Canadian Journal of Cardiology - (2023) 1e14

Special Article
The Canadian Cardiovascular Society Classification of Acute
Atherothrombotic Myocardial Infarction Based on Stages of
Tissue Injury Severity: An Expert Consensus Statement
Andreas Kumar, MD, MSc (Chairperson of the Writing Group),a,b Kim Connelly, MD, PhD,c
Keyur Vora, MD, MS,d Kevin R. Bainey, MD, MSc,e Andrew Howarth, MD, PhD,f
Jonathon Leipsic, MD,g Suzanne Betteridge-LeBlanc, BSc, RN,b,h Frank S. Prato, PhD,i
Howard Leong-Poi, MD,j Anthony Main, MD,a,b Rony Atoui, MD, MSc,k Jacqueline Saw, MD,l
Eric Larose, DVM, MD,m Michelle M. Graham, MD,n Marc Ruel, MD, MPH,o and
Rohan Dharmakumar, PhDp
a
Northern Ontario School of Medicine University, and Department of Cardiovascular Sciences, Health Sciences North, Sudbury, Ontario, Canada; b Health Sciences North,
Sudbury, Ontario, Canada; c Keenan Research Centre for Biomedical Science, Unity Health Toronto, St Michael’s Hospital, University of Toronto, and Department of
Physiology, University of Toronto, Toronto, Ontario, Canada; d Krannert Cardiovascular Research Center, Indiana University School of Medicine, Indianapolis, Indiana,
USA; e University of Alberta, Faculty of Medicine and Dentistry, Mazankowski Alberta Heart Institute, Canadian VIGOUR Centre, Edmonton, Alberta, Canada;
f
Cardiac Sciences, Faculty of Medicine, University of Calgary, and Libin Cardiovascular Institute, Calgary, Alberta, Canada; g Departments of Radiology and Cardiology,
University of British Columbia, Vancouver, British Columbia, Canada; h Northern Ontario School of Medicine University, and Health Sciences North, Sudbury, Ontario,
Canada; i Lawson Research Institute, University of Western Ontario, London, Ontario, Canada; j The Division of Cardiology, St Michael’s Hospital, Unity Health Toronto,
University of Toronto, Toronto, Ontario, Canada; k Northern Ontario School of Medicine University, and Department of Surgery, Health Sciences North, Sudbury,
Ontario, Canada; l Division of Cardiology, Vancouver General Hospital, University of British Columbia, Vancouver, British Columbia, Canada; m Department of
Medicine, University of Laval, Quebec City, Quebec, Canada; n Division of Cardiology, University of Alberta, Faculty of Medicine and Dentistry, Mazankowski Alberta
Heart Institute, Edmonton, Alberta, Canada; o University of Ottawa Heart Institute, Ottawa, Ontario, Canada; p Krannert Cardiovascular Research Center, Indiana
University School of Medicine/IU Health Cardiovascular Institute, Indianapolis, Indiana, USA

https://doi.org/10.1016/j.cjca.2023.09.020
0828-282X/Ó 2023 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
2 Canadian Journal of Cardiology
ABSTRACT
Myocardial infarction (MI) remains a leading cause of morbidity and
mortality. In atherothrombotic MI (ST-elevation MI and type 1 non-ST-
elevation MI), coronary artery occlusion leads to ischemia. Subse-
quent cardiomyocyte necrosis evolves over time as a wavefront within
the territory at risk. The spectrum of ischemia and reperfusion injury is
wide: it can be minimal in aborted MI or myocardial necrosis can be
large and complicated by microvascular obstruction and reperfusion
hemorrhage. Established risk scores and infarct classifications help
with patient management but do not consider tissue injury charac-
teristics. This document outlines the Canadian Cardiovascular Society
classification of acute MI. It is an expert consensus formed on the
basis of decades of data on atherothrombotic MI with reperfusion
therapy. Four stages of progressively worsening myocardial tissue
injury are identified: (1) aborted MI (no/minimal myocardial necrosis);
(2) MI with significant cardiomyocyte necrosis, but without microvas-
cular injury; (3) cardiomyocyte necrosis and microvascular dysfunction
leading to microvascular obstruction (ie, “no-reflow”); and (4) car-
diomyocyte and microvascular necrosis leading to reperfusion hem-
orrhage. Each stage reflects progression of tissue pathology of
myocardial ischemia and reperfusion injury from the previous stage.
Clinical studies have shown worse remodeling and increase in adverse
clinical outcomes with progressive injury. Notably, microvascular injury
is of particular importance, with the most severe form (hemorrhagic
MI) leading to infarct expansion and risk of mechanical complications.
This classification has the potential to stratify risk in MI patients and
lay the groundwork for development of new, injury stage-specific and
tissue pathology-based therapies for MI.
Despite enormous progress in diagnostics and therapy,
myocardial infarction (MI) remains one of the leading causes
of death in Canada and worldwide. The past 50 years have
seen improvement in survival of patients with ST-elevation
MI (STEMI). However, at the same time, heart failure from
ischemic cardiomyopathy in MI survivors has become an
important problem affecting a large patient population.
Multiple scores and classifications have evolved for acute MI
to help with patient care and research. The existing tools play
a fundamental role in clinical care, informing the health care
team about the potential risk of adverse events, and help
determine the intensity of care and surveillance and specifics
for medical and interventional therapy. They frequently have a
Received for publication December 18, 2022. Accepted September 10, 2023.
Corresponding author: Dr Andreas Kumar, Department of Cardiovascular
Sciences, Northern Ontario School of Medicine University, Health Sciences
North, 41 Ramsey Lake Rd, Sudbury, Ontario P3E 5J1, Canada. Tel.: þ1-
705-523-7100 x 3940; fax: þ1-705-671-5358.
E-mail: Andreas.kumar@mac.com
See page 11 for disclosure information.
Volume - 2023

RESUM 
E
L’infarctus du myocarde (IM) demeure l’une des principales causes de
morbidite  et de mortalite . En presence d’IM athe rothrombotique (IM
avec ele
vation du segment ST et IM sans e  le
vation du segment ST type
1), l’occlusion de l’artère coronaire entraîne une ische mie et une
necrose des cardiomyocytes qui se propage tel un front de vague dans
la zone à risque. L’e tendue de l’ischemie et des lesions de reperfusion
sions peuvent être minimes dans le cas d’un IM avorte
est large : les le ;
en revanche, dans le cas d’une ne crose myocardique, elles peuvent
être importantes et être associe es à une obstruction microvasculaire
et à une he morragie de reperfusion. Les indices de risque et les outils
de classification des infarctus du myocarde facilitent la prise en charge
des patients, mais ne prennent pas en conside ration les caracte
ris-
tiques des le sions tissulaires. Le present document donne un aperçu
de la classification de la Socie  te
 cardiovasculaire du Canada pour l’IM
aigu. Cette classification est le fruit d’un consensus d’experts reposant
sur des de cennies de donne es relatives à l’IM athe rothrombotique
avec traitement de reperfusion. Quatre stades d’aggravation progres-
sive des le sions du tissu myocardique sont de finis : 1) IM avorte
(aucune/minime ne crose myocardique); 2) IM avec ne crose des car-
diomyocytes importante, mais aucune le sion microvasculaire; 3)
necrose des cardiomyocytes et dysfonction microvasculaire entraînant
une obstruction microvasculaire (“no-reflow”); 4) ne crose des car-
diomyocytes et ne crose microvasculaire entraînant une he morragie de
reperfusion. Chaque stade reflète la progression de la pathologie tis-
e à l’ische
sulaire lie mie myocardique et des le sions de reperfusion par
rapport au stade pre cedent. Des recherches cliniques ont de montre
qu’une progression des le sions se traduisait par un remodelage
nefaste et une augmentation du nombre d’e  ve
nements cliniques
defavorables. Les le sions microvasculaires sont particulièrement
importantes, et leur forme la plus grave (l’IM he morragique) entraîne
une expansion de l’infarctus et un risque de complications
me caniques. Cette classification permet de stratifier le risque des
patients ayant subi un IM et de favoriser la mise au point de nouveaux
traitements de l’IM adapte s au stade des le sions et de la pathologie
des tissus.
