JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
14, 2019
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VOL. 73, NO.
ª 2019 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
PUBLISHED BY ELSEVIER
JACC REVIEW TOPIC OF THE WEEK
Type 2 Myocardial Infarction
JACC Review Topic of the Week
Yader Sandoval, MD,a Allan S. Jaffe, MDa,b
ABSTRACT
Acute myocardial infarction (MI) can occur from increased myocardial oxygen demand and/or reduced supply in
the absence of acute atherothrombotic plaque disruption; a condition called type 2 myocardial infarction (T2MI).
As with any MI subtype, there must be clinical evidence of myocardial ischemia to make the diagnosis. This condition
is increasingly diagnosed due to the increasing sensitivity of cardiac troponin assays and is associated with adverse
short-term and long-term prognoses. Limited data exist defining optimal management strategies because T2MI is a
heterogeneous entity with varying etiologies and triggers. Thus, these patients require individualized care. A major
barrier is the absence of a uniform definition that can be operationalized with high reproducibility. This document
provides a synthesis of the data about T2MI to assist clinicians’ understanding of its pathobiology, when to deploy
the diagnosis, and its associated treatments. It also clarifies prognosis, identifies gaps in knowledge, and provides
recommendations for moving forward. (J Am Coll Cardiol 2019;73:1846–60) © 2019 by the American College of
Cardiology Foundation.
M yocardial infarction (MI) is a syndrome
where myocardial cells die due to imbal-
ances between myocardial oxygen sup-
ply and demand (1). It can be secondary to acute
CLINICAL PRESENTATION
Patients’ presentations depend on the pathobiology
and clinical context (Figure 1) (2). Data suggest that
atherosclerotic plaque disruption (type 1 myocardial women present more often with T2MIs (w46%),
infarction [T1MI]), or alterations in myocardial whereas men present mostly with T1MIs (w71%)
oxygen supply and/or demand in the absence of (Online Figure 1) (3). Most patients with T2MI
acute atherothrombosis (type 2 myocardial infarc- present with ischemia driven by another illness
tion [T2MI]) (1). (Online Table 1). Some present due to coronary
Based on a comprehensive review of the peer- etiologies.
reviewed published data (Online Appendix), this Diagnosing ischemia is the critical step. Patients
report synthesizes the information on T2MI. It iden- with T2MI have less chest pain and more often
tifies gaps and makes recommendations for moving have dyspnea or other atypical presentations
forward, including a phenotype-specific approach. (Online Table 2) (4). The clinical distinction is
Recognizing the heterogeneity of the mechanisms, it challenging. Certain patient subsets, such as
emphasizes individualized care. women, the elderly, and those with diabetes, can
From the aDepartment of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota; and the bDepartment of Laboratory
Medicine and Pathology, Mayo Clinic, Rochester, Minnesota. Dr. Sandoval has served on the Advisory Board of Abbott Diagnostics
without personal compensation; and has served as a nonsalaried advisor for Roche Diagnostics. Dr. Jaffe has consulted or is
presently consulting for most of the major diagnostic companies, including Beckman, Abbott, Siemens, ET Healthcare, Roche,
Quidel, Sphingotec, and Novartis.
Manuscript received August 21, 2018; revised manuscript received January 29, 2019, accepted February 4, 2019.
ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2019.02.018
JACC VOL. 73, NO. 14, 2019 Sandoval and Jaffe 1847
APRIL 16, 2019:1846–60 Type 2 Myocardial Infarction

acute MI is possible if ischemia is present (1). ABBREVIATIONS

HIGHLIGHTS AND ACRONYMS
In the absence of ischemia, the diagnosis of
 T2MI occurs due to myocardial oxygen acute myocardial injury is favored. Because
CAD = coronary artery disease
supply/demand mismatch without acute T2MIs are often smaller events, there may not
cTn = cardiac troponin
atherothrombotic plaque disruption and be ischemic electrocardiographic (ECG) find-
ECG = electrocardiogram
is associated with adverse short- and ings or imaging abnormalities (5,6). Diag-
nostic evaluations such as advanced imaging MI = myocardial infarction
long-term prognoses.
may be precluded by comorbidities such as OCT = optical coherence
 T2MI is a heterogeneous entity usually tomography
impaired renal function or critical illness.
caused by a noncoronary trigger. Indi- STEMI = ST-segment elevation
vidualized care is needed. PATHOPHYSIOLOGY
myocardial infarction

T1MI = type 1 myocardial

 Consensus is needed about diagnosis. infarction
Imaging may help characterize processes There are multiple mechanisms for supply-
T2MI = type 2 myocardial
leading to myocardial injury, facilitate demand imbalance (Figure 2). Some directly infarction

the identification of acute myocardial
ischemia, and help distinguish MI from
injury.
have either T2MI or T1MI with subtle atypical pre-
sentations (1).
For patients with cardiac troponin (cTn) increases
with a rising and/or falling pattern, a diagnosis of
affect coronary blood flow (Figure 3);
however, most T2MIs are triggered by noncoronary
etiologies that reduce oxygen delivery and/or in-
crease oxygen demand (Online Table 1). In most
cases both supply and demand are likely altered
either directly or indirectly. The presence and
severity of concomitant coronary artery disease
(CAD) likely defines the extent of supply-demand
imbalance necessary to evoke ischemia.

