Author + information
- Received December 9, 2013
- Revision received January 24, 2014
- Accepted February 11, 2014
- Published online May 27, 2014.
- ∗Division of Cardiology, Department of Medicine, Hennepin County Medical Center, Minneapolis, Minnesota
- †Department of Emergency Medicine, Hennepin County Medical Center, Minneapolis, Minnesota
- ‡Department of Laboratory Medicine and Pathology, Hennepin County Medical Center and University of Minnesota, Minneapolis, Minnesota
- ↵∗Reprint requests and correspondence:
Dr. Yader Sandoval, Division of Cardiology, Department of Medicine, Hennepin County Medical Center, 701 Park Avenue, Orange Building, 5th Floor, Minneapolis, Minnesota 55415.
Supply/demand (type 2) myocardial infarction is a commonly encountered clinical challenge. It is anticipated that it will be detected more frequently once high-sensitivity cardiac troponin assays are approved for clinical use in the United States. We provide a perspective that is based on available data regarding the definition, epidemiology, etiology, pathophysiology, prognosis, management, and controversies regarding type 2 myocardial infarction. Understanding these basic concepts will facilitate the diagnosis and treatment of these patients as well as ongoing research efforts.
In 2007, the second Universal Definition of myocardial infarction (MI) introduced and defined five different MI subtypes that were endorsed by the major cardiology societies (1). Type 1 MI (T1MI) corresponds to a spontaneous MI secondary to atherosclerotic plaque rupture, ulceration, fissuring, erosion, or dissection with resulting intraluminal thrombus leading to decreased myocardial blood flow or distal platelet emboli with consequent myocyte necrosis (acute coronary syndrome, [ACS]), whereas type 2 MI (T2MI) was defined as MI due to supply/demand mismatch, without plaque rupture, but also with myocardial necrosis evidenced by a rise and/or fall of cardiac biomarkers above the 99th percentile reference value of a normal population, in addition to at least one of the other criteria for MI (2).
For numerous reasons, there is controversy and reluctance to use the term “T2MI” in clinical practice. Foremost, although the ACS classification of ST-segment elevation myocardial infarction (STEMI), non–ST-segment elevation myocardial infarction (NSTEMI), and unstable angina is widely adopted to guide revascularization and pharmacological treatment, not all have embraced the 5-MI subtype classification (1–6). Notably, recognizing limited availability of some cardiac biomarkers in many settings, the World Health Organization definition of MI limits its discussion on supply/demand MI (4). Another motive for the reluctance relies on the basis that the International Classification of Diseases coding system does not recognize T2MI, and often MI quality review programs (e.g., Centers for Medicaid and Medicare Services) rigorously evaluate for certain measures for anyone with a diagnosis of acute MI, which may be appropriate for ACS (T1MI), but may not be appropriate for an MI (T2MI) not caused by ACS (7).
Distinguishing different etiologies of ischemic myocardial necrosis is essential for clinical purposes, mainly because management differs when cardiac troponin (cTn) is elevated as the result of T1MI, as opposed to T2MI (5,6). The purpose of this article is to provide an evidence-based perspective on supply/demand T2MI.
The Third Universal Definition of MI consensus document defines MI by the evidence of myocardial necrosis in a clinical setting consistent with acute myocardial ischemia, in which there is a rise and/or fall of cTn with at least one value above the 99th percentile of a normal reference population; and the presence of at least one of the following: a) ischemic symptoms; b) new or presumed new significant ST-segment or T-wave changes or new left bundle-branch block; c) development of pathological Q waves in the electrocardiogram; d) imaging evidence of new loss of viable myocardium such as a new regional wall motion abnormality; or e) identification of an intracoronary thrombus by means of angiography or autopsy (2).
On the basis of the above criteria, T2MI is diagnosed in instances in which a supply/demand imbalance leads to myocardial injury with necrosis that is not caused by ACS, including arrhythmias, aortic dissection, severe aortic valve disease, hypertrophic cardiomyopathy, shock, respiratory failure, severe anemia, hypertension with or without left ventricular hypertrophy, coronary spasm, coronary embolism or vasculitis, and coronary endothelial dysfunction without significant coronary artery disease (CAD) (2,8).