direct effect on medical management and allow for research to
be refined. The “universal definition of MI” categorizes MI
according to its etiology1: the dichotomization of STEMI vs
non-STEMI (NSTEMI), on the basis of electrocardiogram
(ECG) changes, helps with risk stratification and manage-
ment. Other helpful tools include, among others, the
Thrombolysis in Myocardial Infarction (TIMI) risk score, the
History, ECG, Age, Risk factors, Troponin (HEART) score
and the Killip classification. These well-established classifica-
tions and scores rely on clinical parameters. However, they do
not take into account underlying myocardial tissue pathology.
The degree and type of tissue injury in MI is predictive of
ventricular remodeling, and adverse events such as heart fail-
ure, arrhythmia, hospitalization, and death. A new classifica-
tion that incorporates tissue-level changes is much needed, to
exploit the predictive power of tissue damage for improving
clinical care and research, beyond clinical parameters alone.
In acute atherothrombotic MI (type 1 MI), cardiomyocyte
necrosis evolves as a wavefront within an area at risk, the latter
being defined as myocardial tissue subtended by the occluded
epicardial coronary artery.2,3 Early reperfusion treatments
emerged as life-saving therapy, halting the wavefront of
Kumar et al.
CCS Classification of Acute Myocardial Infarction
necrosis and saving salvageable myocardium, thereby reducing
final infarct size, and diminishing risk of heart failure,
arrhythmia, and death.4-6
Myocardial necrosis is not the only form of tissue damage
that contributes to acute MI. In the 1970s, autopsy studies
revealed that myocardial edema occurs concomitantly and can
precede myocardial necrosis7; microvascular compromise is
also observed leading to microvascular obstruction (MVO)8
and myocardial hemorrhage.9-11 In recent years, advanced
imaging technologies have allowed tissue changes to be
studied in vivo, in patients as well as in animal models.
Substantial insight has been gained into the pathophysiology
of MI.12 A new picture of MI has now emerged: at the tissue
level, not all MIs are the same. Tissue changes in reperfused
atherothrombotic MI evolve in 4 sequential, progressive
stages. These stages reflect a fundamental biological cascade of
ischemia/reperfusion injury, and yield a new classification of
MI, reflecting the degree of severity of tissue injury. The new
classification is based on the ground truth of pathophysiology
and might help with refined patient risk assessment and
documentation. It might lay the groundwork for development
of future tissue-directed therapies.
Process
This new classification was initially developed by 2 of the
authors (A.K., R.D.). The Canadian Cardiovascular Society
(CCS) endorsed the development of this expert consensus as a
starting point for a proposed novel definition of MI and
requested the formation of a writing group under the over-
sight of the president. It is hoped that this document will serve
as a starting point for continued clinical and scientific
refinement to help define our present understanding of acute
atherothrombotic MI.
Expert Consensus Classification: Underlying
Principles
The CCS classification of acute MI from epicardial coro-
nary atherothrombosis is an expert consensus formed on the
basis of cumulative research on acute MI with reperfusion
therapy over the past 5 decades. It extends the wavefront
paradigm and formulates a new categorization of myocardial
ischemia and reperfusion injury into 4 sequential and pro-
gressive stages: myocardial edema occurs first, followed by
cardiomyocyte necrosis, then MVO, and last, myocardial
hemorrhage. (Figs. 1-4) The injury at each stage adds to and
builds on the injury of the previous stage, following a
sequence of escalating severity. This translates into worsening
patient prognosis with each stage (Fig. 5).
The staging is on the basis of the near universal observation
that edema occurs first, cardiomyocyte necrosis follows, and
never exists without myocardial edema. MVO is a possible
further progression, never observed without cardiomyocyte
necrosis, and therefore represents the next stage of severity.
The final stage is severely damaged capillaries that disrupt with
reperfusion, leading to myocardial hemorrhage. Hemorrhage
is always associated with MVO and never occurs alone; it is a
more severe form of microvascular injury, and the most severe
form of ischemia-reperfusion injury. Mechanical complica-
tions have been strongly associated with hemorrhagic
3
infarction,13 supporting the notion that hemorrhagic MI is
the most serious form of MI. Clinical studies over the past
several decades have shown that patient prognosis deteriorates
with each progressive stage (Fig. 5).
Early initiation of reperfusion therapy along with a short
duration of ischemia can significantly reduce the likelihood of
injury progressing to the next stage with the best case scenario
of near perfect prevention of cardiomyocyte necrosis (aborted
MI; Fig. 6).
A detailed description of the 4 stages of tissue injury is
outlined in the following section (Figs. 1-4).
The 4 CCS Stages of Acute MI Secondary to
Coronary Atherothrombosis
CCS stage 1 MI: Aborted MI
Aborted MI traditionally has been defined as MI with less
than twofold increase in creatine kinase level in blood, as well
as > 50% ST-segment elevation resolution within 90 minutes
post thrombolysis or 30 minutes post primary coronary an-
gioplasty with the absence of residual new pathologic Q
waves.14,15 Alternatively, some have suggested a cutoff of
< 0.5 ng/mL of troponin I,16 albeit others have suggested that
a troponin level above the 99th percentile of normal is too
sensitive for detection of aborted MI.17 A troponin I/T cutoff
of  5 times the upper limit of normal has been used in more
recent clinical trials.15,18 Aborted MI is observed more
frequently with timely reperfusion therapy (typically < 4
hours of ischemic symptoms, but most notably within 1-2
hours after onset of ischemia), which led to the term “golden
hour” of reperfusion.19-22 It is observed more frequently with
prehospital fibrinolysis compared with primary percutaneous
intervention.18 The incidence of aborted MI is reported to be
approximately 5%-15%,14,23,24 but can be as high as 30% in
patients treated within the first hour of myocardial ischemia
(Fig. 5).21,25,26
By definition, the myocardial damage in aborted MI is
minimal, and in the best case the entire area of myocardium at
risk can be salvaged.2,4 In aborted MI, the evolving wavefront
of ischemic injury is halted very early, and further damage to
the cardiomyocytes or the associated vascular bed is prevented
(Figs. 1-4). Cardiac magnetic resonance imaging (CMR)
studies in this population have shown the absence of
myocardial necrosis in approximately half of these patients,
and only minor myocardial necrosis in the remaining pa-
tients.26,27 Increased salvage has also been shown with tech-
netium 99m sestamibi single photon emission computed
tomography imaging.6 Aborted MIs are smaller and less
transmural compared with further evolved MIs.28 Myocardial
edema is observed to occur early, before cardiomyocyte ne-
crosis and reflects reversible myocardial injury (Figs. 2 and 3).