F I G U R E 1 Clinical Framework for T2MI

Emergency department Inpatient wards Post-operative setting Intensive care unit

Main reason leading to clinical presentation (e.g.: chest pain)

Context
Secondary to another illness or process

Coronary spasm
Type 2
myocardial Coronary embolism Not due to
Pure supply
infarction obstructive CAD
reduction
Coronary endothelial dysfunction

Spontaneous coronary artery dissection

Mechanisms
Tachyarrhythmias If concomitant
Increased
CAD:
demand
Severe hypertension
Follow CAD
Supply-demand guidelines, risk
imbalance Bradyarrhythmias
reduction strategies.
Severe hypoxia
Reduced supply If no concomitant
Severe anemia CAD:

Severe hypotension Treat/control trigger.

Venue, context, and mechanism of T2MI should be considered for diagnostic and therapeutic purposes. Reprinted with permission from
Januzzi and Sandoval (2). CAD ¼ coronary artery disease.
1848 Sandoval and Jaffe JACC VOL. 73, NO. 14, 2019

Type 2 Myocardial Infarction APRIL 16, 2019:1846–60

F I G U R E 2 Main Noncoronary Mechanisms Leading to T2MI

Main Noncoronary Mechanisms Leading to Supply/Demand Mismatch and Compensatory Responses

Initial stimuli
↓ Oxygen supply ↑ Oxygen demand

↓Oxygen carrying capacity Hypotension Bradyarrhythmias

Severe anemia Acute respiratory ↓ Cardiac output ↓ Cardiac output

due to acute failure with ↓ Mean arterial pressure (MAP)
blood loss severe hypoxia ↓ Coronary perfusion pressure
↑ Heart rate
Sympathetic ↑ Systemic vascular resistance (SVR)
↓ Preload -↓ Cardiac output - ↓ MAP response ↑ Contractility

Sympathetic ↑ Heart rate

response ↑ Cardiac output
↑ Contractility
Tachyarrhythmias Hypertension
↑ Heart rate + Renin-angiotensin-aldosterone system
↑ SVR
↑ Afterload Endothelial/
↑ Cardiac output
vascular injury
↓ Stroke volume ↓ Diastolic perfusion time
↓ Coronary blood flow

Normal
coronaries Mild coronary artery disease (CAD) Moderate CAD Severe CAD

Most cases of type 2 myocardial infarction (T2MI) are triggered by noncoronary etiologies. The response often evokes compensatory mechanisms involving both supply
and demand. T2MI can occur in patients with normal coronary arteries or in those with obstructive and nonobstructive coronary artery disease.

Distinguishing mechanisms is difficult. For there must be evidence of myocardial ischemia to

example, in sepsis, despite marked increases in
coronary flow, patients can have sufficient alter-
ations in myocardial oxygen demand that ischemia
can occur, especially if coronary abnormalities are
present. The toxic effects of tumor necrosis factor
(TNF), heat shock proteins, and catecholamines can
also cause cTn release.
Thus, elevated cTn values alone, even if rising, do
not make a diagnosis of T2MI. At times, both T2MI
and myocardial injury are present. If clinicians focus
only on supply-demand issues, opportunities to
discover novel insights into pathobiology and treat-
ments may be missed. The critical principle is that
diagnose T2MI.
EPIDEMIOLOGY
The heterogeneous epidemiology of T2MI is shown in
Figure 4 (Online Table 3) (6–45). The frequency of
T2MI is dependent on the population, comorbidities,
disease definitions, adjudication processes, and the
cTn assay and concentration thresholds used to
detect myocardial injury (46). In the absence of uni-
form definitions, rates vary. Further, as difficult as it
is to distinguish T1MI and T2MI, it is also difficult to
distinguish T2MI from myocardial injury (3), with
JACC VOL. 73, NO. 14, 2019
APRIL 16, 2019:1846–60
F I G U R E 3 Coronary Etiologies of T2MI
Prevalence relates to how often these etiologies are considered. T2MI ¼ type 2 myocardial infarction.
trained adjudicators having agreement rates of
64% (47).
Most studies use broad criteria evaluating all
clinical information (3). Others use specific criteria
(32) with strict thresholds (e.g., supraventricular
tachyarrhythmia lasting $20 min with a ventricular
rate >150 beats/min, and so on) to define a
mismatch. These latter criteria do not take into ac-
count that the threshold for myocardial ischemia
varies based on the coronary anatomy. Finally,
because hemodynamic abnormalities are easy to
observe, it is seductive to think that all cTn eleva-
tions are secondary to them, potentially under-
appreciating other mechanisms.
Several investigations suggest T2MI
frequent than T1MI in all-comers studies compared
with chest pain populations. Such findings are com-
mon in U.S. studies where 57% to 75% of MIs are T2MI
Sandoval and Jaffe 1849
Type 2 Myocardial Infarction
(18,25,36,38), potentially reflecting that cTn is used
more broadly in the United States (48).
12-LEAD ECG AND ECHOCARDIOGRAPHY
The ECG classification of ST-segment elevation
myocardial infarction (STEMI) and non-STEMI ap-
plies to T2MI as it does for T1MI. ST-segment
elevation occurs in 1% to 24% of patients with
T2MI (3). The frequency depends on the given
population involved and how closely those entities
are looked for, for example, using intracoronary
imaging.
Patients with T2MI are less likely to have ischemic
is more ECG changes and regional wall motion abnormalities
(5,6,19,28). We support the concept that the more
severe the ST-segment changes, the worse the out-
comes (49).
1850 Sandoval and Jaffe JACC VOL. 73, NO. 14, 2019