It should be noted that in contrast with the 2007 Universal Definition of MI, the 2012 recommendations incorporated coronary endothelial dysfunction as one of the variables to consider when encountering supply/demand ischemia (1,2). Coronary endothelial dysfunction has been associated with myocardial ischemia and increased cardiac events, and certainly these patients may have cTn increases and meet the definition for MI (9–11). However, it is unclear if endothelial-dependent coronary flow reserve assessment with acetylcholine infusion is warranted in the acute MI setting.
From an electrocardiographic perspective, the use of the terms NSTEMI and STEMI has been applied to T2MI. Saaby et al. (12) recently reported 144 T2MI, of which 3.4% were categorized as STEMI and 96.6% as NSTEMI (12). The significance of applying these electrocardiographic classifications to T2MI is unclear, as they are clinically intended to guide reperfusion therapy in T1MI (ACS) (5,6).
The interpretation of cTn increases in conditions in which supply/demand is being considered can be challenging, largely due to the paucity of specific criteria for what exactly constitutes a T2MI. Several major expert opinion documents have provided some guidance in regard to what should be considered a T2MI, but none of these documents have defined specific criteria for T2MI (2,8,13).
Saaby et al. (12) have proposed certain novel, specific criteria for T2MI, in order to avoid the implicit subjectivity in the clinical diagnosis (criteria detailed in Table 1). However, the development of strict criteria for the diagnosis of T2MI is complicated by the multifactorial nature of supply/demand ischemia, as patients may have any number of factors leading to increased demand or decreased supply, which in addition may or may not be in the setting of distinct pre-existing conditions such as flow-limiting CAD. Thus, advocating for any strict criteria and cutoffs of variables such as heart rate or blood pressure may have its own limitations. Most studies have used adjudicators who can assess all contributing variables and give a subjective diagnosis of T2MI without applying strict parameters.
Among patients with no pre-existing conditions such as underlying CAD, a clearly recognizable acute and/or sustained supply/demand mismatch should be present to consider T2MI. Conversely, in patients with underlying comorbidities such as significant CAD and/or the presence of several supply/demand imbalances, lower thresholds of supply/demand mismatches may be required to elicit ischemia. In these patients, an individualized diagnostic approach should be favored.
The current “gold-standard” definition for T2MI remains undetermined, and any future MI consensus document should ideally provide further clarification in this challenging area to guide both clinicians and researchers and bring homogeneity to this field. Details including definitions used across selected heterogeneous studies, which have reported T2MI, are summarized in Table 1.
With the use of current contemporary cTn assays, T2MI is frequently encountered in clinical practice (Table 1). It is expected that after the anticipated Food and Drug Administration (FDA) clearance (likely 2014) of high-sensitivity cTn assays, these assays will be as commonly used in clinical practice in the United States, as they currently are in the rest of the world. This use will likely lead to an increased incidence of cTn elevations above the 99th percentile in clinical settings consistent with T2MI (14). However, little epidemiologic data is available on T2MI, possibly due to the relatively recent introduction of this term, suspected underreporting, and confusion as to what specifically constitutes a T2MI given lack of specific criteria.
There are a limited number of studies addressing the frequency of T2MI. Morrow et al. (15) described the value of the Universal Definition of MI in the context of a clinical trial. In follow-up of 1,218 MIs, T2MI was infrequent and consisted of 3.5% (n = 43) of all MIs, in contrast to 32.6% T1MI and 49.5% (n = 603) peri-percutaneous coronary intervention (type 4A) MI. This study was limited because it was an ACS trial, which included a pre-selected population, and therefore was not reflective of the true epidemiology of T2MI. Javed et al. (16) performed a prospective study to identify the percentage of hospitalized patients with a positive cTn who fulfilled the criteria for MI and classified them according to the Universal Definition using a contemporary, sensitive cTn assay (ADVIA TnI-Ultra, 99th percentile: 40 ng/l) over a 3-month period. In this large, prospective study, cTnI was obtained in 2,979 patients, with 701 having at least one increased cTnI: 216 had MI according to the Universal Definition of MI, of which 143 (66.2%) had a T1MI and 64 (29.6%) had T2MI (the remaining 4.2% [n = 9] were type 3 and 4 MI). Melberg et al. (17) studied the implications of the Universal Definition of MI by retrospectively studying all patients hospitalized in 2004 with suspected MI using the 4th generation Roche cTnT assay. Their cohort of 1,093 patients with MI consisted of 967 (88.5%) with T1MI and 17 (1.6%) with T2MI (the remaining 9.9% [n = 109] were classified as type 3 to 5 MI).
