The advent of more sensitive troponin assays together with widespread (and sometimes indiscriminate) use of troponin testing has led to more recognition of how prevalent myocardial injury may be. Troponin measurement is typically performed to seek acute myocardial infarction (MI), but all forms of myocardial injury (including nonischemic forms) are reflected in elevated troponin concentrations. This may lead to clinician confusion and uncertainty. Furthermore, due to increasing medical complexity and more chronic coronary artery disease, the incidence of type 2 MI (due to supply-demand imbalance) is also higher. Differentiating type 2 MI from myocardial injury is a relevant challenge with several considerations.

Defining Type 2 MI Versus Myocardial Injury

To more precisely define acute MI and in recognition of its various presentations, the Universal Definition of MI was first published in 2007.¹ Over the past decade, serial modifications to the definition have been made. The latest iteration, the Fourth Universal Definition, was published in 2018.² As defined by the Task Force, an MI is defined as a rise and/or fall in cardiac troponin (conventional or high sensitivity) with at least 1 value above the 99th percentile of the upper reference limit (URL) and at least 1 of the following:

• Symptoms of ischemia
• New electrocardiographic evidence of ischemia
• New pathological Q waves
• New regional wall motions on imaging in an ischemic territory
• Coronary thrombus on angiography

There are 5 recognized types of MI; the most frequently encountered are type 1 MI (characterized by atherosclerotic processes such as plaque rupture, ulceration, fissuring, erosion, or dissection resulting in coronary thrombosis) and type 2 MI (myocardial necrosis resulting from a mismatch in myocardial oxygen supply-demand and occurring in the absence of an atherothrombotic event).

In the contemporary era, a vast number of patients with elevated troponin concentrations do not have evidence of ischemia.³ To address this, the Fourth Universal Definition of MI introduced the entity myocardial injury, which is defined by at least 1 cardiac troponin concentration above the 99th percentile URL. Myocardial injury is considered acute if there is a rise and/or fall of cardiac troponin concentrations exceeding biological and/or analytical variation. No standard exists for how much rise and/or fall of cardiac troponin identifies acute injury; typically, an increase in the concentration greater than the reference change value (biological variation of an assay) is considered acute if the initial troponin value is <99th percentile.⁴ If the first troponin level is >99th percentile, then an increase of at least 50% of the 99th percentile or a change >20% may be considered acute.⁴ A cardiac troponin result above the 99th percentile URL without a rise and/or fall over a period of serial measurements is characteristic of chronic myocardial injury.

Patients with myocardial injury are often misdiagnosed as having a type 2 MI in clinical practice. In one study, ~42% of patients diagnosed with type 2 MI actually had myocardial injury without ischemia and thus were misdiagnosed.⁵ Differentiating between the entities can be challenging (Table 1). Both entities can have overlapping precipitants (e.g., heart failure and sepsis), but they are differentiated by the presence of ischemia, which is a prerequisite to diagnosing a type 2 MI.⁶ In the absence of evidence of ischemia (as outlined by the Fourth Universal Definition of MI), a diagnosis of type 2 MI cannot (and should not) be made.

Table 1: Comparison of Myocardial Injury Versus Type 2 MI

	Myocardial Injury	Type 2 MI
Definition	At least 1 cardiac troponin concentration above the 99th percentile URL	A rise and/or fall of cardiac troponin with at least 1 value above the 99th percentile URL occurring with evidence of ischemia. One of the following must be present: Symptoms of myocardial ischemia New ischemic electrocardiographic changes Development of pathological Q waves Imaging evidence of new loss of viable myocardium or new ischemic regional wall motion abnormalities Type 2 MI is an MI occurring from a mismatch in myocardial oxygen supply-demand and occurring in the absence of an atherothrombotic event.
Mechanism of Troponin Elevation	Myocardial strain, inflammation, apoptosis, and cell injury, or those that a decrease in cardiac troponin clearance such as acute or chronic kidney injury	Ischemia
Prognosis	In-hospital all-cause mortality ~11% Post-discharge 30-day mortality ~7% 5-year all-cause mortality ~72% 5-year major adverse cardiovascular events (cardiovascular death or MI) ~31%	In-hospital all-cause mortality ~9% Post-discharge 30-day morality ~4% 5-year all-cause mortality ~63% 5-year major adverse cardiovascular events (cardiovascular death or MI) ~30%
30-Day Readmission Rate	~21%	~23%
Strategies to Reduce Mortality or Major Adverse Cardiovascular Events	Undefined	Undefined
Strategies to Reduce 30-Day Readmission	Undefined	Undefined
ICD 10 Code	No	I21.A1
ICD 10 Code Included in the Hospital Readmissions Reduction Program and Hospital Value Based Purchasing Program	N/A	No

