Myocardial Infarction Type 2 and Myocardial Injury

Definition of T2MI

The Third Universal Definition of MI task force document defines T2MI in instances of myocardial injury with necrosis where a condition without an acute atherothrombotic event contributes to an imbalance between myocardial oxygen supply and/or demand, such as coronary endothelial dysfunction, coronary artery spasm, coronary embolism, tachyarrhythmias, bradyarrhythmias, anemia, respiratory failure, hypotension, and hypertension with or without left ventricular hypertrophy (9).

Although the pathophysiological mechanism leading to ischemic myocardial injury in the context of a primary supply and/or demand mismatch, without plaque-rupture, is a concept embraced by clinicians, the absence of clear criteria and/or guidance has made the diagnosis and/or adjudication of T2MI an ambiguous process and contributed to the disparate incidence of T2MI observed across studies (Fig. 2) (10–11).

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Fig. 2. Frequency of T2MI in selected studies.

Baron et al. (13); Bonaca et al. (14); Javed et al. (15); Melberg et al. (16); Saaby et al. (18) Shah et al. (20); Smith et al. (21); Stein et al. (22); Szymański et al. (23).

Selected studies have shown variable frequencies of T2MI ranging from 1.6% to 29.6% of the total numbers of MI (Fig. 2; also see Table 1 in the Data Supplement that accompanies the online version of this review at http://www.clinchem.org/content/vol63/issue1). Among women, T2MI is more frequent than T1MI, whereas in men, T1MI is more frequent than T2MI (see online Supplemental Figs. 1 and 2).

Specific vs Broad Criteria for T2MI

Surveys have differed in whether the diagnosis of T2MI is established by using specific predetermined oxygen mismatch criteria or whether applying a more wide-ranging approach to support this term (12–23). Specific criteria were employed in a prospective study of unselected patients who had cardiac troponin I (cTnI) measured on clinical indication, in which 4499 consecutive patients were enrolled through 1 year with the purpose of elucidating the incidence and features of T2MI using standards developed partly on the basis of data from literature (18). Applying these standards, 26% (144 out of 553) MI patients were adjudicated as having T2MI (18).

The main advantage of using strict, specific criteria is the reduction in the ambiguity and subjectivity in diagnosing T2MI, which may facilitate the replication of findings by other researchers. Conversely, it remains questionable if there should or should not be a specific imbalance threshold of increased demand and/or decreased supply required for T2MI, seeing that supply and/or demand ischemia is a multifactorial process dependent on multiple anatomic and physiologic variables (11). Most studies addressing the occurrence of T2MI have used broader and more practical approaches when considering what thresholds across the supply and/or demand variables constitute a significant mismatch (see online Supplemental Table 1).

Although the Universal Definition of MI Task Force never intended that patients with concomitant infection and/or sepsis be classified as T2MI, numerous studies have included patients with infection (12, 13, 20, 22, 24), including some specifically citing sepsis as the etiology for T2MI (20, 22, 24). In the SWEDEHEART registry, infection was among the most common discharge diagnosis, considered to be the most likely triggering mechanism in patients with T2MI (12). Others have categorized such cases as myocardial injury, even despite the presence of concomitant myocardial ischemia (18, 25). Improved guidance in the future Universal Definition of MI documents is urgently needed in this regard owing to the discrepant perspectives and prevailing uncertainty on whether patients with coexisting conditions (e.g., sepsis, infection, congestive heart failure, chronic kidney disease) should be classified as myocardial injury or T2MI, particularly if there are accompanying features of myocardial ischemia.