Smith et al. (18), in a retrospective study of 662 consecutive patients with ischemic symptoms presenting to the emergency department (ED) in which cTnI was obtained with the use of the Siemens Stratus CS (Tarrytown, New York) (99th percentile: 99 ng/l), found that of 139 who had MI, 40 (28.8%) had T1MI and 99 (71.2%) had T2MI. In a subsequent study at the same institution, among 1,119 consecutive patients presenting to the ED who had serial cTnI measured (Ortho-Clinical Diagnostics cTnI contemporary assay; 99th percentile, 34 ng/l), T1MI occurred in 106 patients (9.5% of the total population, 37.9% of total MIs; STEMI [n = 29], NSTEMI [n =77]) and T2MI in 174 patients (15.5% of the total population, 62.1% of total MIs); cTnI concentrations were higher in NSTEMI (T1MI) versus T2MI at both 0 and 6 hours (p = 0.01), with a trend at 3 h (p = 0.08) (19).
Saaby et al. (12) assessed the frequency of T2MI, defining it by non-guideline clinical standards using a contemporary cTnI assay (Architect, 99th percentile 28 ng/l). Using their distinct approach in which specific criteria were delineated to qualify as a T2MI, 553 patients had an MI, of which 397 (71.8%) had T1MI and 144 (26%) had T2MI. The remaining 2.2% (n = 12) were type 4 and 5 MIs. For cTnI concentrations, T2MI had significantly lower peak cTnI values in comparison to T1MI (1.09 μg/l vs. 2.96 μg/l, p < 0.001).
Remarkably, several studies report very low T2MI frequencies. These studies are limited by selection bias, as the selected study population (e.g., retrospective or prospective analyses on patients with an ACS diagnosis) favors T1MI (ACS) frequency (15,20,21). Conversely, studies using a less selected approach reported much higher T2MI frequencies (12,16,19).
Frequencies and cTn assays that were used across studies focusing on T2MI are shown in Table 1. Review of these studies demonstrates that despite a proposed definition of T2MI by the Universal Definition consensus, there is no validated reproducible definition by which to make a consistent diagnosis. It remains challenging to adjudicate T1MI versus T2MI for research, clinical, and regulatory purposes because there are no consistently accurate and reliable criteria for the diagnosis (22).
The disparity in diagnosis definitions, variations in adjudication processes, along with differences in cTn assays and cutoff values used, as well as the studied population (e.g., patients with chest pain in the ED vs. unselected hospitalized patients, etc.) complicates the epidemiological evaluation of T2MI and is reflected in the heterogeneous prevalence of T2MI shown in Table 1.
We opine that the included study population, as well as the specific patients in which cTn is being measured also plays a significant role in the heterogeneous T2MI prevalence. Despite recommendations suggesting that cTn evaluation should be performed only if clinically indicated for suspected MI, in clinical practice many cTn measurements are obtained in a wide variety of clinical situations, many of which have a very low pretest probability of T1MI (8). This may be explained by the “fear” of missing T1MI presenting with atypical symptoms, as over 25% of patients with ACS complain of a symptom other than chest pain, such as abdominal pain or dyspnea (23). The serious liabilities related to failure to diagnose and treat ACS may tempt physicians to obtain cTn in several “atypical” situations with low pretest probability for ACS. The variability in cTn measurement patterns across medical centers likely contributes to the heterogeneous T2MI prevalence. Additionally, clinicians may obtain cTn, even in the absence of ACS, because of its prognostic value in other non-ACS conditions (e.g., pulmonary embolism) (14). The consequences of testing a broader unselected population may have resource utilization, therapeutic, and financial implications, which are not well understood.
