Professional Documents
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14, 2019
PUBLISHED BY ELSEVIER
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.
Manuscript received August 21, 2018; revised manuscript received January 29, 2019, accepted February 4, 2019.
the identification of acute myocardial affect coronary blood flow (Figure 3);
ischemia, and help distinguish MI from however, most T2MIs are triggered by noncoronary
injury. etiologies that reduce oxygen delivery and/or in-
crease oxygen demand (Online Table 1). In most
cases both supply and demand are likely altered
have either T2MI or T1MI with subtle atypical pre- either directly or indirectly. The presence and
sentations (1). severity of concomitant coronary artery disease
For patients with cardiac troponin (cTn) increases (CAD) likely defines the extent of supply-demand
with a rising and/or falling pattern, a diagnosis of imbalance necessary to evoke ischemia.
Coronary spasm
Type 2
myocardial Coronary embolism Not due to
Pure supply
infarction obstructive CAD
reduction
Coronary endothelial dysfunction
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:
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
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.
Prevalence relates to how often these etiologies are considered. T2MI ¼ type 2 myocardial infarction.
trained adjudicators having agreement rates of (18,25,36,38), potentially reflecting that cTn is used
64% (47). more broadly in the United States (48).
Most studies use broad criteria evaluating all
clinical information (3). Others use specific criteria 12-LEAD ECG AND ECHOCARDIOGRAPHY
(32) with strict thresholds (e.g., supraventricular
tachyarrhythmia lasting $20 min with a ventricular The ECG classification of ST-segment elevation
rate >150 beats/min, and so on) to define a myocardial infarction (STEMI) and non-STEMI ap-
mismatch. These latter criteria do not take into ac- plies to T2MI as it does for T1MI. ST-segment
count that the threshold for myocardial ischemia elevation occurs in 1% to 24% of patients with
varies based on the coronary anatomy. Finally, T2MI (3). The frequency depends on the given
because hemodynamic abnormalities are easy to population involved and how closely those entities
observe, it is seductive to think that all cTn eleva- are looked for, for example, using intracoronary
tions are secondary to them, potentially under- imaging.
appreciating other mechanisms. Patients with T2MI are less likely to have ischemic
Several investigations suggest T2MI is more ECG changes and regional wall motion abnormalities
frequent than T1MI in all-comers studies compared (5,6,19,28). We support the concept that the more
with chest pain populations. Such findings are com- severe the ST-segment changes, the worse the out-
mon in U.S. studies where 57% to 75% of MIs are T2MI comes (49).
1850 Sandoval and Jaffe JACC VOL. 73, NO. 14, 2019
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
%
40
30
20
10
0
N- an g
W TIM es
at ( 8)
Gu S ein IRG )
B im it (A O)
do n ( es I S)
Bo an WE TRA AS)
ca c ( HE R)
Sh L H-T Pl )
ah op IM us)
ig Cu D)
EA a
Sa D P S)
y T- va
-A )
el G A I)
rg en ora
PA e
Sh )
Ja h
Pu d
an Ce ot
(B el
ad )
H dad
Du on
(U ig ll
gg l ( S OP r
in DI an IA)
AB ND l
NC )
A)
AS O va
St (V AT
W IS T
EF ES
CE
-H CC
LA -T
TR he
ST nc
(A ad
a
TO L ber
ve
va
M
n di
Ra aro ara h (M CSI
C
(B AM AR
t
d
na ovi DE CE
Sp hite I 3
ab AP ai
(H ez- I E
(C AM do
be re r
(D D
z O
v S ( D
EI A
h- e
an
er sl
el
e
M
M
(A
um
al
m
ov
RI
hi
Ne
Ga ova
nd
(T
Do
st
Sa
ca
nd
Ne
na
Sa
Bo
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 angina and those who are asymptomatic (52). The
CORONARY ANGIOGRAPHY timing of coronary angiography is also important, as
following treatment, findings may change.
Coronary angiography is routinely used to evaluate T2MI can occur with or without obstructive CAD
patients with T1MI. For patients with T2MI, there and in patients with angiographically normal coro-
is greater variability (range 5% to 60%), often nary arteries, such as due to spasm, embolism, SCAD,
reflecting the population involved (Online Table 4). endothelial dysfunction, or with aortic dissection
Coronary angiography is not 100% sensitive for (54–58) (Figure 3). Intracoronary thrombus is not
plaque disruption. If the information will influence exclusive of T1MI and can result from obstruction, as
care, intracoronary imaging with optical coherence in coronary spasm (59).
tomography (OCT) or intravascular ultrasound can be MI with nonobstructive coronary arteries (60)
helpful (50–53). Ruptured plaques, however, are not does not refer to MI subtypes. In SWEDEHEART
exclusive to MI and are seen in patients with stable (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
0 20 40 60 80 100
(%)
Obstructive Coronary Artery Disease Coronary Angiography Performed
C E NT R AL IL L U STR AT IO N Diagnostic Approach for Patients With Suspected Acute Myocardial Ischemia
Normal
work-up
Emergent coronary angiography Serial cTn and ECGs
Atherothrombosis Non-atherothrombotic Diagnostic work-up considerations Elevated cardiac troponin >99th URL
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
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 Syndromes (APACE) study suggests that compared
influenced by the assay and/or threshold used before to cTnT, most new MIs identified using hs-cTn are
and after hs-implementation (66). In some studies, T1MIs (65).