Type 2 Myocardial Infarction APRIL 16, 2019:1846–60

F I G U R E 4 Epidemiology of T2MI

Type 2 Myocardial Infarction: Incidence (%) in those with Acute Myocardial Infarction
80

70

60

50
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40

30

20

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Marked variability in the proportion of T2MI diagnoses among patients with acute MI. ACSIS ¼ Acute Coronary Syndrome Israeli Survey;
ADAPT-DES ¼ Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents; AMIS Plus ¼ Acute Myocardial Infarction in
Switzerland registry; APACE ¼ Advantageous Predictors of Acute Coronary Syndromes Evaluation; BACC ¼ Biomarkers in Acute Cardiac Care;
BWH-TIMI ED ¼ Brigham and Women’s Hospital-Thrombolysis In Myocardial Infarction Emergency Department Chest Pain Study;
CASABLANCA ¼ Catheter Sampled Blood Archive in Cardiovascular Diseases; DEF-AMI ¼ Consequences of the universal 2007 DEFinition of
Acute Myocardial Infarction studied in a Danish consecutive hospital population; DIAMOND-T ¼ Diagnostic Improved Accuracy for Myocardial
infarctiON with Delta Troponin; High-STEACS ¼ High-Sensitivity Troponin in the Evaluation of patients with suspected Acute Coronary
Syndrome; MIDAS ¼ Myeloperoxidase in the Diagnosis of Acute Coronary Syndromes; OAT ¼ Occluded Artery Trial; SWEDEHEART ¼ Swedish
Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies
registry; TRACER ¼ Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome; TRITON-TIMI 38 ¼ Trial to
Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis In Myocardial Infarction 38;
UTROPIA ¼ Use of TROPonin I in Acute coronary syndromes; VIRGO ¼ Variation in Recovery: Role of Gender on Outcomes of Young AMI
Patients.

ADVANCED IMAGING AND
CORONARY ANGIOGRAPHY
Coronary angiography is routinely used to evaluate
patients with T1MI. For patients with T2MI, there
is greater variability (range 5% to 60%), often
reflecting the population involved (Online Table 4).
Coronary angiography is not 100% sensitive for
plaque disruption. If the information will influence
care, intracoronary imaging with optical coherence
tomography (OCT) or intravascular ultrasound can be
helpful (50–53). Ruptured plaques, however, are not
exclusive to MI and are seen in patients with stable
angina and those who are asymptomatic (52). The
timing of coronary angiography is also important, as
following treatment, findings may change.
T2MI can occur with or without obstructive CAD
and in patients with angiographically normal coro-
nary arteries, such as due to spasm, embolism, SCAD,
endothelial dysfunction, or with aortic dissection
(54–58) (Figure 3). Intracoronary thrombus is not
exclusive of T1MI and can result from obstruction, as
in coronary spasm (59).
MI with nonobstructive coronary arteries (60)
does not refer to MI subtypes. In SWEDEHEART
(Swedish Web-system for Enhancement and
JACC VOL. 73, NO. 14, 2019 Sandoval and Jaffe 1851
APRIL 16, 2019:1846–60 Type 2 Myocardial Infarction

F I G U R E 5 Prevalence of CAD Among Patients With T2MI Undergoing Coronary Angiography

Radovanovic (AMIS Plus)

Javed (>50%) (Angiogram within 2 Years)

Gaggin (CASABLANCA) (≥50% 2-Vessels)

Baron (SWEDEHEART) (≥50%)

Saaby (DEF-AMI) (≥50%)

Sandoval (DIAMOND-T) (>50%)

Guimaraes (TRACER) (≥70%)

Gaggin (CASABLANCA) (≥70% 2-Vessels)

Neumann (BACC) (≥50%)

Lopez Cuenca (≥50%)

Spatz (VIRGO) (≥50%)

0 20 40 60 80 100
(%)
Obstructive Coronary Artery Disease Coronary Angiography Performed

Note variability. Abbreviations as in Figure 4.

Development of Evidence-based care in Heart dis- computed tomography–derived fractional flow