It can be assessed using T2-weighted CMR.7,27,29,30 Using
quantitative CMR, subendocardial injury, mostly less than
5% of left ventricular (LV) myocardial mass is observed.26,28
Angiographically, aborted MIs have normal coronary flow (ie,
TIMI 3 flow).31
Absence of cardiomyocyte necrosis or minimal car-
diomyocyte necrosis, and near complete salvage of myocar-
dium at risk in CCS stage 1 MI translate into markedly
reduced event rates and favourable patient outcome. The
4 Canadian Journal of Cardiology
Volume - 2023

Figure 1. Schematic representation of the 4 stages of the Canadian Cardiovascular Society (CCS) classification of acute atherothrombotic
myocardial infarction on a macroscopic heart. CCS stage 1: aborted myocardial infarction (MI) with myocardial edema, and no or minimal car-
diomyocyte necrosis. CCS stage 2: MI with cardiomyocyte necrosis, but no microvascular injury. CCS stage 3: MI with microvascular obstruction.
CCS stage 4: MI with reperfusion hemorrhage. Although rare extracapillary erythrocytes might be observed at stage 3, there is mass extravasation
and gross myocardial hemorrhage that defines stage 4.

long-term event rate is multifold lower compared with
nonaborted MI,26 with absolute event rates often < 5%
(Figs. 2, 5).4,15,22,23,26,31
CCS stage 2 MI: Cardiomyocyte necrosis without
microvascular injury
Stage 2 MI is defined by significant myocardial necrosis
that exceeds the level of necrosis observed in the stage of
aborted MI (CCS stage 1). However, this stage of injury does
not extend to microvascular injury (CCS stages 3 and 4). At
CCS stage 2, the window of near complete salvage of aborted
MI is surpassed and significant myocardial necrosis has
occurred. At this stage, ischemic damage remains mostly
restricted to cardiomyocyte necrosis; the vascular bed is intact
and microvascular flow and tissue perfusion are mostly pre-
served after the reestablishment of epicardial blood flow.
Cardiomyocyte necrosis occurs in the subendocardium first
and subsequently progresses transmurally with its final extent
being determined by the duration and severity of
ischemia.3-5,32 This concept is substantiated clinically, with
longer time to reperfusion leading to a higher cardiomyocyte
necrosis-related enzyme level increase, reflecting larger MI
size. MI might present with or without ST-elevation on
the ECG33; ST-elevation is a well-established marker of very
high risk, with an indication for immediate reperfusion
therapy.34
CMR with late gadolinium enhancement is a highly accu-
rate method to quantify ischemic myocardial necrosis and
infarct size in vivo in patients35,36 and has validated early pa-
thology findings: MIs always involve the subendocardium, and
evolve toward the epicardium within an area at risk with
increasing duration of ischemia. The longer ischemia persists,
the greater the loss of salvageable myocardium; the size of MI
and transmurality are larger. Progressive loss of salvageable
myocardium is associated with reduced functional recovery,
worse LV systolic function, and progressive increase in mor-
tality and adverse events including ventricular arrhythmia, heart
failure, and hospitalization. Infarct size is a strong predictor of
adverse outcome, independent of and stronger than LV
dysfunction alone (Fig. 5).4-6,37 The tissue damage at this stage
will frequently lead to regional wall motion abnormality
detectable on echocardiography. Revascularization therapy will
result in restoration of normal coronary flow (TIMI 3 flow).
The incidence of CCS stage 2 MI is yet to be assessed in
contrast to CCS stages 1, 3, and 4. Because CCS stage 1
(aborted MI) occurs at a rate of approximately 10% and MI
with reperfusion injury (stages 3 and 4) occurs at a rate of
approximately 40%-60%, then CCS stage 2 will likely
represent 30%-50% of patients with acute MI (Fig. 5).
CCS stage 3 MI: Cardiomyocyte necrosis combined with
MVO
At CCS stage 3, the ischemic injury extends beyond car-
diomyocyte injury to now involve the myocardial microvas-
culature resulting in MVO. MVO was first described in the
heart by Kloner et al.,8 followed by others.9,11 Ischemic
Kumar et al.
CCS Classification of Acute Myocardial Infarction
Figure 2. The Canadian Cardiovascular Society (CCS) classification of acute atherothrombotic myocardial infarction: representation of tissue injury
at CCS stages 1-4 in a left ventricular short axis schematic.
microvascular injury leads to endothelial swelling, compres-
sion of capillaries by tissue edema, and upregulation of
endothelial cell adhesion molecules and subsequent luminal
obstruction with erythrocytes, white blood cells, and activated
platelets, driven by inflammatory mediators.38 Distal coronary
artery blood flow is obstructed, leading to the clinical obser-
vation of “no reflow” on coronary angiography when the
affected area is large enough. Epicardial coronary thrombus
embolization can also contribute to MVO (Figs. 1-3).39,40
Only rarely can isolated erythrocytes be observed with
MVO in the extravascular space on histology, if any at all.
This is distinct from hemorrhagic MI (stage 4), where hem-
orrhage becomes the predominant tissue component.
The clinical importance of MVO was first established
when semiquantitative epicardial coronary flow assessment
studies showed a marked increase in adverse outcome events
in patients with reduced flow in acute reperfused MI. When
5
TIMI flow or TIMI frame count remained reduced, despite
successful treatment of the culprit lesion, an increase in
mortality was observed, with mortality increase correlating
with decreasing TIMI frame count.41-43 Subsequently, studies
using myocardial contrast echocardiography44-47 and CMR
confirmed MVO as an independent predictor of adverse
ventricular remodeling and a key independent predictor of
major adverse cardiovascular events beyond infarct size
alone.48
Myocardial contrast echocardiography and CMR are used
to assess perfusion at the tissue level (as opposed to coronary
angiography methods, which rely on epicardial coronary artery
flow), and have been shown to be more sensitive than coro-
nary angiography in detecting reduced tissue perfu-
sion.45,47,49,50 They might identify patients with reduced
tissue perfusion despite normal epicardial coronary flow.
Contrast echocardiography perfusion studies have also shown
6 Canadian Journal of Cardiology
Volume - 2023

Figure 3. The Canadian Cardiovascular Society (CCS) classification of acute atherothrombotic myocardial infarction: representation of defining
pathological tissue changes that occur in the 4 progressive stages of ischemia and reperfusion injury in acute myocardial infarction.

predictive power for adverse ventricular remodeling, reduced
functional recovery, and adverse cardiovascular
events.45,47,49-52
On CMR, MVO is detected with contrast enhanced tech-
niques, using gadolinium enhancement-based approaches.53
MVO detected using CMR has been shown to predict mor-
tality, adverse cardiac events, and adverse ventricular remodel-
ing. The major cardiac event rate is increased two- to sixfold at
long-term follow-up and is independent of infarct size and
ventricular systolic function when MVO is present
(Fig. 5).54-59 There is further loss of salvageable myocardium at
CCS stage 3 compared with the previous CCS stage 2.4 The
incidence of MVO in acute reperfused MI depends on the
patient population studied and the method used to assess it, but
can be higher than 50% of all reperfused MIs (Fig. 5).40 As a
limitation, in many studies on MVO myocardial hemorrhage
was not concomitantly assessed, which might be confounding
in the assessment of patient prognosis.