Frequency of ST-Segment Elevation in T2MI

Studies have reported various rates of ST-segment elevation from 3.4% to 24% among patients with T2MI (13, 18, 22–24). Saaby et al. reported that 3.4% of patients with T2MI had ST elevation (18). According to the presence or absence of concomitant significant coronary artery disease (CAD), Spatz et al. reported that 17% and 15% of T2MI cases had ST elevation, respectively (24). In the SWEDEHEART registry, Baron reported that 16% of cases of T2MI with obstructive CAD and 11% of T2MI without obstructive CAD had ST elevation (13). However in contrast, Matsue et al. have demonstrated that patients with T2MI because of coronary vasospasm have much higher frequency of ST elevation of 52% (26). Although the variability in reported rates of ST elevation may reflect various underlying causes of T2MI, lingering suspicion for unstable CAD should lead to coronary angiography (CAG) or other ischemia tests to establish an appropriate treatment.

Occurrence of Concomitant Coronary Artery Disease

Whether patients with T2MI should be further categorized according to the presence or absence of CAD is another matter of debate. However, the Universal MI Task Force has refrained from recommending CAG realizing that the access to this procedure is limited in various regions of the world. Nevertheless, several studies have reported a rate of concomitant CAD ranging from 28% to 78% of the T2MI patients that are selected to undergo CAG (Fig. 3A) (13, 15, 18, 24).

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Fig. 3. Prevalence of coronary artery disease among patients with T2MI undergoing coronary angiography (A) and proportion of patients with T2MI undergoing coronary angiography (B).

Baron et al. (13); Javed et al. (15); Saaby et al. (18) Shah et al. (20); Stein et al. (22); Spatz et al. (24); Gard et al. (25).

In SWEDEHEART, among 4083 T2MIs, 32% underwent CAG, and of these, 53% had significant CAD (13). Interestingly, a separate study examining patients registered and not registered in SWEDEHEART highlighted important differences in the incidence of T2MI according to whether patients were included or not in the registry (incidence of T1MI and T2MI in registered patients: 82% T1MIs and 11% T2MIs vs patients not registered in SWEDEHEART: 37% T1MIs and 31% T2MIs) (25).

It should be noted that these studies are observational and retrospective in nature, and therefore unable to control for selection bias. As demonstrated (Fig. 3B), clinicians pursue CAG only in a subset of T2MI patients, ranging from 7% to 50% of the cases (13, 15, 18, 20, 22, 25). Therefore, the overall prevalence of concomitant CAD among all patients with T2MI is uncertain. Studies assessing for the presence of concomitant significant CAD in T2MI have relied solely on CAG, yet other myocardial ischemia tests are warranted if CAG is inaccessible to distinguish T2MI from nonischemic myocardial injury with necrosis. Furthermore, even if CAG is available, patients with angiographically normal coronary arteries (particularly women) may have underlying plaque rupture and ulceration as detected by other methods, such as intravascular ultrasound, resulting in misclassification (27).

Interrelationship between T2MI and Myocardial Injury

Myocardial injury is a prerequisite for the diagnosis of MI in the setting of acute myocardial ischemia. However, myocardial injury is also an entity in itself. For patients with increased cardiac troponin concentrations above the 99th percentile upper reference limit (URL), clinicians must distinguish whether patients have myocardial injury or MI (Fig. 4). Myocardial injury, whether ischemic or nonischemic, defined as any cardiac troponin concentration above the 99th percentile URL (9) is frequently encountered and associated with a poor prognosis (20, 28–30). It may be acute, as evidenced by a newly detected dynamic rise and/or fall of cardiac troponin values above the 99th percentile URL, or chronic, in the setting of persistently increased cardiac troponin levels. Chronic myocardial injury is often met in patients with comorbidities, such as advanced chronic kidney disease and heart failure (30).

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Fig. 4. Conceptual models for myocardial injury and myocardial infarction.