ease Evaluated According to Recommended Thera-
pies registry), MI with nonobstructive coronary
arteries occurred in 8% of MIs undergoing coronary
angiography (61), of which 18% were T2MIs and
82% T1MIs.
Among patients with T2MI
coronary angiography, CAD is common (Figure 5). In
CASABLANCA (Catheter Sampled Blood Archive in
Cardiovascular Diseases) (18), where all patients with
subsequent T2MI had angiography, nearly 60%
had $50% obstruction in 2 vessels. In other studies,
a bimodal distribution is observed with either no
disease or severe CAD (32).
Cardiac magnetic resonance imaging (CMR) is
helpful in discerning alternative
myocardial injury. In some cases, CMR confirms acute
MI despite the absence of an angiographic culprit
(62). Similarly, coronary computed
angiography (CTA) can help assess for underlying
CAD. DEMAND-MI (Determining the Mechanism of
Myocardial Injury and Role of Coronary Disease in
Type 2 Myocardial Infarction)
where patients undergo CMR, and either: 1) coronary
CTA, computed tomographic calcium scoring, and
reserve fractional flow reserve; or 2) invasive coro-
nary angiography with OCT and invasive fractional
flow reserve, should provide novel insights.
CARDIAC TROPONIN
who undergo
T2MI is increasingly recognized because of more
sensitive cTn assays (63). Nearly all investigations
indicate that patients with T2MI manifest lower cTn
values (Online Table 5). Absolute concentrations and
changes across serial measurements are greater with
T1M1 than T2MI (19,27). Sufficient overlap exists,
however, that neither absolute values nor serial cTn
changes (delta) distinguish T1MI from T2MI or
etiologies for myocardial injury (38).
An added challenge is that patients who present
late after onset of symptoms may not manifest a
tomography rise and/or fall in cTn over short intervals because
of the slower downslope of the time-concentration
curve. In some series, #26% of MIs present this
way (64).
(NCT03338504), Implementation of high-sensitivity (hs) cTn assays
may translate into more acute MI diagnoses, partic-
ularly if transitioning from less sensitive assays (65).
1852 Sandoval and Jaffe JACC VOL. 73, NO. 14, 2019

Type 2 Myocardial Infarction APRIL 16, 2019:1846–60

C E NT R AL IL L U STR AT IO N Diagnostic Approach for Patients With Suspected Acute Myocardial Ischemia

Possible ischemic presentation

Immediate 12-lead ECG

Suspected STEMI Suspected NSTE-ACS Unstable angina

Normal
work-up
Emergent coronary angiography Serial cTn and ECGs

Acute coronary occlusion Normal coronaries or non-obstructive CAD Non-cardiac

Atherothrombosis Non-atherothrombotic Diagnostic work-up considerations Elevated cardiac troponin >99th URL

• Echocardiography If clinical uncertainty

T1MI T2MI • Cardiac MRI Clinical evidence of acute myocardial ischemia
• CT scan
PCI/CABG • Intracoronary imaging Yes No
GDMT for CAD (IVUS/OCT)
Acute myocardial Myocardial
* If difficult to • Provocative testing for spasm
infarction injury
distinguish consider
IVUS/OCT
MINOCA

Non-atherothrombotic
Non-atherothrombotic Myocardial
non-coronary T1MI T2MI T1MI T2MI
coronary etiology injury
etiology
Examples: SCAD, Examples: Marked Example: Example: Examples: PCI/CABG Individualized
coronary embolism, supply/demand mismatch Non-obstructive Coronary Myopericarditis GDMT for CAD phenotype-
coronary spasm, etc. with underlying stable atherosclerotic vasospasm Pulmonary specific
CAD plaque disruption confirmed with embolism management &
provocative Takotsubo therapeutic
testing cardiomyopathy approach, including
possible revascularization
if indicated

Individualized care • Treat underlying • GDMT for CAD Individualized Individualized care
tailored for each trigger GDMT for CAD • Consider care tailored tailored for each
etiology • Consider role of revascularization for each etiology
revascularization if etiology
no contraindications

Sandoval, Y. et al. J Am Coll Cardiol. 2019;73(14):1846–60.

In the absence of myocardial ischemia, the diagnosis of myocardial injury is favored, whereas in the presence of ischemia, T1MI or T2MI are possible. CABG ¼ coronary
artery bypass graft; CAD ¼ coronary artery disease; CT ¼ computed tomography; cTn ¼ cardiac troponin; ECG ¼ electrocardiogram; GDMT ¼ guideline-directed
medical therapy; IVUS ¼ intravascular ultrasound; MINOCA ¼ myocardial infarction with nonobstructive coronary arteries; MRI ¼ magnetic resonance imaging; NSTE-
ACS ¼ non–ST-segment elevation acute coronary syndrome; NSTEMI ¼ non–ST-segment elevation myocardial infarction; OCT ¼ optical coherence tomography;
PCI ¼ percutaneous coronary intervention; SCAD ¼ spontaneous coronary artery dissection; STEMI ¼ ST-segment elevation myocardial infarction; T1MI ¼ type 1
myocardial infarction; T2MI ¼ type 2 myocardial infarction; URL ¼ upper-reference limit.

The magnitude of the effect on diagnostic rates is
influenced by the assay and/or threshold used before
and after hs-implementation (66). In some studies,
there is no increase in T2MI diagnoses (36). Given
T2MI is associated with lower cTn values, it is
conceivable that the relative number of T2MIs will
increase more than T1MI. In contrast, data from
the Advantageous Predictors of Acute Coronary
Syndromes (APACE) study suggests that compared
to cTnT, most new MIs identified using hs-cTn are
T1MIs (65).
APPROACH TO ASSESSMENT AND DIAGNOSIS
An algorithmic approach to T2MI is shown in the
Central Illustration. The diagnosis requires: 1) a rising
JACC VOL. 73, NO. 14, 2019 Sandoval and Jaffe 1853
APRIL 16, 2019:1846–60 Type 2 Myocardial Infarction

F I G U R E 6 Relationship Between cTn Concentrations and the Clinical Evidence of Acute Myocardial Ischemia