CCS stage 4 acute MI: Cardiomyocyte necrosis, MVO,
and reperfusion hemorrhage
CCS stage 4 MI is the most severe form of ischemic and
reperfusion injury across the 4 stages. Very severe, sustained
Kumar et al. 7
CCS Classification of Acute Myocardial Infarction

Figure 4. Overview of typical clinical findings at each stage of the Canadian Cardiovascular Society (CCS) classification of acute atherothrombotic
myocardial infarction (MI). Typical changes are shown; precise diagnostic criteria will require further research and expert consensus. The stages
build on each other, reflecting progression of severity of tissue injury. Timely reperfusion can halt tissue injury at an earlier stage and prevent
progression to a more severe stage of injury. Hemorrhagic infarction is the worst stage, can cause infarct expansion, and is associated with
mechanical complications. Wall motion abnormalities and electrocardiogram (ECG) changes also depend on the size of the affected myocardium.
LV, left ventricle; MRI, magnetic resonance imaging; MVO, microvascular obstruction; STEMI, ST-elevation myocardial infarction; TIMI, Thrombolysis
In Myocardial Infarction.

ischemia affects the cardiac microvasculature well beyond
MVO (CCS stage 3): histological studies have revealed
anatomical capillary integrity is compromised at this stage,
and reperfusion will lead to capillary rupture and intra-
myocardial hemorrhage. The presence of intramyocardial
hemorrhage is the hallmark injury of CCS stage 4 MI (Figs. 1-
4). Hemorrhagic MI has been strongly associated with me-
chanical complications including myocardial rupture.13 Since
the first observations of myocardial hemorrhage in experi-
mental models and patient autopsy studies,9-11 CMR tech-
niques have been validated and established as an accurate
method for diagnosing and quantifying hemorrhage in living
patients.60,61
Hemorrhage leads to an additional injury by blood
extravasation into the necrotic tissue (Fig. 3).62 In patients
and in experimental animal models, hemorrhage-driven
infarct expansion has been observed, leading up to a
doubling of infarct size after reperfusion.9,63 Hemorrhage
culminates in the deposition of ferric iron crystals within MI
tissue, triggering a sustained pro-inflammatory response not
observed in nonhemorrhagic infarction,64 contributing to
adverse remodeling and a unique inflammatory pathway to-
ward heart failure.65,66 Hemorrhage has been proposed as a
mechanism for generation of ventricular arrhythmia.67,68
Hemorrhagic infarction leads to fatty degeneration of car-
diac tissue driven by macrophage activation, lipid peroxida-
tion, foam cell formation, and ceroid production, which is not
observed in nonhemorrhagic MIs.69 Fatty metaplasia of
infarct scar has been identified as a driver of increased ven-
tricular arrhythmia risk.70
Although higher troponin levels and incomplete resolution
of ST elevation have been reported in hemorrhagic MI, T2*
CMR is the standard diagnostic strategy for accurately
detecting myocardial hemorrhage patients with acute MI.
Currently, there are no biochemical-, echocardiographic-, or
coronary angiography-based methods that exist to detect
8 Canadian Journal of Cardiology
Volume - 2023

Figure 5. Typical reported incidence and incremental adverse prognosis associated with the 4 stages of the Canadian Cardiovascular Society (CCS)
classification of acute atherothrombotic myocardial infarction (MI). The numbers presented for incidence and increased adverse event risk are
estimates on the basis of published research data. Although there is general consensus on the basis of published data that the major adverse
event rate (MACE) increases with each stage, the precise numbers in the literature vary depending on the patient population studied, the exact
diagnostic criteria applied, and the method of investigation used in those studies. This explains the ranges of incidence shown in the illustration.
Furthermore, in many research studies on microvascular obstruction (MVO), myocardial hemorrhage (H), which occurs in a subset of patients with
MVO, was not concomitantly assessed. Studies that differentiated MVO without and with hemorrhage have shown an added risk of adverse events
associated with hemorrhage, independent of MVO.48,73,74,76,77

hemorrhage in the clinical setting.60 Most CMR patient
studies showed an incidence of hemorrhage between 25% and
40%; a large meta-analysis reported an incidence of 39%
(Fig. 5).71-74 Hemorrhagic MI is associated with marked
infarct expansion resulting in additional loss of salvageable
myocardium. Larger infarct size relative to the myocardium at
risk is associated with impaired LV systolic function after
reperfusion therapy.63 Hemorrhagic MI has been identified as
a key predictor of adverse cardiovascular events, with some
studies reporting more than a doubling of cardiovascular event
rates with hemorrhagic MI compared with nonhemorrhagic
MI (Figs. 4 and 5).73-77
In autopsy studies of patients with fatal mechanical com-
plications such as myocardial rupture, hemorrhage has been
observed in as many as 80% of cases. Hemorrhagic MI is thus
considered a predisposing factor for mechanical complications
and might also result in intramural dissecting hematoma.13,78
Discussion
Wavefronts of ischemia and reperfusion injury
The expert consensus leading to the CCS classification of
acute atherothrombotic myocardial infarction presented
Kumar et al. 9
CCS Classification of Acute Myocardial Infarction

Figure 6. Factors associated with infarct injury progression. Duration of ischemia and delay of reperfusion are identified as factors associated with
injury progression in patients with acute atherothrombotic myocardial infarction (MI). Edema occurs within minutes, followed by cardiomyocyte
necrosis, which will start after approximately 1 hour after onset of no-flow ischemia (2-4 hours if troponin level increase is used as a marker).
Experimental studies showed onset of microvascular obstruction (MVO) in animal models after 4 hours of ischemia8; in patient studies, MVO
(Canadian Cardiovascular Society [CCS] stage 3) and hemorrhagic infarction (CCS stage 4) are associated with longer duration of ischemia before
reperfusion, usually several hours, and consistently longer than MI without microvascular reperfusion injury (CCS stage 1, CCS stage 2). Other risk
factors for injury progression are listed in the illustration and include larger area at risk and lack of collaterals. Several factors were identified in
limited-size observational studies; further research will be required to deepen our understanding of factors that lead to infarction progression.74-76
ECG, electrocardiogram; LAD, left anterior descending artery; MC, mechanical complication; TIMI, Thrombolysis In Myocardial Infarction.

herein is the first to define stages of MI on the basis of un-
derlying tissue pathology (Figs. 1-5). These 4 stages of tissue
injury are not independent; they build on each other and
reflect the progressive and sequential damage that occurs
within the myocardium in acute ischemia and reperfusion
injury due to epicardial coronary atherothrombosis (Fig. 6).
Advanced imaging techniques that have evolved over the
past few decades have repeatedly shown the validity of the
wavefront hypothesis of ischemic cardiomyocyte death of
Reimer and Jennings,3 which can now be considered an
evidence-based paradigm. The occurrence of reperfusion
injury in the subendocardium first, then extending toward the
epicardium with progressive injury severity, allows for MVO
and hemorrhage to be regarded as additional wavefronts of
reperfusion injury. The classification presented herein cap-
tures fundamental pathophysiology in an easily applicable
schematic for clinical care and research. Timely reperfusion
therapy can halt injury at an early stage and prevent pro-
gression to the next worse stage.
Implications for clinical care and research
We envision this classification to be an important frame-
work for the advancement of clinical care and research. An
overview of how the classification can be used for clinical
translation is provided in Table 1. This classification scheme
allows for a simplified understanding of pathophysiology.