Prognosis Following a Diagnosis of Type 2 MI or Myocardial Injury

It is well-established that patients with type 2 MI or nonischemic myocardial injury have a poor prognosis compared with patients with troponin concentrations less than the 99th percentile.^7,8 In these patients, all-cause mortality rates for hospitalized patients are high: ~8.7% for type 2 MI and 10.6% for myocardial injury.⁵ Following discharge, 30-day mortality rates are 4.4% for type 2 MI and 7.4% for myocardial injury. Readmission rates at 30-days are also excessive: 22.7% for type 2 MI and 21.1% for myocardial injury.⁵

Long-term outcomes are similarly morbid.^8,9 Chapman and colleagues found that 5-year all-cause mortality rates for type 2 MI and myocardial injury were 62.5% and 72.4%, respectively.⁸ The majority of patients with type 2 MI and myocardial injury die from non-cardiovascular causes; however, the rates of major adverse cardiovascular events (defined as nonfatal MI or cardiovascular death) at 5 years were also concerning for both cohorts: 30.1% for patients with type 2 MI and 31% for those with myocardial injury.⁸

Coding and Value-Based Programs

Correct documentation and coding of type 1 MI, type 2 MI, and myocardial injury are important to correctly categorize these distinct disease entities that differ in their pathophysiology and prognosis. To differentiate between type 1 and type 2 MI, an ICD-10 (10th edition of the International Statistical Classification of Diseases and Related Health Problems) code for type 2 MI (I21.A1) was introduced in October 2017. However, an ICD-10 code specific for myocardial injury has yet to be introduced. Currently, the code for "abnormal troponin" is a non-specific code for an abnormal laboratory test.

Beyond research, accurate coding is also important for assessing hospital quality metrics and for value-based programs.^5,10-12 The Hospital Readmissions Reduction Program (HRRP) was established in 2010 with the intent of reducing avoidable readmissions. Under the HRRP, hospitals must publicly report 30-day admission rates, and if their readmission rates exceed that of their peers, penalties accrue. Acute MI is 1 of only 6 conditions included in the program. Prior to the introduction of an ICD-10 code, patients with type 2 MI were either not coded or coded as a non-ST-segment elevation MI (NSTEMI).¹³ When patients with acute MI included in the HRRP for fiscal year 2016 were examined at a single institution, approximately 10% were found to have a type 2 MI.¹⁴ Due to concerns regarding a lack of evidence-based strategies to prevent readmission of type 2 MI patients,^10,11 the ICD-10 code for type 2 MI will not be included in the HRRP for fiscal year 2020. Because hospital performance under the HRRP is determined retrospectively, it will be fiscal year 2023 (at which point the entire performance period occurs after October 2017) before patients with type 2 MI are definitively excluded from the program. Another mandatory value-based program is the Hospital Value-Based Purchasing Program, which rewards or penalizes hospitals based on the quality of their inpatient care.¹⁰ One of their performance domains includes 30-day mortality for acute MI. However, like the HRRP, the ICD-10 code for type 2 MI has not been included in the diagnostic codes for acute MI for fiscal year 2020. Thus, in order for hospitals to avoid penalization for patients with type 2 MI under value-based programs, they must accurately code the diagnosis as I21.A1 rather than the other NSTEMI codes. It is equally important that physicians do not incorrectly code nonischemic myocardial injury as a NSTEMI due to the risk of penalization by these programs.

Evaluation and Treatment

Differentiating type 2 MI from nonischemic myocardial injury is important when evaluating patients with elevated troponin concentrations because the underlying mechanisms of troponin release are different. Type 2 MI is an ischemic process, and thus consideration for assessment for underlying obstructive coronary artery disease may be reasonable if the patient's coronary anatomy has not previously been delineated. In contrast, nonischemic myocardial injury may result from many mechanisms including myocardial strain and resultant apoptosis (heart failure, valvular heart disease, or hypertension) or direct cardiotoxicity (chemotherapy and illicit substance use). The evaluation of nonischemic myocardial injury will often focus on a structural examination of the heart with echocardiogram and/or cardiac magnetic resonance imaging.

Unfortunately, despite the prevalence of both conditions and increasing awareness of their prognoses, there remains no evidence-based therapies for improving patient outcomes. Prescriptions of secondary prevention medications are low for both type 2 MI and myocardial injury, as are revascularization rates.⁷ The role of revascularization for the treatment of type 2 MI and myocardial injury is under investigation in the ACT-2 trial (Appropriateness of Coronary Investigation in Myocardial Injury and Type 2 Myocardial Infarction).¹⁵

Conclusions

Patients with type 2 MI and myocardial injury are frequently encountered in clinical practice and are at high risk of both major adverse cardiovascular events and non-cardiac death. Differentiation between the two entities is relevant for clinical research and epidemiologic studies and also important to enable appropriate evaluation and treatment of patients because the mechanism of troponin release varies between type 2 MI and myocardial injury. Furthermore, accurate documentation and coding of the diagnoses is crucial to avoid potential penalties under value-based programs.