Acute myocardial
ischemia

Normal cTn Evidence of myocardial injury quantified by cTn

↑Likelihood of

Acute myocardial ischemia

acute myocardial infarction
++
With ischemia

Unstable
Type 1 myocardial infarction
angina

+ Type 2 myocardial infarction

Clinical evidence
of acute myocardial Stress cardiomyopathy
ischemia
CHF Myocarditis

Without myocardial ischemia

↑Likelihood of
Without ischemia

myocardial injury
Normal
– or
low-risk Sepsis Critical illness

ESRD/CKD

Cardiomyopathy

Stroke
Magnitude of
– + ++ +++ troponin increases

99th percentile URL of cardiac troponin

The y-axis refers to myocardial ischemia and the x-axis refers to cardiac troponin (cTn) concentrations based on the 99th percentile
URL. Those without ischemia and cTn <99th URL are low risk. Those with ischemia with cTn <99th URL have unstable angina.
Those without ischemia and increased cTn >99th URL have myocardial injury. Those with ischemia and cTn >99th URL can have
type 1 or 2 myocardial infarction. CHF ¼ congestive heart failure; CKD ¼ chronic kidney disease; ESRD ¼ end-stage renal disease;
URL ¼ upper-reference limit.

and/or falling cTn with $ value >99th percentile; prompt cardiovascular diagnosis and/or therapy are
and 2) clinical evidence of myocardial ischemia (1). indicated, evaluations can wait until underlying
When symptoms and signs are unclear, emphasis problems are stabilized.
should be placed on finding objective evidence of
myocardial ischemia (5), for example with cardiac PROGNOSIS
imaging.
The first steps include a careful history and Patients with T2MI have similar or higher all-cause
physical examination, cTn measurements, and mortality than patients with T1M1 (Figure 7, Online
12-lead ECGs. Imaging studies should be used Table 3), in part because many studies include
selectively. If clear evidence of acute myocardial critically ill patients with comorbidities. They are
ischemia cannot be identified, the term myocardial at high risk for cardiovascular mortality and
injury is favored (Figure 6). If myocardial ischemia is major adverse cardiovascular events. In the TRITON-
present, distinguishing T2MI from T1MI is clinically TIMI 38 (Trial to Assess Improvement in Therapeutic
based. Outcomes by Optimizing Platelet Inhibition with
Most cases of T2MI are non-STEMIs secondary to Prasugrel-Thrombolysis In Myocardial Infarction 38)
another illness. Therefore, except for cases where trial, patients with T2MI had a nearly 3-fold
1854 Sandoval and Jaffe JACC VOL. 73, NO. 14, 2019

Type 2 Myocardial Infarction APRIL 16, 2019:1846–60

F I G U R E 7 Variability in Mortality Across T1MI and T2MI

70
In-Hospital 30 to 180 Days 1 Year 2 to 5 Years

60

50

40
Mortality, %

30

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Type 2 Myocardial Infarction Type 1 Myocardial Infarction

Type 2 myocardial infarction (T2MI) (blue) and type 1 myocardial infarction (T1MI) (orange). Abbreviations as in Figure 4.

increased risk for cardiovascular death (10). In and critical illness increase death rates (67).
CASABLANCA, incident T2MI predicted all-cause and Nonetheless, studies with long-term follow-up
cardiovascular death, as well as the composite of all- indicate that cardiovascular mortality is common and
cause death, nonfatal MI, heart failure (HF), stroke, explains 24% to 43% of deaths (13,18,35). Thus,
transient ischemic attack, peripheral arterial opportunities exist to identify high-risk patients and
complication, and cardiac arrhythmia (18). improve their outcomes.
Studies focused only on patients with chest pain Among patients with T2MI or myocardial injury,
often exclude high-risk or critically ill patients, CAD is an independent predictor of cardiovascular
such as those with advanced renal disease, and death or recurrent MI (13). In these studies, however,
suggest a more benign prognosis (27,28). In APACE, only small numbers of patients underwent coronary
patients with T2MI had 120-day rates of cardiovas- angiography (39,61).
cular and all-cause death rate of 1.7% and 4.6%,
respectively (27). TREATMENT
Most patients with T2MI die from non-
cardiovascular causes (Figure 8), as in studies of the Recognizing the heterogeneous mechanisms
critically ill where conjoint cardiovascular disease leading to T2MI, we endorse a phenotype-specific
JACC VOL. 73, NO. 14, 2019 Sandoval and Jaffe 1855
APRIL 16, 2019:1846–60 Type 2 Myocardial Infarction

F I G U R E 8 Mode of Death in T2MI

5-years (Chapman)

4-Years (Gaggin) (CASABLANCA)

3.2-Years (Lambrecht) (DEF-AMI)

2-Years (Neumann) (BACC)

2-Years (Guimaraes) (TRACER)

1-Year (Radovanovic) (AMIS Plus)

1-Year (Dhesi)

120-Days (Nestelberger) (APACE)

90-Days (Nestelberger) (APACE)

60-Days (Nestelberger) (APACE)

30-Days (Dhesi)

In-Hospital (Putot)

In-Hospital (Dhesi)

In-Hospital (Arora)

0 20 40 60 80 100
(%)
Cardiovascular Mortality All-Cause Mortality

Proportion of T2MI deaths due to cardiovascular versus noncardiovascular reasons. Abbreviations as in Figure 4.

