Definition and Pathophysiology
Type 2 myocardial infarction (MI) is defined as an ischaemic myocardial injury occurring in the context of a mismatch between myocardial oxygen supply and demand, which is not related to acute coronary atherothrombosis. By definition, acute atherothrombotic plaque disruption is not a feature of Type 2 MI. The pathophysiology of Type 2 MI is fundamentally distinct from that of Type 1 MI, which is driven by plaque rupture and thrombosis.
The mechanisms leading to Type 2 MI are diverse and can be broadly categorised by whether they primarily reduce myocardial oxygen supply or increase myocardial oxygen demand. These mechanisms may involve coronary or non-coronary factors, and ischaemic thresholds vary substantially between individuals depending on the magnitude of the stressor, the presence of non-cardiac comorbidities, and the extent of underlying coronary artery disease (CAD) and structural cardiac abnormalities.
Mechanisms involving reduced myocardial perfusion include fixed coronary atherosclerosis without plaque rupture, coronary artery spasm, coronary microvascular dysfunction (encompassing endothelial dysfunction, smooth muscle cell dysfunction, and dysregulation of sympathetic innervation), coronary embolism, and spontaneous coronary artery dissection with or without intramural haematoma. Spontaneous coronary artery dissection is defined as spontaneous dissection of the coronary artery wall with accumulation of blood within the false lumen, which compresses the true lumen to varying degrees; this non-atherosclerotic condition may occur especially in young women. Non-coronary mechanisms that reduce oxygen supply include severe bradyarrhythmia, respiratory failure with severe hypoxaemia, severe anaemia, and hypotension or shock.
Conversely, mechanisms that increase myocardial oxygen demand include sustained tachyarrhythmia and severe hypertension, with or without left ventricular hypertrophy. In patients with stable known or presumed CAD, an acute stressor—such as an acute gastrointestinal bleed causing a precipitous drop in haemoglobin, or a sustained tachyarrhythmia—may result in insufficient blood flow to meet the increased myocardial oxygen demand, precipitating Type 2 MI.
It is also crucial to distinguish Type 2 MI from acute and chronic myocardial injury. Myocardial injury is characterised by myocyte necrosis and troponin elevation due to mechanisms other than myocardial ischaemia. Acute myocardial injury may arise from conditions such as sepsis, myocarditis, or takotsubo syndrome, while chronic myocardial injury may be seen in heart failure, cardiomyopathies, and severe valvular heart disease. Type 2 MI and non-ischaemic myocardial injury may coexist, and certain disease entities can span both categories; for example, acute heart failure may occur in the context of acute myocardial ischaemia, though abnormal cardiac troponin (cTn) values in the setting of acute or chronic heart failure are often better categorised as myocardial injury.
Clinical Presentation and Symptoms
Patients with Type 2 MI frequently present with acute chest pain and troponin elevation. The clinical manifestation is typically driven by an acute stressor superimposed on the patient's baseline cardiovascular state. For instance, a patient with stable CAD may present with clinical manifestations of myocardial ischaemia following an acute gastrointestinal bleed or a sustained tachyarrhythmia.
Symptoms of acute myocardial ischaemia are required for a formal diagnosis of Type 2 MI. However, clinical presentations can be heterogeneous. In the context of acutely decompensated heart failure, shortness of breath is the cardinal symptom and may act as an ischaemic equivalent, though caution is advised in interpreting it without corroborating evidence of a coronary mechanism. The clinical context and the underlying mechanism of the oxygen supply/demand imbalance must be carefully considered when evaluating the patient.
Evaluation and Physical Examination
The evaluation of a patient with suspected Type 2 MI requires a comprehensive assessment of all available clinical information to distinguish the condition from Type 1 MI. An algorithmic approach is recommended. The physical examination should focus on identifying the precipitating illness or stressor causing the oxygen supply/demand mismatch. This includes evaluating for signs of hypotension or shock, severe hypertension, tachyarrhythmias or bradyarrhythmias, respiratory failure, and severe anaemia.
