patient has:

• Type 1 myocardial infarction

• Type 2 myocardial infarction

• Acute non-ischaemic myocardial injury

• Chronic myocardial injury

A troponin result should not delay urgent intervention in patients with STEMI. Conversely, an elevated troponin without evidence of ischaemia should not automatically trigger treatment as acute coronary thrombosis.

Suspected type 1 myocardial infarction

When acute myocardial injury is accompanied by clinical evidence of acute myocardial ischaemia and the overall presentation supports coronary atherothrombosis, management follows the acute coronary syndrome pathway. The source material emphasises that biomarker assessment should be obtained as soon as possible but should not delay intervention in STEMI.

Type 2 myocardial infarction

Type 2 infarction results from oxygen supply–demand imbalance unrelated to acute coronary atherothrombosis. Relevant precipitants include:

• Hypotension or shock

• Severe anaemia

• Respiratory failure

• Coronary spasm or microvascular dysfunction

• Coronary embolism or dissection

• Sustained bradyarrhythmia

• Sustained tachyarrhythmia

• Severe hypertension or hypertensive crisis

• Critical aortic stenosis

• Severe hypertrophic cardiomyopathy

• Sepsis and acute viral infection

Treatment should focus on identifying and correcting the precipitating supply–demand disturbance. The source material does not provide a specific medication regimen or procedural algorithm for type 2 infarction.

Acute non-ischaemic myocardial injury

Treatment should target the underlying disorder, such as:

• Sepsis

• Myocarditis

• Pulmonary embolism

• Acute pulmonary hypertension

• Heart failure

• Renal dysfunction

• Tachyarrhythmia or bradyarrhythmia

• Takotsubo syndrome

• Cardioversion or defibrillation-related injury

• Critical systemic illness

In sepsis-associated myocardial dysfunction, ventricular function may recover completely once the sepsis is treated. This reinforces the need to avoid assuming permanent coronary damage solely from troponin elevation or reduced ejection fraction.

Chronic myocardial injury

Chronic stable troponin elevation should prompt assessment for the structural or systemic disorder responsible. In stable ischaemic heart disease, higher high-sensitivity troponin and natriuretic peptide levels identify patients at greater cardiovascular risk. More intensive preventive treatment may be relevant, although the therapeutic implications of chronic troponin elevation remain incompletely established.

Periprocedural injury and infarction

After percutaneous coronary intervention or coronary artery bypass grafting, procedure-related myocardial injury must be distinguished from procedure-related infarction. Based on the provided ARC-2 criteria:

The definitions apply when baseline biomarkers are normal or are elevated but stable or falling. New Q waves require a duration of at least 40 ms and depth of at least 1 mm in at least two contiguous leads.

Reinfarction

Reinfarction should be assessed from the clinical presentation, ECG and at least two serial troponin measurements. If troponin is already elevated but stable or falling when recurrent symptoms occur, a further increase of more than 20% indicates reinfarction. If the initial troponin is normal, standard assay-specific diagnostic criteria and sampling intervals should be used.

Drugs and doses

The source material does not provide drug doses or a comprehensive pharmacological regimen for myocardial injury, type 1 infarction or type 2 infarction. It does note that more intensive preventive therapies, including tighter blood-pressure control and, in selected patients with type 2 diabetes, possible use of sodium–glucose cotransporter 2 inhibitors, may attenuate chronic injury or associated adverse risk. These observations do not constitute a dose-specific treatment protocol.

Guideline Recommendations

The provided recommendations can be summarised as follows:

• Use the term myocardial injury when at least one cardiac troponin value exceeds the 99th-percentile upper reference limit.

• Call the injury acute when there is a rise and/or fall in serial troponin values.

• Diagnose myocardial infarction only when acute myocardial injury is accompanied by clinical evidence of acute myocardial ischaemia.

• Use cardiac troponin I or T as the preferred biomarker, preferably with a high-sensitivity assay.

• Measure troponin in all patients with suspected acute coronary syndrome.

• Obtain troponin as soon as possible at the initial encounter.

• In STEMI, do not delay intervention while awaiting biomarker results.

• Know the local assay’s 99th-percentile upper reference limit.

• Use serial high-sensitivity troponin testing, commonly at presentation and 1–3 hours later; conventional assays generally require repeat testing at 3–6 hours.

• Interpret troponin in conjunction with symptoms, ECG, imaging and the clinical context.

• Do not label non-ischaemic myocardial injury as myocardial infarction.

• In acute decompensated heart failure, obtain both an ECG and troponin promptly to assess for ischaemia as a precipitant.

• In critically ill patients, use clinical judgement after recovery to determine whether further evaluation for coronary artery disease or structural heart disease is indicated.

• Do not routinely measure both troponin and CK-MB, since CK-MB is less sensitive and specific and adds little when troponin is available.

Prognosis and Follow-up

Prognostic significance

Troponin elevation is consistently associated with adverse outcomes, but its prognostic meaning depends on the clinical setting.

Among hospitalized patients with COVID-19, myocardial injury has been associated with arrhythmias, respiratory failure, increased need for mechanical ventilation, acute kidney injury, acute respiratory distress syndrome, coagulation disorders and increased mortality. It is more common in older patients and those with comorbidities. Whether troponin is a direct contributor to adverse outcomes or primarily a marker of disease severity remains uncertain.

In critically ill patients, troponin elevation is common and predicts adverse prognosis regardless of the underlying illness. In pulmonary embolism, elevated troponin identifies higher risk when combined with clinical and imaging findings, while a low high-sensitivity troponin has a high negative predictive value for adverse in-hospital outcomes in selected normotensive patients.

In stable ischaemic heart disease, increasing high-sensitivity troponin concentrations are associated with a graded increase in subsequent cardiovascular death, myocardial infarction and heart failure. Higher natriuretic peptide concentrations similarly identify patients at increased cardiovascular risk.

Follow-up assessment

Follow-up should be determined by the cause and persistence of the injury:

• Patients with suspected type 1 infarction require appropriate post-infarction assessment and secondary prevention, although specific regimens are not detailed in the source material.

• Patients with type 2 infarction should be reassessed for the precipitating disorder and for the presence or absence of coronary artery disease, since both may influence prognosis and future management.

• Patients with acute non-ischaemic myocardial injury should undergo follow-up directed at the underlying systemic, myocardial or pulmonary condition.

• Patients with persistent or increasing troponin or natriuretic peptide levels should be considered for echocardiographic assessment, particularly when structural heart disease is suspected.

• After critical illness, evaluation for coronary artery disease or structural heart disease should be guided by clinical recovery and judgement rather than by the troponin result alone.

• Recurrent symptoms with an already elevated troponin require serial testing and ECG comparison to distinguish reinfarction from persistent or chronic elevation.

The central principle is that troponin is a highly sensitive indicator of myocardial injury and a valuable prognostic marker, but it becomes diagnostic of myocardial infarction only when its dynamic change is linked to clinical evidence of acute myocardial ischaemia.