approach (2). A conceptual model is proposed in revascularization remains uncertain. At present,

Table 1, which can be refined using phenomapping careful decisions should be made following clinical-
and machine learning, as with HF with preserved practice guidelines, while balancing the risk/
ejection fraction (68). benefit of dual-antiplatelet therapy. Studies indicate
For those who present with a primary coronary wide variations in revascularization (PCI or CABG)
problem, the appropriate treatment is dictated (Online Table 4), with a recent meta-analysis
by that process (54–58). For those with T2MI showing a PCI use rate of 40% (range 0% to
caused by supply-demand mismatch, individualized 87.5%) (70).
therapies should be tailored to the specific condi-
tions (1,3). SPECIAL SCENARIOS
Observational studies suggest that T2MI patients
with CAD have adverse outcomes (13,61). Thus, PERIOPERATIVE MYOCARDIAL INJURY AND
those with known or suspected CAD, more marked INFARCTION. The perioperative setting is unique
ST-segment depression, and/or higher cTn concen- and T2MI is common (71). Pre-operative cTn mea-
trations may require evaluation for CAD. ACT-2 surements and surveillance sampling are recom-
(Appropriateness of Coronary investigation in mended for those at risk (1). Because of analgesics,
myocardial injury and Type 2 myocardial infarc- few patients have symptoms (71). Although ischemic
tion) is a randomized trial comparing invasive changes are rarely detected on routine ECGs, studies
coronary angiography (or coronary CTA) versus using continuous 12-lead Holter monitoring show that
conservative management on 2-year all-cause mor- transient tachycardia and ST-segment changes are
tality that should provide insights into manage- common and correlate with cTn (72). Using OCT, most
ment (69). perioperative MIs are T2MI (53). However, autopsy
For patients with T2MI and CAD, guideline- data suggest that fatal events are evenly distributed
directed therapies are appropriate. The role of between plaque rupture and nonplaque rupture
1856 Sandoval and Jaffe JACC VOL. 73, NO. 14, 2019

Type 2 Myocardial Infarction APRIL 16, 2019:1846–60

T A B L E 1 Phenotype-Specific Approach to T2MI: A Conceptual Model

Type 2 Myocardial Infarction Phenotypes Examples Suggested Approach

Noncoronary Phenotypes

Older patients with many comorbid conditions Example: Older patient with chronic kidney
(þþþ) including CAD or suspected CAD who
are critically ill: Poor prognosis, often
burdened with many comorbidities such as
CAD, chronic kidney disease, and congestive
heart failure in addition to the primary
illness/condition/trigger leading to secondary
myocardial ischemia.
Older patients with some comorbid conditions
(þ) including CAD or suspected CAD: Fair
prognosis in the absence of critical illness,
particularly when trigger/illness leading to
T2MI can be easily corrected.
Older patients with T2MI with no evidence of
obstructive CAD.
Younger patients with minimal to no Examples: Young patient with chest pressure
comorbidities: Prognosis good, particularly
when in the absence of known or suspected
coronary artery disease and other major
underlying comorbidities.
Stabilize first; in most cases, management should
disease, COPD, stable CAD, HFpEF admitted focus on correction/control of the trigger/
with acute gastrointestinal hemorrhage condition/illness leading to secondary
found to have critical anemia and identified to myocardial ischemia, with more aggressive
have ST–T-wave changes and increased cTn. management (e.g.: angiography) reserved for
those with high-risk features of objective
myocardial ischemia once the acute issues
have been resolved and in whom further
action is reasonable after careful risk/benefit
assessment (e.g., profound ST–T-wave
changes, marked cTn increases, large new
regional wall motion abnormalities).
Examples: Middle-age or elderly patient Requires correction/control of the trigger/
without overt critical illness or extensive condition/illness leading to secondary
comorbidities; e.g., patients with atrial myocardial ischemia. If no history of CAD,
fibrillation with rapid ventricular rate and may require risk stratification for such. If CAD
underlying stable CAD with increased cTn and present, follow CAD guidelines (i.e., aspirin,
ECG changes. statin). Definite role of revascularization
uncertain; at present, follow
revascularization guidelines (symptoms,
ischemia, physiology-guided
revascularization) and balance risk/benefit of
DAPT in such population.
Example: Patient with chest discomfort in the Requires correction/control of the trigger/
context of hypertensive emergency requiring condition/illness leading to secondary
intravenous antihypertensive therapy in myocardial ischemia.
whom there is increase in cTn. Consider primary prevention for CAD as
indicated.
Most often requires only correction of the
found to have prolonged supraventricular trigger/condition/illness leading to secondary
tachycardia and ECG changes with myocardial ischemia.
increased cTn. If no history of CAD, may require risk
stratification for such.

Coronary Phenotypes

Often have clear definite evidence of acute
myocardial ischemia; many manifest as
STEMI. Likely a diagnosis of exclusion once
atherosclerotic plaque disruption (T1MI) has
been excluded.
SCAD, coronary embolism, coronary spasm, Most often will require invasive angiography to
endothelial dysfunction confirm the diagnosis. May require use of
intracoronary imaging (IVUS/OCT) and/or
coronary physiology to confirm or exclude
diagnoses. Individualized care tailored for
each etiology.