Because the shortness of breath associated with acute heart failure may be an ischaemic equivalent, the clinician must maintain a high level of suspicion for Type 1 MI if there is a significant rise and/or fall in troponin, particularly if accompanied by chest discomfort, new ischaemic ECG changes, or loss of myocardial function on non-invasive testing. Knowledge of the patient's coronary artery anatomy may aid in interpreting abnormal cTn results, but further information—such as renal function, myocardial perfusion studies, coronary angiography, or cardiac magnetic resonance (CMR)—is often required to understand the cause of deviant troponin values fully.
Diagnostics
The diagnosis of Type 2 MI requires a thorough diagnostic workup, integrating biochemical markers, electrocardiography, and imaging.
Diagnostic Criteria for Type 2 MI
The formal diagnosis requires the detection of a rise and/or fall of cTn values, with at least one value above the 99th percentile upper reference limit (URL). This must be accompanied by evidence of an imbalance between myocardial oxygen supply and demand unrelated to acute coronary atherothrombosis, requiring at least one of the following:
Symptoms of acute myocardial ischaemia
New ischaemic ECG changes
Development of pathological Q waves
Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with an ischaemic aetiology
Electrocardiography (ECG)
An ECG should always be promptly recorded in patients with suspected Type 2 MI, particularly in the setting of acutely decompensated heart failure, to identify or exclude myocardial ischaemia. The frequency of ST-segment elevation in Type 2 MI varies considerably, reported to range from 3% to 24%. New ischaemic ECG changes are a key criterion for establishing the diagnosis.
Imaging
Targeted echocardiography and/or coronary angiography (invasive or coronary computed tomography angiography [CCTA]) should be utilised once the patient has been stabilised and precipitating illnesses treated. Imaging is used to identify contributory and prognostically important cardiac conditions and to guide appropriate long-term cardiovascular treatments. Imaging evidence of new loss of viable myocardium or new regional wall motion abnormalities consistent with an ischaemic aetiology fulfils the diagnostic criteria for Type 2 MI. CMR has an enhanced role in the diagnosis of myocardial infarction and inflammatory conditions of the myocardium.
Coronary Angiography
In patients who undergo timely coronary angiography, the description of a ruptured plaque with thrombus in the infarct-related artery may be helpful in distinguishing Type 1 MI from Type 2 MI. However, angiography is not always definitive, nor is it always clinically indicated or required to establish the diagnosis of Type 2 MI. Coronary atherosclerosis is a common finding in Type 2 MI patients selected for angiography, and these patients generally have a worse prognosis than those without CAD.
Biomarkers and Laboratory Findings
High-sensitivity cardiac troponin (hs-cTn) assays are central to the diagnosis of Type 2 MI and myocardial injury, though they are not specific for MI. Acute MI requires a rising and/or falling pattern of cTn values. While acute myocardial injury may also manifest such a dynamic pattern, troponin values may be stable and unchanging if the injury is related to structural heart disease.
In patients presenting with acutely decompensated heart failure, measurable hs-cTn concentrations may be present in nearly all patients, with a significant percentage exceeding the 99th percentile URL, particularly in those with more severe heart failure syndromes. Beyond Type 1 and Type 2 MI, multiple mechanisms may explain elevated troponin in heart failure, including cardiomyocyte apoptosis and autophagy due to wall stretch, direct cellular toxicity from inflammation or neurohormones, infiltrative processes, and exocytosis of the early releasable cytosolic troponin pool from stressed cardiomyocytes. If a patient has elevated hs-cTn values without evidence of acute myocardial ischaemia, a diagnosis of myocardial injury can be made; however, this diagnosis can change if subsequent investigations indicate that the patient meets the criteria for MI.