there is no increase in T2MI diagnoses (36). Given
T2MI is associated with lower cTn values, it is APPROACH TO ASSESSMENT AND DIAGNOSIS
conceivable that the relative number of T2MIs will
increase more than T1MI. In contrast, data from An algorithmic approach to T2MI is shown in the
the Advantageous Predictors of Acute Coronary 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
↑Likelihood of
Unstable
Type 1 myocardial infarction
angina
Clinical evidence
of acute myocardial Stress cardiomyopathy
ischemia
CHF Myocarditis
myocardial injury
Normal
– or
low-risk Sepsis Critical illness
ESRD/CKD
Cardiomyopathy
Stroke
Magnitude of
– + ++ +++ troponin increases
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
70
In-Hospital 30 to 180 Days 1 Year 2 to 5 Years
60
50
40
Mortality, %
30
20
10
)
n) (E l (D ra)
In -H erio ad esi)
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18
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
5-years (Chapman)
1-Year (Dhesi)
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.
Noncoronary Phenotypes
Older patients with many comorbid conditions Example: Older patient with chronic kidney Stabilize first; in most cases, management should
(þþþ) including CAD or suspected CAD who disease, COPD, stable CAD, HFpEF admitted focus on correction/control of the trigger/
are critically ill: Poor prognosis, often with acute gastrointestinal hemorrhage condition/illness leading to secondary
burdened with many comorbidities such as found to have critical anemia and identified to myocardial ischemia, with more aggressive
CAD, chronic kidney disease, and congestive have ST–T-wave changes and increased cTn. management (e.g.: angiography) reserved for
heart failure in addition to the primary those with high-risk features of objective
illness/condition/trigger leading to secondary myocardial ischemia once the acute issues
myocardial ischemia. 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).
Older patients with some comorbid conditions Examples: Middle-age or elderly patient Requires correction/control of the trigger/
(þ) including CAD or suspected CAD: Fair without overt critical illness or extensive condition/illness leading to secondary
prognosis in the absence of critical illness, comorbidities; e.g., patients with atrial myocardial ischemia. If no history of CAD,
particularly when trigger/illness leading to fibrillation with rapid ventricular rate and may require risk stratification for such. If CAD
T2MI can be easily corrected. 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.
Older patients with T2MI with no evidence of Example: Patient with chest discomfort in the Requires correction/control of the trigger/
obstructive CAD. 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.
Younger patients with minimal to no Examples: Young patient with chest pressure Most often requires only correction of the
comorbidities: Prognosis good, particularly found to have prolonged supraventricular trigger/condition/illness leading to secondary
when in the absence of known or suspected tachycardia and ECG changes with myocardial ischemia.
coronary artery disease and other major increased cTn. If no history of CAD, may require risk
underlying comorbidities. stratification for such.
Coronary Phenotypes
Often have clear definite evidence of acute SCAD, coronary embolism, coronary spasm, Most often will require invasive angiography to
myocardial ischemia; many manifest as endothelial dysfunction confirm the diagnosis. May require use of
STEMI. Likely a diagnosis of exclusion once intracoronary imaging (IVUS/OCT) and/or
atherosclerotic plaque disruption (T1MI) has coronary physiology to confirm or exclude
been excluded. 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 injury. These patients are often intubated and/or
fatal ones may be T1MI. sedated, which limits the ability to assess symp-
Defining therapies is challenging because of the toms and signs, and ECGs are often not helpful.
risk for bleeding. A randomized trial suggested that Upon recovery, if appropriate, these patients may
dabigatran may be effective (74); however, uncer- require further evaluation to clarify the etiology of
tainty persists. For now, treatment should be indi- their cardiac injury to improve their adverse long-
vidualized and include correction of supply-demand term prognosis (75).
imbalance.
HEART FAILURE. Patients with acute or chronic HF
CRITICAL ILLNESS. It is challenging to distinguish frequently manifest increased cTn (76). Myocardial
acute and chronic myocardial injury from T1MI ischemia can be a trigger for HF. For patients with
and T2MI in this context. Absent evidence of acute HF, there often is a rise and/or fall in cTn. One
myocardial ischemia, most cTn rises, especially mechanism for this is acute left ventricular stretch
those with sepsis, are likely due to myocardial 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
Myocardial injury
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
Clinical Controversies
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
ADDRESS FOR CORRESPONDENCE: Dr. Allan S. Jaffe,
T2MI is frequent and explains a significant proportion Department of Cardiovascular Diseases and Depart-
of cTn increases in clinical practice. The mechanisms ment of Laboratory Medicine and Pathology, Mayo
are heterogeneous, for which reason, individualized Clinic, Gonda 468, 200 1st, SW, Rochester, Minne-
approaches to diagnosis, management, and risk sota 55905. E-mail: jaffe.allan@mayo.edu. Twitter:
stratification are needed. A consensus is needed @MayoClinicCV, @yadersandoval.
JACC VOL. 73, NO. 14, 2019 Sandoval and Jaffe 1859
APRIL 16, 2019:1846–60 Type 2 Myocardial Infarction
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