CAD ¼ coronary artery disease; COPD ¼ chronic obstructive pulmonary disease; cTn ¼ cardiac troponin; DAPT ¼ dual antiplatelet therapy; ECG ¼ electrocardiogram;
HFpEF ¼ heart failure with preserved ejection fraction; IVUS ¼ intravascular ultrasound; OCT ¼ optical coherence tomography; SCAD ¼ spontaneous coronary artery dissection;
T1MI ¼ type 1 myocardial infarction; T2MI ¼ type 2 myocardial infarction.

events (73). Thus, while most events are T2MI, the
fatal ones may be T1MI.
Defining therapies is challenging because of the
risk for bleeding. A randomized trial suggested that
dabigatran may be effective (74); however, uncer-
tainty persists. For now, treatment should be indi-
vidualized and include correction of supply-demand
imbalance.
CRITICAL ILLNESS. It is challenging to distinguish
acute and chronic myocardial injury from T1MI
and T2MI in this context. Absent evidence of
myocardial ischemia, most cTn rises, especially
those with sepsis, are likely due to myocardial
injury. These patients are often intubated and/or
sedated, which limits the ability to assess symp-
toms and signs, and ECGs are often not helpful.
Upon recovery, if appropriate, these patients may
require further evaluation to clarify the etiology of
their cardiac injury to improve their adverse long-
term prognosis (75).
HEART FAILURE. Patients with acute or chronic HF
frequently manifest increased cTn (76). Myocardial
ischemia can be a trigger for HF. For patients with
acute HF, there often is a rise and/or fall in cTn. One
mechanism for this is acute left ventricular stretch
with proteolysis and release of cTn with cell death
JACC VOL. 73, NO. 14, 2019 Sandoval and Jaffe 1857
APRIL 16, 2019:1846–60 Type 2 Myocardial Infarction

F I G U R E 9 Coding Algorithm for Patients With cTn Increases

Cardiac troponin concentration(s) ≥99th percentile upper-reference limit (URL)

Myocardial injury

Dynamic rise/fall present Dynamic rise/fall absent

Acute myocardial injury * Rarely late AMI

With myocardial ischemia Without myocardial ischemia Chronic myocardial injury

Acute myocardial infarction Isolated myocardial injury without associated infarction

Code ICD-10 R79.89; Document reason/etiology for isolated myocardial injury

Type 1 AMI Type 2 AMI Cardiac** Systemic** Chronic injury**

(Atherothrombotic MI) (Oxygen imbalance) • Heart failure • Sepsis/infection • Chronic kidney
• Type 2 MI code: ICD-10 121.A1 • Myocarditis • Stroke disease
• STEMI*: ICD-10
• Cor Pulmonale • Pulmonary embolism • Chronic heart failure
121.0 to 121.3
Document Type 2 MI AND • Coronary intervention • Acute toxicity • Infiltrative disorders
• NSTEMI*: ICD-10 121.4
cause/etiology • Angioplasty • Strenuous exercise such as amyloidosis
Examples:coronary spasm, • EP ablation • Rhabdomyolysis or sarcoidosis
* At present codes
coronary embolism, coronary, • Cardiac surgery • Critical illness
121.01-121.4 for STEMI
coronary endothelial dysfunction • Defibrillation • Burns
and NSTEMI will only be
spontaneous coronary artery • Cardiac contusion
assigned for Type 1 MIs
dissection, tachyarrhythmias,
severe hypertension,
bradyarrhythmias, severe hypoxia, ** These conditions can be due to isolated myocardial injury but in some
severe anemia, severe hypotension situations can also be classified as AMI. For example, acute heart failure
could be classified as isolated injury or in some cases MI.

Acute Myocardial Infarction Diagnosis

Rise and/or fall in cTn concentrations with at least 1
value ≥ sex-specific 99th percentile PLUS at least 1 of the following:
Ischemic symptoms
New or presumed new significant ST-T wave changes or new LBBB
Development of pathological Q waves in the ECG
Imaging evidence of new loss of viable myocardium or new regional
wall motion abnormality
Other Documentation Tips
1. Do not use the terms troponinitis, troponinemia, troponin leak, etc.,
but rather refer to events as either acute myocardial infarction or
myocardial injury (acute or chronic).
2. For type 2 myocardial infarction and isolated myocardial injury
without infarction must specify the suspected reason or etiology
leading to such.

Identification of intracoronary atherothrombosis (T1MI) or acute

angiographic culprit (e.g., vasopasm, SCAD, coronary embolism, etc.)
by angiography or autopsy (T2MI)

Tool for clinicians/coders to categorize patients with increased cTn. *At present, these codes are being applied only to T1MI for coding purposes. AMI ¼ acute
myocardial infarction; ECG ¼ electrocardiogram; ICD ¼ International Classification of Diseases; MI ¼ myocardial infarction; NSTEMI ¼ non-ST-segment elevation
myocardial infarction; STEMI ¼ ST-segment elevation myocardial infarction; T1MI ¼ type 1 myocardial infarction; other abbreviations as in Figures 2 and 6.