Clinical translation could help with risk stratification of
patients; the risk of cardiovascular complications increases
with each stage, from comparatively low risk at CCS stage 1
(aborted MI) to highest risk of adverse events at stage 4,
including risk for infarct expansion and mechanical compli-
cations (Figs. 5 and 6). Applying the classification we have put
forth herein can improve clinical care by differentiating high-
risk and lower-risk patients. Advancing our understanding of
injury stage progression could lay the groundwork for devel-
opment of much needed cardioprotective therapies.
There is an enormous body of research on ventricular
remodeling, heart failure, and arrhythmia after acute MI.
Most studies take into account underlying clinical patient
characteristics (such as STEMI vs NSTEMI, LV ejection
fraction), but fail to take into account the underlying tissue
changes associated with MI. Compelling data support that
ventricular remodeling and risk of arrhythmia strongly depend
on the underlying tissue composition. The CCS classification
presented herein has the potential to enable the assessment of
heart failure and arrhythmia risk in context of stages of
severity of tissue injury. This could lead to a more refined
understanding of pathophysiology, arrhythmia, and heart
failure risk after MI and might profoundly affect patient
management in the future.
The new classification might enable research and develop-
ment of more differentiated, tissue injury stage-specific thera-
pies; it seems plausible to assume that optimal medical therapies
for acute MI will evolve to be different for each stage, because
the underlying tissue injury is very different with each stage.
10
Table 1. Clinical application of the CCS classification of acute atherothrombotic MI
Infarction stage
CCS stage 1
CCS stage 1(þ)
CCS stage 2
CCS stage 2(þ)
CCS stage 3
CCS stage 3(þ)
CCS stage 4
MC
The table shows the diagnostic criteria to facilitate clinical application of the CCS infarction stages.
CCS, Canadian Cardiovascular Society; CMR, cardiac magnetic resonance imaging; ECG, electrocardiogram; MI, myocardial infarction; PCI, percutaneous
coronary intervention.
Future clinical trials might therefore benefit from applying the
CCS classification of acute MI for subgroup analyses.
Myocardial ischemia and reperfusion injury are progressive;
cardioprotective therapeutic interventions might target halting
tissue injury progression to the next worse stage. The classi-
fication presented herein provides a metric to capture and
document the extent of tissue injury in clinical trials. The
CCS stages of acute MI could be applied as outcome measures
and end points for research in patients with acute MI.
Incorporating tissue injury end points into clinical research
might help identify therapeutic opportunities that might
otherwise go undiscovered, if only traditional clinical end
points and outcome measures are used. The CCS stages of
acute MI might serve as therapeutic targets in this context.
The classification stages could also be applied as quality
outcome measures to assess the effectiveness of health care
systems, beyond traditional measures like door-to-balloon
time.
Table 2. Potential implications of CCS classification of acute atherothrombotic myocardial infarction
Areas of focus
Clinical care
Clinical trials
Basic and translational research
Health systems research
CCS, Canadian Cardiovascular Society; MI, myocardial infarction.
Canadian Journal of Cardiology
Volume - 2023
Clinical diagnostic criteria
Aborted MI:  50% ST-segment resolution of the initial ST-segment elevation
on the presenting ECG at either 90 minutes post fibrinolysis or 30 minutes
post PCI in pharmacoinvasive and primary PCI patients, respectively. In
addition, a lack of enzyme biomarker increase of cardiac troponin I/T levels
 5 times the upper limit of normal on at least 2 measurements within
24 hours of reperfusion. Reperfusion ECGs should show no evidence of
significant new Q-wave development. Normal reperfusion flow on angiogram.
No microvascular obstruction on contrast perfusion echocardiogram and CMR
Apparent aborted MI according to all clinically available diagnostic tests, but
complete assessment with all diagnostic methods not performed, therefore
worse stage cannot be excluded
“Classic” MI. Infarction progressed with significant cardiomyocyte necrosis,
exceeding criteria for aborted MI. No evidence for no-reflow on angiogram, no
microvascular obstruction on contrast echocardiography or CMR
Apparent stage 2 MI according to all clinically available diagnostic tests, but
complete assessment for reperfusion injury was not performed and thus injury
more severe than stage 2 cannot be excluded
MI with microvascular obstruction ascertained according to no-reflow on
angiogram or perfusion deficit on contrast perfusion echocardiogram or
microvascular obstruction on CMR. No hemorrhage detected on CMR
Apparent stage 3 MI according to all clinically available diagnostic tests, but
hemorrhagic infarction cannot be excluded (CMR assessment for hemorrhage
nondiagnostic or not performed)
Hemorrhagic MI, ascertained according to CMR (presently there are no other
diagnostic tests for hemorrhagic MI)
“MC” to be added for presence of mechanical complication (ventricular septal
defect, free wall rupture, papillary muscle rupture): for example, “CCS stage 4
MC”
In a patient who presents with acute MI, the ultimate goal
would be to limit tissue injury to stage 1, where the patient
remains at low risk and the injury is minimal and mostly or
completely reversible.
In brief, future personalized therapies and research in acute
MI should take the type and severity of tissue injury into
account; the CCS classification of acute MI presented herein
is a tool to facilitate that (Table 2).
Although this new classification is formed on the basis of a
strong body of evidence, challenges remain for its clinical
translation. The classification relies on the comprehensive use
of extensive patient data, including ECG, blood work, angi-
ography, and advanced imaging data (Fig. 4, Table 1). Not all
patients, however, will receive this complete and compre-
hensive workup. For example, currently, most patients with
acute MI will not undergo a CMR study. For those patients,
the writing group suggests determining the infarction stage
using the best available information (Fig. 4, Table 1). If MVO
Potential implications
CCS stages of acute MI as a risk stratification tool on the basis of tissue injury in
acute MI patients
CCS stages of acute MI as endpoints/outcome measures, refined assessment of MI
beyond commonly used traditional clinical markers
CCS stages of acute MI to be used as tissue-specific therapeutic targets for
cardioprotective therapy
CCS stage of acute MI could be used as metric to monitor effectiveness of care
delivery at a health systems level
Kumar et al.
CCS Classification of Acute Myocardial Infarction
and hemorrhage cannot be excluded (for example because a
contrast echocardiogram or CMR were not performed), then
we suggest that the best evidenced stage be quoted for patient
care, with addition of “(þ)” indicating that a worse degree of
injury might be possible but was not ascertained; such a pa-
tient could be labelled for example as “CCS stage 2(þ).” We
also recommend for documentation that “MC” be added to
the stage when a mechanical complication occurs. Not all
diagnostic tests will concur on a given stage, hence the infarct
stage should be defined according to the worst documented
injury marker. For example, if coronary artery flow is normal
post angioplasty in an acute MI patient (TIMI 3 flow), but
CMR shows MVO and absence of hemorrhage, then the
patient should be labelled “CCS stage 3,” accounting for
MVO. In principle, the available evidence of worst tissue
injury should determine the stage of MI. The clinical appli-
cation of the MI stages is presented in Table 2.