Etiology and Pathophysiology of Type 2 MI
Numerous pathologies can cause disequilibrium in the balance between oxygen supply and demand. This balance is a critical determinant of the normal cardiac function, and understanding the variables involved is fundamental to understand the ischemic response in T2MI (24). Myocardial oxygen demand relies on three major determinants: systolic wall tension, contractility, and heart rate, whereas myocardial oxygen supply relies on the coronary blood flow and oxygen-carrying capacity (24–26). Disequilibrium in the myocardial supply and demand caused by alteration of the factors involved in these complex hemodynamic interactions may lead to myocardial ischemia. For example, both hypoxia and anemia can decrease oxygen carrying capacity, leading to an imbalance secondary to supply mismatch. This may result in ischemia, which, if severe enough, may lead to myocardial cell death with symptoms and/or ECG changes and release of cTn. If cTn exceeds the 99th percentile and there is a rising and/or falling pattern in conjunction with any other MI criteria in the absence of plaque rupture, this would then be, by definition, a T2MI. It is also important to note that stable CAD, with significant stenosis, may limit coronary blood flow, leading to ischemia under conditions of increased oxygen demand or decreased supply.
Based on these concepts, any mismatch may be explained by a similar pathophysiologic approach. Overall, in a clinical setting consistent with myocardial ischemia coincident with a rise and/or fall in cTn, if a clinician cannot readily identify any clear “alternate” factor that would alter this supply/demand balance, one must be cautious before labeling an MI as T2MI. Moreover, to further complicate matters, patients may manifest more than one type of MI simultaneously or sequentially (1).
Without any systematic data, an accurate estimate of the various etiologies that can lead to T2MI is limited and subject to misinterpretation. An analysis assessing the frequency of T2MI showed that anemia, tachyarrhythmias, and respiratory failure were the most common conditions predisposing to T2MI (12).
There are certain scenarios in which distinguishing T1MI from T2MI might be particularly challenging, such as the post-operative setting, heart failure, end-stage renal disease, sepsis, and the critically ill (2,13,27–33). In patients with heart failure, cTn is often increased and occurs either in a non-MI setting or may be related to either a T1MI or T2MI. It has been described that T2MI in the setting of heart failure may be caused by small-vessel coronary obstruction, increased transmural pressure, endothelial dysfunction, and/or supply/demand mismatch related to subendocardial ischemia alone (2,28).
In the post-operative setting, myocardial oxygen supply/demand balance can be easily altered and lead to a perioperative MI. Post-operative oxygen supply/demand imbalance is most commonly caused by tachycardia, although many other scenarios can lead to a mismatch, including hemorrhage-related hypotension, hypertension in the setting of elevated stress hormones, anemia, and hypoxemia, among other conditions (27).
Among critically ill patients in the intensive care unit and individuals with sepsis, the etiologic assessment of cTn increases is remarkably difficult. Many patients are sedated and intubated, which impedes any direct ischemic symptom evaluation, which is an essential MI criterion. Additionally, cTn elevations may not only be due to T1MI or T2MI but also mediated by circulating substances (sepsis-induced), vasopressors, and catecholamine toxicity (2,32,33).
There is limited data regarding outcomes of patients with T2MI. The most robust analysis comes from the TIMI group and the TRITON–TIMI 38 trial in which, even after adjusting for clinical covariates, all subtypes of MI were associated with an increased risk of cardiovascular death (34). T2MI had a 3-fold increased risk (adjusted hazard ratio [HR]: 2.8; 95% confidence interval [CI]: 0.9 to 8.8; p = 0.085). The cumulative incidence of cardiovascular death at 180 days was comparable between T1MI and T2MI (8.3% vs. 7.3%). T2MI had significantly worse mortality rates when compared with no MI (7.3% vs. 1.3%, p < 0.001).
Our group recently showed that 180-day mortality rates were similar among NSTEMI (T1MI) (17%) and T2MI (24%), but mortality rates for both were increased (each p < 0.001) compared with patients having no MI and normal cTnI at baseline (4.9%) (19).
Further research is required to validate these findings and confirm if T2MI has worse outcomes independent of other comorbidities, such as renal and heart failure, and independent of the severity of the underlying illness that resulted in T2MI.