Few studies have compared the incidence and clinical features of T2MI vs myocardial injury. Javed et al. examined 701 consecutive patients with increased cTnI values, of whom 9.1% were classified as T2MI, and 66% as myocardial injury (15). By using a high-sensitivity (hs)-cTnI assay, in a cohort study examining 310 all-comer consecutive patients presenting to the emergency department, 17.3% had increased hs-cTnI values due to T2MI, whereas 74.8% of the patients had myocardial injury (19). Similarly, Sarkisian et al. in a cohort of 1577 patients with increased cTnI values found 69% with myocardial injury and 7.5% with T2MI (28). However, in a study by Shah et al. examining patients with increased cTnI values they found that no more than 24% had myocardial injury, whereas 20% of the patients had T2MI (20).

The key distinction between myocardial injury and T2MI is made on a clinical basis, with MI being diagnosed when there is clinical evidence of overt myocardial ischemia, as supported by the presence of at least one of the following: ischemic symptoms, new ischemic electrocardiographic changes, imaging evidence of new loss of viable myocardium or new regional wall motion abnormality, along with a dynamic rise and/or fall of cardiac troponin concentrations.

Prognosis

Several studies have reported both short- and long-term outcomes for patients with T2MI (12, 13, 20, 22, 28, 29, 31). Overall, despite variations in the composition of the included T2MI patients, studies demonstrate a very poor prognosis in these patients, with a long-term mortality rate reaching 63% after more than 3 years at follow-up (28). A similar poor long-term survival has been observed in patients with myocardial injury (20, 28–30). Studies have focused on all-cause mortality, rather than cardiac mortality; however; future studies are needed to clarify whether T2MI patients die from cardiac or noncardiac causes.

Management of T2MI

While the term T2MI has been endorsed since 2007, no clinical practice guidelines address how to manage this entity. Several observational studies have reported how patients with T2MI are treated less often with revascularization, angiotensin converting enzyme inhibitors, β-blockers, platelet inhibitors, and statins in comparison to those with T1MI (12, 13, 20, 31). Even among those with significant CAD, patients with T2MI have lower rates of treatment with aspirin and statins when compared to T1MI patients (13).

Shah et al. examined the impact of lowering the diagnostic threshold of a sensitive cardiac troponin assay on the incidence, management, and outcomes of T1MI, T2MI, and myocardial injury (20). This approach was associated with an increase in healthcare resource utilization and improved prognosis for T1MI patients. Conversely, for patients with T2MI, lowering the cTnI diagnostic threshold led to an increase in cardiology referrals, echocardiograms, and angiography, without leading to changes in the treatment and with no impact on the prognosis. However, these patients did not receive additional therapies, potentially representing a missed opportunity to improve outcomes (20).

Despite the dearth of scientific information that can help to make management decisions it appears expedient in the acute setting to treat the underlying ischemic imbalance of oxygen supply and demand. This treatment may include: volume adjustment, blood pressure support, administration of blood products, heart rate control, and respiratory support (11, 32). Additionally, depending on the clinical situation, CAG may be indicated to assess the likelihood of CAD. If that is present, the MI guidelines may be applied, including the implementation of β-blockers, statins, ACE inhibitors, or other medications on an ad hoc basis. However, if CAD is absent, the benefit of cardiovascular risk reduction strategies with T2MI remains uncertain (10, 11, 32).

Cardiac Troponin

The preferred biomarker for myocardial injury and MI is cardiac troponin, which has both high myocardial tissue specificity and clinical sensitivity, although not decisive for a disease (9). Hence, clinicians and researchers are challenged with distinguishing whether cardiac troponin increases are due to myocardial injury in the absence of other supportive ischemic features or an acute MI.

From a biomarker perspective, patients with T1MI have an overall trend towards higher maximum cardiac troponin concentrations than those with T2MI (12, 15, 18–20, 29). Whether serial cardiac troponin changes (δ) can aid in distinguishing T1MI from T2MI has been proposed as a strategy requiring evaluation, by the ESC Biomarkers Study Group of the Acute Cardiovascular Care Association (33). Yet, in a retrospective cohort study of patients presenting to the emergency department in which cTnI was measured on clinical indication, δ cTnI did not help in distinguishing T1MI from T2MI (29).