Reperfusion injury in patients with acute MI is progressive
in the first hours and few days post reperfusion. The infarct
size at the moment of presentation will almost universally be
smaller than what will be observed later at the moment of
reperfusion, because ischemic injury will have progressed
following the wavefront phenomenon; an additional injury
caused by hemorrhagic conversion might lead to a further
increase in infarct size post reperfusion within 24-72 hours.63
Infarct size is thus dynamic in the acute phase. For clinical and
research purposes, the best time to determine infarct stage
might be in the subacute phase, 3-7 days post presentation.37
The boundaries between CCS infarct stages as defined are
not sharp and will require further clarification through future
research and expert consensus. For example, the troponin
cutoff between CCS stages 1 and 2 needs to be better defined
and might depend on the troponin assay used. ECG changes
for stage 3 vs stage 4 are also ill defined and need further
investigation. Future research might lead to further refinements
of the classification to empower patient care and research.
The classification encompasses MI from epicardial coro-
nary disease (atherothrombosis), which includes STEMI and
type 1 NSTEMI according to the universal definition of MI.1
It remains to be determined, to what extent the principles
of pathophysiology captured in this classification might apply
to other types of MI, such as those due to spontaneous cor-
onary artery dissection, coronary embolism, and supply/de-
mand mismatch (for example noncardiogenic shock).1 The
CCS classification is mostly on the basis of data derived from
MI treated with reperfusion therapy, and its application to
primarily nonreperfused MI remains to be investigated. The
current classification has been developed using data at discrete
time points. The evolution of post MI remodeling remains a
continuous process. Further research, with more intensive
clinical characterization along with imaging or biomarker-
based assessments might yield greater insight into the evolu-
tion of acute and subacute phases of tissue injury and facilitate
further refinements of the proposed classification.
Outlook
The CCS classification of acute MI developed by expert
consensus captures the pathophysiology of myocardial
ischemia and reperfusion injury in a clinically applicable 4-
stage schematic.
11
Although it is premature to apply the classification
immediately to guide clinical treatment at this time, this
proposed classification might help to incorporate stages of
tissue injury into clinical care for future patient risk assess-
ment, management, and documentation.
The classification provides outcome measures and end
points for MI research at the clinical and health systems level.
It provides the fundamental framework for the development
of future therapies.
Not all MIs are the same, and the best possible treatment
might not be “one size fits all.” The best possible individu-
alized treatment needs to take into account the underlying
tissue pathology. The CCS classification of acute MI as out-
lined could be instrumental in facilitating the development of
such treatments and ultimately help with the delivery of
personalized, differentiated, tissue injury-directed care in the
future. It can facilitate research in acute MI by providing the
stages of MI as useful outcome measures, clinical study end
points, and therapeutic targets.
Ethics Statement
This is an expert consensus document, not an original
research report. Ethics guidelines of the authors’ affiliated
institutions were respected.
Patient Consent
The authors confirm that patient consent is not applicable
to this article; patient data are not presented in this report.
Funding Sources
Dr Kumar is in part supported by a research grant from the
Northern Ontario Academic Medicine Association, grant C-
22-8. Dr Connelly holds the Keenan Research Chair in
Leadership at Unity Health at St Michael’s Hospital, Uni-
versity of Toronto, Toronto, Ontario, Canada. Dr Dharma-
kumar was funded in part by grants from the United States
National Institutes of Health (HL133407, HL136578, and
HL147133).
Disclosures
Dr Kumar is the President of the Canadian Society of
Cardiovascular Magnetic Resonance Imaging. Dr Dharma-
kumar has an ownership interest in Cardio-Theranostics,
LLC. Dr Leipsic is a consultant and has stock options in
Heartflow and Circle CVI, and is a consultant to Arineta. The
remaining authors have no conflicts of interest to disclose.
References
1. Thygesen K, Alpert JS, Jaffe AS, et al. Fourth universal definition of
myocardial infarction (2018). Circulation 2018;138:e618-51.
2. Reimer KA, Lowe JE, Rasmussen MM, Jennings RB. The wavefront
phenomenon of ischemic cell death. 1. Myocardial infarct size vs duration
of coronary occlusion in dogs. Circulation 1977;56:786-94.
3. Reimer KA, Jennings RB. The “wavefront phenomenon” of myocardial
ischemic cell death. II. Transmural progression of necrosis within the
12
framework of ischemic bed size (myocardium at risk) and collateral flow.
Lab Invest 1979;40:633-44.
4. Eitel I, Desch S, Fuernau G, et al. Prognostic significance and de-
terminants of myocardial salvage assessed by cardiovascular magnetic
resonance in acute reperfused myocardial infarction. J Am Coll Cardiol
2010;55:2470-9.
5. Larose E, Rodes-Cabau J, Pibarot P, et al. Predicting late myocardial
recovery and outcomes in the early hours of ST-segment elevation
myocardial infarction traditional measures compared with microvascular
obstruction, salvaged myocardium, and necrosis characteristics by car-
diovascular magnetic resonance. J Am Coll Cardiol 2010;55:2459-69.
6. Milavetz JJ, Giebel DW, Christian TF, Schwartz RS, Holmes DR,
Gibbons RJ. Time to therapy and salvage in myocardial infarction. J Am
Coll Cardiol 1998;31:1246-51.
7. Willerson JT, Scales F, Mukherjee A, et al. Abnormal myocardial fluid
retention as an early manifestation of ischemic injury. Am J Pathol
1977;87:159-88.
8. Kloner RA, Ganote CE, Jennings RB. The “no-reflow” phenomenon
after temporary coronary occlusion in the dog. J Clin Invest 1974;54:
1496-508.
9. Bresnahan GF, Roberts R, Shell WE, Ross J Jr, Sobel BE. Deleterious
effects due to hemorrhage after myocardial reperfusion. Am J Cardiol
1974;33:82-6.
10. Lie JT, Lawrie GM, Morris GC Jr, Winters WL. Hemorrhagic
myocardial infarction associated with aortocoronary bypass revasculari-
zation. Am Heart J 1978;96:295-302.
11. Fishbein MC, Y-Rit J, Lando U, Kanmatsuse K, Mercier JC, Ganz W.
The relationship of vascular injury and myocardial hemorrhage to ne-
crosis after reperfusion. Circulation 1980;62:1274-9.
12. Reindl M, Eitel I, Reinstadler SJ. Role of cardiac magnetic resonance to
improve risk prediction following acute ST-elevation myocardial infarc-
tion. J Clin Med 2020;9:1041.
13. Honda S, Asaumi Y, Yamane T, et al. Trends in the clinical and path-
ological characteristics of cardiac rupture in patients with acute
myocardial infarction over 35 years. J Am Heart Assoc 2014;3:e000984.
14. Verheugt FW, Gersh BJ, Armstrong PW. Aborted myocardial infarction:
a new target for reperfusion therapy. Eur Heart J 2006;27:901-4.
15. Dianati Maleki N, Van de Werf F, Goldstein P, et al. Aborted myocardial
infarction in ST-elevation myocardial infarction: insights from the
STrategic Reperfusion Early After Myocardial infarction trial. Heart
2014;100:1543-9.
16. Jackson L, Kendall J, Castle N. Does prehospital thrombolysis increase
the proportion of patients who have an aborted myocardial infarction?
Emerg Med J 2009;26:206-9.
17. Vasile VC, Babuin L, Ting HH, et al. Aborted myocardial infarction: is it
real in the troponin era? Am Heart J 2009;157:636-41.
18. Armstrong PW, Gershlick AH, Goldstein P, et al. Fibrinolysis or primary
PCI in ST-segment elevation myocardial infarction. N Engl J Med
2013;368:1379-87.
19. Boersma E, Maas AC, Deckers JW, Simoons ML. Early thrombolytic
treatment in acute myocardial infarction: reappraisal of the golden hour.