There are no formal guidelines available regarding the management of T2MI. Despite its incidence and association with worse outcomes (12,34), there are no guidelines addressing the acute or long-term management of this entity. This absence of guidance is likely to result in variable clinical decision-making when dealing with T2MI, which could lead to wide variations in cost-effectiveness and resource utilization. It has been proposed that aspirin and beta-blockers may have a role in T2MI (35). There is an urgent need for evidence-based diagnostic and therapeutic strategies, primarily randomized, controlled clinical trials. Until data from appropriate clinical trials are available, there will continue to be wide variability in the management of these patients.
Furthermore, T1MI and T2MI may not be easily distinguished, which may lead to erroneous initiation of T1MI (ACS) guideline-driven therapies in patients with T2MI (5,6,14). At present, most clinicians would agree that for T2MI, one must treat the underlying etiology and correct the altered variable within the myocardial oxygen supply/demand balance.
Among patients with cTn increases in the intensive care unit, it has been proposed that if the event appeared to be related to underlying CAD, further evaluation for CAD (invasive or noninvasive) or structural heart disease should be considered (2,36). This is a reasonable approach in similar clinical situations, even outside the intensive care unit setting.
Current Controversies and Future Steps
Supply/demand MI is a matter of discussion and controversy in both clinical practice and research trials for several reasons (Table 2). First, it is unclear if most clinicians have embraced the Universal Definition of MI. Second, despite recognition of T2MI by the cardiology societies, there is no clear consensus regarding the exact definition of T2MI. The current definition is vague, leading to subjectivity in the diagnosis. Clinicians and researchers may need to develop a standardized, detailed definition to facilitate the consistent analysis of clinical findings.
Third, in the United States, where Centers for Medicaid and Medicare Services and National Center for Health Statistics uses the International Classification of Diseases codes, it must be emphasized that despite the recognition of this disease by the major societies, the Universal Definition of MI subtypes remain ignored. This is of great concern because clinicians are unable to diagnose a patient with T2MI without being penalized by International Classification of Diseases coders for deviating from the accepted guideline-driven ACS therapies that are required by Centers for Medicaid and Medicare Services (e.g., aspirin on arrival and discharge, beta-blocker, statin prescribed on discharge, and so on), even though these therapies might not be appropriate for T2MI.
Finally, there are several circumstances in which the distinction between T1MI and T2MI might be uncertain, and consequently both clinical decision-making and event adjudication may be difficult. In this context, it is controversial about whether to default to T1MI until proven otherwise, or vice versa. This clinical distinction is usually done by coronary angiography; however, up to 15% of patients undergoing catheterization for suspected CAD have angiographically “normal” coronaries, and intravascular ultrasound may often detect occult disease in these patients (37–39). Thus, although visualization of a culprit lesion on angiography is often required to define a T1MI by clinicians and/or researchers, it may result in misclassification.
Research data over the next several years will demonstrate the growing occurrence of T2MI. Anticipating future guidelines addressing in detail the complexity behind T2MI to guide clinicians and researchers, we propose our insights in Table 3 as a starting point for discussion.
Supply/demand T2MI is a commonly encountered clinical challenge, and it is anticipated that it will be detected even more once high-sensitivity cTn assays are approved for clinical use in the United States. Understanding the basic concepts involved in myocardial oxygen supply and demand will facilitate the diagnosis and treatment of patients with increased cTn values. Future efforts are required to consolidate the definition of T2MI to bring consistency to this diagnosis in clinical practice, adjudicated research studies, and clinical trials, as well as for regulatory compliance. Studies are urgently required to produce evidence-driven classification, which will assist in management guidelines.
Dr. Apple is a consultant to T2 Biosystems and Instrumentation Laboratory; has received honoraria from Abbott Laboratories; and has received research funding, without salary, from the majority of manufacturers marketing cardiac troponin assays. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- acute coronary syndrome(s)
- coronary artery disease
- cardiac troponin
- emergency department
- myocardial infarction
- non–ST-segment elevation myocardial infarction
- ST-segment elevation myocardial infarction
- type 1 myocardial infarction
- type 2 myocardial infarction
- Received December 9, 2013.
- Revision received January 24, 2014.
- Accepted February 11, 2014.
- American College of Cardiology Foundation
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