References

1. Thygesen K, Alpert JS, White HD, et al. Universal definition of myocardial infarction. Circulation 2007;116:2634-53.
2. Thygesen K, Alpert JS, Jaffe AS, et al. Fourth Universal Definition of Myocardial Infarction (2018). J Am Coll Cardiol 2018;72:2231-64.
3. Sandoval Y, Smith SW, Sexter A, et al. Type 1 and 2 Myocardial Infarction and Myocardial Injury: Clinical Transition to High-Sensitivity Cardiac Troponin I. Am J Med 2017;130:1431-1439.e4.
4. Wu AHB, Christenson RH, Greene DN, et al. Clinical Laboratory Practice Recommendations for the Use of Cardiac Troponin in Acute Coronary Syndrome: Expert Opinion from the Academy of the American Association for Clinical Chemistry and the Task Force on Clinical Applications of Cardiac Bio-Markers of the International Federation of Clinical Chemistry and Laboratory Medicine. Clin Chem 2018;64:645-55.
5. McCarthy C, Murphy S, Cohen JA, et al. Misclassification of Myocardial Injury as Myocardial Infarction: Implications for Assessing Outcomes in Value-Based Programs. JAMA Cardiol 2019;4:460-64.
6. McCarthy CP, Raber I, Chapman AR, et al. Myocardial Injury in the Era of High-Sensitivity Cardiac Troponin Assays: A Practical Approach for Clinicians. JAMA Cardiol 2019;Aug 7: [Epub ahead of print].
7. Chapman AR, Adamson PD, Shah ASV, et al. High-Sensitivity Cardiac Troponin and the Universal Definition of Myocardial Infarction. Circulation 2020;141:161-71.
8. Chapman AR, Shah ASV, Lee KK, et al. Long-Term Outcomes in Patients With Type 2 Myocardial Infarction and Myocardial Injury. Circulation 2018;137:1236-45.
9. Gaggin HK, Liu Y, Lyass A, et al. Incident Type 2 Myocardial Infarction in a Cohort of Patients Undergoing Coronary or Peripheral Arterial Angiography. Circulation 2017;135:116-27.
10. McCarthy CP. Type 2 Myocardial Infarction and Value-Based Programs: Cutting the Supply in the Absence of Demand. Am J Med 2019;132:1117-8.
11. McCarthy CP, Vaduganathan M, Singh A, et al. Type 2 Myocardial Infarction and the Hospital Readmission Reduction Program. J Am Coll Cardiol 2018;72:1166-70.
12. McCarthy CP, McWalters ST, Wasfy JH. ICD-10 Coding of Type 2 Myocardial Infarction and Myocardial Injury as It Relates to US Centers for Medicare & Medicaid Services Value-Based Payment Programs-Reply. JAMA Cardiol 2019;Aug 14:[Epub ahead of print].
13. Díaz-Garzón J, Sandoval Y, Smith SW, et al. Discordance between ICD-Coded Myocardial Infarction and Diagnosis according to the Universal Definition of Myocardial Infarction. Clin Chem 2017;63:415-19.
14. Martin LM, Januzzi JL Jr, Thompson RW, et al. Clinical Profile of Acute Myocardial Infarction Patients Included in the Hospital Readmissions Reduction Program. J Am Heart Assoc 2018;7:e009339.
15. Lambrakis K, French JK, Scott IA, et al. The appropriateness of coronary investigation in myocardial injury and type 2 myocardial infarction (ACT-2): A randomized trial design. Am Heart J 2019;208:11-20.

Clinical Topics: Acute Coronary Syndromes, Cardio-Oncology, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Prevention, Stable Ischemic Heart Disease, Valvular Heart Disease, Atherosclerotic Disease (CAD/PAD), Novel Agents, Acute Heart Failure, Interventions and ACS, Interventions and Coronary Artery Disease, Interventions and Imaging, Interventions and Structural Heart Disease, Angiography, Magnetic Resonance Imaging, Nuclear Imaging, Hypertension

Keywords: Acute Coronary Syndrome, Angiography, Angiography, Apoptosis, Benchmarking, Cardiotoxicity, Coronary Artery Disease, Coronary Thrombosis, Diabetes Mellitus, Type 2, Electrocardiography, Diagnostic Errors, Heart Failure, Hospitalization, Heart Valve Diseases, Incidence, Hypertension, Magnetic Resonance Imaging, International Classification of Diseases, Inpatients, Oxygen, Myocardial Infarction, Myocardium, Patient Discharge, Prevalence, Patient Readmission, Retrospective Studies, Troponin, Troponin I, Sepsis, Secondary Prevention, Prognosis, Value-Based Purchasing

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