Lancet 1996;348:771-5.
20. Antman EM, Cooper HA, Gibson CM, et al. Determinants of
improvement in epicardial flow and myocardial perfusion for ST eleva-
tion myocardial infarction; insights from TIMI 14 and InTIME-II. Eur
Heart J 2002;23:928-33.
Canadian Journal of Cardiology
Volume - 2023
21. Bainey KR, Ferguson C, Ibrahim QI, Tyrrell B, Welsh RC. Vital Heart
Response Registry Investigators. Impact of reperfusion strategy on
aborted myocardial infarction: insights from a large Canadian ST-
elevation myocardial infarction clinical registry. Can J Cardiol 2014;30:
1570-5.
22. Fu Y, Goodman S, Chang WC, Van De Werf F, Granger CB,
Armstrong PW. Time to treatment influences the impact of ST-segment
resolution on one-year prognosis: insights from the assessment of the
safety and efficacy of a new thrombolytic (ASSENT-2) trial. Circulation
2001;104:2653-9.
23. Lamfers EJ, Hooghoudt TE, Hertzberger DP, Schut A, Stolwijk PW,
Verheugt FW. Abortion of acute ST segment elevation myocardial
infarction after reperfusion: incidence, patients’ characteristics, and
prognosis. Heart 2003;89:496-501.
24. Lamfers EJ, Hooghoudt TE, Uppelschoten A, Stolwijk PW,
Verheugt FW. Effect of prehospital thrombolysis on aborting acute
myocardial infarction. Am J Cardiol 1999;84:928-30, A6-7.
25. Taher T, Fu Y, Wagner GS, et al. Aborted myocardial infarction in
patients with ST-segment elevation: insights from the Assessment of the
Safety and Efficacy of a New Thrombolytic Regimen-3 Trial Electro-
cardiographic Substudy. J Am Coll Cardiol 2004;44:38-43.
26. Eitel I, Desch S, Sareban M, et al. Prognostic significance and magnetic
resonance imaging findings in aborted myocardial infarction after primary
angioplasty. Am Heart J 2009;158:806-13.
27. Lee KH, Choi SI, Chun EJ, et al. Aborted myocardial infarction: eval-
uation of changes in area at risk, late gadolinium enhancement, and
perfusion over time and comparison with overt myocardial infarction.
AJR Am J Roentgenol 2012;199:328-35.
28. Patel MR, Westerhout CM, Granger CB, et al. Aborted myocardial
infarction after primary percutaneous coronary intervention: magnetic
resonance imaging insights from the Assessment of Pexelizumab in Acute
Myocardial Infarction (APEX-AMI) trial. Am Heart J 2013;165:226-33.
29. Abdel-Aty H, Cocker M, Meek C, Tyberg JV, Friedrich MG. Edema as a
very early marker for acute myocardial ischemia: a cardiovascular mag-
netic resonance study. J Am Coll Cardiol 2009;53:1194-201.
30. Ugander M, Bagi PS, Oki AJ, et al. Myocardial edema as detected by pre-
contrast T1 and T2 CMR delineates area at risk associated with acute
myocardial infarction. JACC Cardiovasc Imaging 2012;5:596-603.
31. Birkemeyer R, Rillig A, Treusch F, et al. Abortion of myocardial
infarction by primary angioplasty mainly depends on preprocedural
TIMI flow. EuroIntervention 2011;6:854-9.
32. Stiermaier T, Eitel I, de Waha S, et al. Myocardial salvage after primary
percutaneous coronary intervention in patients with ST-elevation
myocardial infarction presenting early versus late after symptom onset.
Int J Cardiovasc Imaging 2017;33:1571-9.
33. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC
guideline for the management of patients with non-ST-elevation acute
coronary syndromes: a report of the American College of Cardiology/
American Heart Association Task Force on Practice Guidelines. J Am
Coll Cardiol 2014;64:e139-228.
34. O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA
guideline for the management of ST-elevation myocardial infarction: a
report of the American College of Cardiology Foundation/American
Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol
2013;61:e78-140.
35. Simonetti OP, Kim RJ, Fieno DS, et al. An improved MR imaging
technique for the visualization of myocardial infarction. Radiology
2001;218:215-23.
Kumar et al.
CCS Classification of Acute Myocardial Infarction
36. Kim RJ, Fieno DS, Parrish TB, et al. Relationship of MRI delayed
contrast enhancement to irreversible injury, infarct age, and contractile
function. Circulation 1999;100:1992-2002.
37. Ibanez B, Aletras AH, Arai AE, et al. Cardiac MRI endpoints in
myocardial infarction experimental and clinical trials: JACC scientific
expert panel. J Am Coll Cardiol 2019;74:238-56.
38. Bainey KR, Armstrong PW. Clinical perspectives on reperfusion injury in
acute myocardial infarction. Am Heart J 2014;167:637-45.
39. Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med
2007;357:1121-35.
40. Niccoli G, Scalone G, Lerman A, Crea F. Coronary microvascular
obstruction in acute myocardial infarction. Eur Heart J 2016;37:
1024-33.
41. Gibson CM, Cannon CP, Murphy SA, et al. Relationship of TIMI
myocardial perfusion grade to mortality after administration of throm-
bolytic drugs. Circulation 2000;101:125-30.
42. Gibson CM, Murphy SA, Rizzo MJ, et al. Relationship between TIMI
frame count and clinical outcomes after thrombolytic administration.
Thrombolysis In Myocardial Infarction (TIMI) Study Group. Circula-
tion 1999;99:1945-50.
43. Morishima I, Sone T, Okumura K, et al. Angiographic no-reflow phe-
nomenon as a predictor of adverse long-term outcome in patients treated
with percutaneous transluminal coronary angioplasty for first acute
myocardial infarction. J Am Coll Cardiol 2000;36:1202-9.
44. Swinburn JM, Lahiri A, Senior R. Intravenous myocardial contrast
echocardiography predicts recovery of dysynergic myocardium early after
acute myocardial infarction. J Am Coll Cardiol 2001;38:19-25.
45. Xie F, Qian L, Goldsweig A, Xu D, Porter TR. Event-free survival
following successful percutaneous intervention in acute myocardial
infarction depends on microvascular perfusion. Circ Cardiovasc Imaging
2020;13:e010091.
46. Khumri TM, Nayyar S, Idupulapati M, et al. Usefulness of myocardial
contrast echocardiography in predicting late mortality in patients with
anterior wall acute myocardial infarction. Am J Cardiol 2006;98:1150-5.
47. Galiuto L, Garramone B, Scara A, et al. The extent of microvascular
damage during myocardial contrast echocardiography is superior to other
known indexes of post-infarct reperfusion in predicting left ventricular
remodeling: results of the multicenter AMICI study. J Am Coll Cardiol
2008;51:552-9.
48. Hamirani YS, Wong A, Kramer CM, Salerno M. Effect of microvascular
obstruction and intramyocardial hemorrhage by CMR on LV remodeling
and outcomes after myocardial infarction: a systematic review and meta-
analysis. JACC Cardiovasc Imaging 2014;7:940-52.
49. Ito H, Okamura A, Iwakura K, et al. Myocardial perfusion patterns
related to thrombolysis in myocardial infarction perfusion grades after
coronary angioplasty in patients with acute anterior wall myocardial
infarction. Circulation 1996;93:1993-9.