Treatment and Management
The management of Type 2 MI differs from that of Type 1 MI due to its distinct pathophysiology and the wide range of precipitating causes. There are currently no specific recommended pharmacological interventions for patients with Type 2 MI due to a lack of robust scientific evidence. Therefore, management should focus on identifying and treating any precipitating conditions alongside strict control of cardiovascular risk factors.
Acute Management
In the acute setting, treatment should focus on stabilising the patient and correcting the underlying ischaemic imbalance of oxygen supply and demand. Specific acute interventions may include:
Volume adjustment
Blood pressure management
Administration of blood products (e.g., for severe anaemia)
Heart-rate control (e.g., for sustained tachyarrhythmias)
Respiratory support (e.g., for severe hypoxaemia)
Routine measures to limit infarct size apply to all patients with ischaemic symptoms. Maintaining the patient at rest and relieving pain can minimise myocardial oxygen consumption. Adrenergic agonists should be avoided whenever possible. All forms of tachyarrhythmia require prompt treatment as they increase myocardial oxygen needs. Heart failure should be treated swiftly to minimise increases in adrenergic tone and hypoxaemia. If ongoing ischaemia occurs, severe anaemia should be corrected. Associated conditions, particularly infections accompanied by tachycardia, fever, and elevated myocardial oxygen needs, require targeted management.
Long-term Management
Once the acute phase has resolved, targeted echocardiography and/or coronary angiography (invasive or CCTA) can be used to identify contributory cardiac conditions and guide appropriate long-term cardiovascular treatments. Depending on the clinical situation, coronary evaluations may be indicated to assess the likelihood of CAD. If CAD is present, standard MI guidelines may be applied in accordance with the ECG findings of STEMI or NSTEMI. However, if CAD is absent, the benefits of cardiovascular risk reduction strategies in Type 2 MI remain uncertain. Long-term management should also include strict control of cardiovascular risk factors.
Guideline Recommendations
Guidelines emphasise the importance of distinguishing Type 2 MI from Type 1 MI and from non-ischaemic myocardial injury. The fourth universal definition of MI provides the framework for this algorithmic approach.
Guideline updates highlight the following key concepts regarding Type 2 MI:
The settings of oxygen demand and supply imbalance are unrelated to acute coronary atherothrombosis.
The presence or absence of coronary artery disease is highly relevant to prognosis and therapy.
There is a clear need to differentiate myocardial injury from Type 2 MI.
The diagnosis of MI carries significant implications for individuals and society, affecting advice on lifestyle changes, treatment, prognosis, psychological status, life and health insurance, professional careers, and driving or pilot licences. It also affects diagnosis-related coding, hospital reimbursement, public health statistics, and disability attestation. Physicians must be adequately informed of the diagnostic criteria to meet these challenges.
Prognosis and Follow-up
Type 2 MI is a common clinical entity and is associated with a prognosis similar to Type 1 MI. The short- and long-term mortality rates for patients with Type 2 MI are generally higher than for Type 1 MI patients in most, though not all, studies. This increased mortality is largely attributable to a higher prevalence of comorbid conditions in the Type 2 MI population.
The occurrence of Type 2 MI varies depending on the diagnostic criteria used, with some reports relying on specific predetermined oxygen mismatch criteria while others apply more liberal criteria. Most studies indicate a higher frequency of Type 2 MI in women. The presence of coronary atherosclerosis is a common finding in Type 2 MI patients and portends a worse prognosis compared to those without CAD. Prospective evaluations using consistent definitions and approaches are needed to further elucidate the importance of CAD in Type 2 MI.
Several gaps in the optimal management strategy remain. The optimal management strategy in older, frail, comorbid adults is currently unknown. Furthermore, the benefits of cardiovascular risk reduction strategies in patients with Type 2 MI but without CAD remain uncertain. Further research is required to better differentiate Type 2 from Type 1 MI before invasive assessment and to evaluate the contribution of social determinants of health.