due to apoptosis via a calpain mediated mechanism CHALLENGES AND FUTURE DIRECTIONS
(77). Chronically, cTn values track reasonably with
left ventricular end-diastolic pressure, suggesting We have identified gaps where more data are
subendocardial hypoperfusion. In some patients, needed. There are disease coding issues, including
coronary endothelial dysfunction may also exist. the proper use of the new International Classification
Unless there is evidence of acute myocardial of Disease (ICD)–10 code for T2MI (code I12A1)
ischemia, cTn increases should be considered (Figure 9), hospital reimbursement, mortality
myocardial injury. statistics, performance and quality measures, health
1858 Sandoval and Jaffe JACC VOL. 73, NO. 14, 2019

Type 2 Myocardial Infarction APRIL 16, 2019:1846–60

T A B L E 2 Present Challenges and Future Directions

Clinical Controversies

1. Who should undergo cTn testing?

 The incidence rate largely relates to the tested population (i.e., if only patients with chest discomfort are tested with cTn, then T1MI may
be more common, whereas if all-comers with various symptoms are tested, then T2MI becomes more common). More clarity is needed as to
whom should be tested with cTn measurements.
2. Noninvasive advanced cardiac imaging
 Making the distinction between T1MI, T2MI, and myocardial injury is challenging and often subjective. More studies, for example using advanced
cardiac imaging (CMR or coronary CTA), are needed to better inform diagnostic pathways. If diagnostic uncertainty prevails, cardiac imaging
should be used more often to determine whether findings supportive of overt acute myocardial ischemia are present to diagnose acute MI or
to help assess for other potential etiologies of myocardial injury. It is acknowledged that some patients may have small MIs that are not large
enough to cause regional wall motion abnormalities.
3. Intracoronary imaging
 Coronary angiography is often seen as the gold standard; however, it is neither 100% sensitive nor specific for plaque-rupture events. More
data is needed with intracoronary imaging (OCT/IVUS).
4. Should the criteria used to diagnose T2MI be made more specific?
 The absence of established diagnostic criteria allows for the term T2MI to be loosely used in conditions in which supply-demand mismatch
is suspected, when clear evidence of myocardial ischemia is lacking. However, atypical ischemic presentations in the elderly, diabetic patients,
and women could be inadvertently disadvantaged. Additional evidence is needed to answer this question.
5. Personalized care
 Recognizing the distinct heterogeneous mechanisms leading to T2MI, it should be understood that care needs to be individualized and that
a phenotype-based approach may be best suited to inform how to best treat these patients.
 For patients with T2MI with concomitant CAD, further research is required to understand the value of both medical intensification and/or
revascularization in the absence of atherothrombosis.
Disease Coding
1. ICD-10 code (I12AI)
 The adoption of a code specific for T2MI should facilitate both epidemiologic and outcomes assessments.
 Inappropriate use of the T2MI code should be avoided; that is, there should be clear evidence of acute myocardial ischemia before the
diagnosis/code is deployed.
 At present, coders may opt to reserve the STEMI and NSTEMI codes to T1MI (Figure 9). Unless coding is done more consistently, the
ability to look across various venues to compare data will be impossible.
 For patients with T2MI, clinicians should specify the trigger(s); for example, T2MI secondary to atrial fibrillation with rapid ventricular rate, or
T2MI due to coronary vasospasm.
Performance and Quality Measures
1. The 2017 AHA/ACC Performance and Quality Measures (e.g., aspirin at discharge, beta-blocker at discharge, and so on) pertain only to T1MI.
2. Hospital Readmission Reduction Program (HRRP): patients with T2MI are included in the HRRP and hospitals are subject to financial penalties if their
30-day readmission rates exceed risk-standardized readmission rates (78).
Research
1. The absence of operational diagnostic criteria as to what constitutes T2MI has created inconsistencies across the peer-reviewed published data, with
clinicians and researchers having distinct perspectives in how the diagnosis is established.
2. Defining and then insisting on objective evidence of myocardial ischemia would likely facilitate disease coding and adjudication.
3. Recognizing the heterogeneous mechanisms/conditions leading to T2MI, the development of evidence-based therapies will benefit from phenotype
specific-approach study/trial designs.
4. Outcomes may differ across T2MI phenotypes. For example, young patients without comorbidities with arrhythmias may have different outcomes than
older sicker patients.

CMR ¼ cardiac magnetic resonance; CTA ¼ computed tomographic angiography; MI ¼ myocardial infarction; other abbreviations as in Table 1.

policy, societal implications, and research, among about how the diagnosis is established, to facilitate
others (78). Selected issues are described in Table 2. evidence-based therapies geared toward improving
outcomes.

CONCLUSIONS
T2MI is frequent and explains a significant proportion
of cTn increases in clinical practice. The mechanisms
are heterogeneous, for which reason, individualized
approaches to diagnosis, management, and risk
stratification are needed. A consensus is needed
ADDRESS FOR CORRESPONDENCE: Dr. Allan S. Jaffe,
Department of Cardiovascular Diseases and Depart-
ment of Laboratory Medicine and Pathology, Mayo
Clinic, Gonda 468, 200 1st, SW, Rochester, Minne-
sota 55905. E-mail: jaffe.allan@mayo.edu. Twitter:
@MayoClinicCV, @yadersandoval.
JACC VOL. 73, NO. 14, 2019
APRIL 16, 2019:1846–60
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KEY WORDS acute myocardial infarction,
cardiac troponin, myocardial injury, type 2
myocardial infarction, Universal Definition of
Myocardial Infarction
A PPE NDI X For supplemental tables and a
figure, please see the online version of this
paper.