50. Porter TR, Li S, Oster R, Deligonul U. The clinical implications of no
reflow demonstrated with intravenous perfluorocarbon containing
microbubbles following restoration of Thrombolysis In Myocardial
Infarction (TIMI) 3 flow in patients with acute myocardial infarction.
Am J Cardiol 1998;82:1173-7.
51. Ito H, Tomooka T, Sakai N, et al. Lack of myocardial perfusion
immediately after successful thrombolysis. A predictor of poor recovery of
left ventricular function in anterior myocardial infarction. Circulation
1992;85:1699-705.
13
52. Song JM, Lee JH, Kim YH, et al. Intravenous versus intracoronary
myocardial contrast echocardiography for evaluation of no-reflow after
primary percutaneous coronary intervention. Echocardiography 2005;22:
818-25.
53. Mather AN, Lockie T, Nagel E, et al. Appearance of microvascular
obstruction on high resolution first-pass perfusion, early and late gado-
linium enhancement CMR in patients with acute myocardial infarction.
J Cardiovasc Magn Reson 2009;11:33.
54. Klug G, Mayr A, Schenk S, et al. Prognostic value at 5 years of micro-
vascular obstruction after acute myocardial infarction assessed by car-
diovascular magnetic resonance. J Cardiovasc Magn Reson 2012;14:46.
55. van Kranenburg M, Magro M, Thiele H, et al. Prognostic value of
microvascular obstruction and infarct size, as measured by CMR in
STEMI patients. JACC Cardiovasc Imaging 2014;7:930-9.
56. Regenfus M, Schlundt C, Krahner R, et al. Six-year prognostic value of
microvascular obstruction after reperfused ST-elevation myocardial
infarction as assessed by contrast-enhanced cardiovascular magnetic
resonance. Am J Cardiol 2015;116:1022-7.
57. Symons R, Pontone G, Schwitter J, et al. Long-term incremental prog-
nostic value of cardiovascular magnetic resonance after ST-segment
elevation myocardial infarction: a study of the collaborative registry on
CMR in STEMI. JACC Cardiovasc Imaging 2018;11:813-25.
58. Galea N, Dacquino GM, Ammendola RM, et al. Microvascular
obstruction extent predicts major adverse cardiovascular events in patients
with acute myocardial infarction and preserved ejection fraction. Eur
Radiol 2019;29:2369-77.
59. de Waha S, Patel MR, Granger CB, et al. Relationship between micro-
vascular obstruction and adverse events following primary percutaneous
coronary intervention for ST-segment elevation myocardial infarction: an
individual patient data pooled analysis from seven randomized trials. Eur
Heart J 2017;38:3502-10.
60. Kumar A, Green JD, Sykes JM, et al. Detection and quantification of
myocardial reperfusion hemorrhage using T2*-weighted CMR. JACC
Cardiovasc Imaging 2011;4:1274-83.
61. Basso C, Corbetti F, Silva C, et al. Morphologic validation of reperfused
hemorrhagic myocardial infarction by cardiovascular magnetic resonance.
Am J Cardiol 2007;100:1322-7.
62. Roberts CS, Schoen FJ, Kloner RA. Effect of coronary reperfusion on
myocardial hemorrhage and infarct healing. Am J Cardiol 1983;52:
610-4.
63. Liu T, Howarth AG, Chen Y, et al. Intramyocardial hemorrhage and the
“wave front” of reperfusion injury compromising myocardial salvage.
J Am Coll Cardiol 2022;79:35-48.
64. Kali A, Kumar A, Cokic I, et al. Chronic manifestation of postreperfusion
intramyocardial hemorrhage as regional iron deposition: a cardiovascular
magnetic resonance study with ex vivo validation. Circ Cardiovasc Im-
aging 2013;6:218-28.
65. Kali A, Cokic I, Tang R, et al. Persistent microvascular obstruction after
myocardial infarction culminates in the confluence of ferric iron oxide
crystals, proinflammatory burden, and adverse remodeling. Circ Car-
diovasc Imaging 2016;9:e004996.
66. Ghugre NR, Pop M, Thomas R, et al. Hemorrhage promotes inflam-
mation and myocardial damage following acute myocardial infarction:
insights from a novel preclinical model and cardiovascular magnetic
resonance. J Cardiovasc Magn Reson 2017;19:50.
67. Cokic I, Kali A, Yang HJ, et al. Iron-sensitive cardiac magnetic resonance
imaging for prediction of ventricular arrhythmia risk in patients
with chronic myocardial infarction: early evidence. Circ Cardiovasc
14
Imaging 2015;8:e003642. https://doi.org/10.1161/CIRCIMAGING.
115.003642.
68. Mather AN, Fairbairn TA, Ball SG, Greenwood JP, Plein S. Reperfusion
haemorrhage as determined by cardiovascular MRI is a predictor of
adverse left ventricular remodelling and markers of late arrhythmic risk.
Heart 2011;97:453-9.
69. Cokic I, Chan SF, Guan X, et al. Intramyocardial hemorrhage drives fatty
degeneration of infarcted myocardium. Nat Commun 2022;13:6394.
70. Sung E, Prakosa A, Zhou S, et al. Fat infiltration in the infarcted heart as
a paradigm for ventricular arrhythmias. Nat Cardiovasc Res 2022;1:
933-45.
71. Mather AN, Fairbairn TA, Artis NJ, Greenwood JP, Plein S. Relation-
ship of cardiac biomarkers and reversible and irreversible myocardial
injury following acute myocardial infarction as determined by cardio-
vascular magnetic resonance. Int J Cardiol 2013;166:458-64.
72. Bekkers SC, Smulders MW, Passos VL, et al. Clinical implications of
microvascular obstruction and intramyocardial haemorrhage in acute
myocardial infarction using cardiovascular magnetic resonance imaging.
Eur Radiol 2010;20:2572-8.
73. Eitel I, Kubusch K, Strohm O, et al. Prognostic value and determinants
of a hypointense infarct core in T2-weighted cardiac magnetic resonance
Canadian Journal of Cardiology
Volume - 2023
in acute reperfused ST-elevation-myocardial infarction. Circ Cardiovasc
Imaging 2011;4:354-62.
74. Vyas R, Changal KH, Bhuta S, et al. Impact of intramyocardial hem-
orrhage on clinical outcomes in ST-elevation myocardial infarction: a
systematic review and meta-analysis. J Soc Cardiovasc Angiogr Interv
2022;1:100444.
75. Husser O, Monmeneu JV, Sanchis J, et al. Cardiovascular magnetic
resonance-derived intramyocardial hemorrhage after STEMI: influence
on long-term prognosis, adverse left ventricular remodeling and rela-
tionship with microvascular obstruction. Int J Cardiol 2013;167:
2047-54.
76. Reinstadler SJ, Stiermaier T, Reindl M, et al. Intramyocardial haemor-
rhage and prognosis after ST-elevation myocardial infarction. Eur Heart J
Cardiovasc Imaging 2019;20:138-46.
77. Carrick D, Haig C, Ahmed N, et al. Myocardial hemorrhage after acute
reperfused ST-segment-elevation myocardial infarction: relation to
microvascular obstruction and prognostic significance. Circ Cardiovasc
Imaging 2016;9:e004148.
78. Becker AE, van Mantgem JP. Cardiac tamponade. A study of 50 hearts.
Eur J Cardiol 1975;3:349-58.