The development of a plaque-rupture specific biomarker to aid in the distinction of myocardial injury due to plaque rupture (T1MI) vs myocardial injury from other pathologies would represent a unique clinical breakthrough (10). Advanced cardiac imaging, such as cardiac magnetic resonance, may be particularly useful in distinguishing whether myocardial injury occurs due to an acute MI vs due to other nonischemic conditions such as myocarditis.

For investigators and clinicians doing cardiac troponin diagnostic performance studies, a conundrum often faced is whether analyses should be based on patients with any MI (including both types 1 and 2) or T1MI alone. Recent studies demonstrate heterogeneous designs in this regard, with some studies basing their analysis on all MIs (including both T1MI and T2MI), others focusing exclusively on T1MI, and others not clearly describing the adjudication of MI types despite reporting adherence to the Universal Definition of MI recommendations (34–38). The choice to focus studies on T1MI alone is supported by the following arguments: (a) ruling in plaque-rupture–mediated events that have evidence-based guideline recommendation, (b) safely ruling out T1MI, which if missed has major medicolegal consequences, and (c) avoiding the inclusion of T2MI events owing to the current lack of diagnostic standards. Conversely, the argument for conducting studies assessing all MIs has been that cases meeting MI criteria, regardless of types (T1MI or T2MI), should constitute the MI-group.

Moving forward, a practical approach may be to focus on ruling out myocardial injury, which encompasses both T1MI and T2MI, while continuing to rule in MI and its subtypes. Due to paucity of expert-consensus documents and/or guidelines addressing this matter, heterogeneous study designs prevail, limiting the opportunity to achieve consistency and/or replicate findings.

Critical Clinical Concepts

For patients with cardiac troponin values exceeding the 99th percentile URL, cases should be categorized as either (a) myocardial injury, when there is isolated presence of myocardial necrosis, or (b) MI, when there is additional clinical evidence of overt myocardial ischemia together with a rise and/or fall of cardiac troponin values. For those with acute MI, further MI subtype categorization (types 1 through 5 MI) according to the Universal Definition of MI should be made.

T2MI should be diagnosed when there is evidence of acute myocardial injury with necrosis, as evidenced by a rise and/or fall of cardiac troponin with at least 1 value above the 99th percentile URL, in a clinical setting consistent with overt myocardial ischemia, with an evident acute and/or sustained oxygen supply and demand imbalance, without plaque rupture within the coronary arteries, plus at least 1 other MI criterion according to the Universal Definition of MI.

Clinicians and researchers should describe whether there is presence or absence of concomitant significant CAD. Future studies are needed, ideally in all-comers with T2MI (rather than only those selected to undergo CAG that are subject to selection bias), to determine the frequency and implications of concomitant CAD in patients with T2MI.

In equivocal, difficult cases with acute myocardial injury, in which the clinical distinction between myocardial injury, T1MI, and T2MI is challenging, further diagnostic efforts may be considered in an appropriate clinical context to discern the underlying mechanism, primarily due to the potential therapeutic implications if deemed related to atherosclerotic plaque rupture.

Myocardial injury, ischemic or nonischemic, defined as any cardiac troponin concentration above the 99th percentile URL is frequently encountered and associated with a poor prognosis. Nonischemic myocardial injury may appear secondary to cardiac conditions such as myocarditis having a dynamic rise and/or fall in cardiac troponin, or may be seen secondary to systemic conditions such as renal failure.

In cases of myocardial necrosis occurring primarily as a consequence of sepsis, renal failure, heart failure, cardioversion, electrophysiological ablation, myocarditis, toxic agents, or infiltrative diseases, the term myocardial injury condition applies rather than MI.

Studies addressing outcomes, including cardiac morbidity and mortality as well as management strategies, including therapeutic investigations, are urgently needed to better define the risk and management of both T2MI and myocardial injury.