PRIMER

­­ T-​segment elevation myocardial

S
infarction
Birgit Vogel1, Bimmer E. Claessen1, Suzanne V. Arnold2,3, Danny Chan4, David J. Cohen2,3,
Evangelos Giannitsis5, C. Michael Gibson6, Shinya Goto7, Hugo A. Katus5, Mathieu Kerneis6,
Takeshi Kimura8, Vijay Kunadian4,9, Duane S. Pinto10, Hiroki Shiomi8, John A. Spertus2,3,
P. Gabriel Steg11,12 and Roxana Mehran1*
Abstract | ST-​segment elevation myocardial infarction (STEMI) is the most acute manifestation
of coronary artery disease and is associated with great morbidity and mortality. A complete
thrombotic occlusion developing from an atherosclerotic plaque in an epicardial coronary vessel
is the cause of STEMI in the majority of cases. Early diagnosis and immediate reperfusion are the
most effective ways to limit myocardial ischaemia and infarct size and thereby reduce the risk of
post-​STEMI complications and heart failure. Primary percutaneous coronary intervention (PCI)
has become the preferred reperfusion strategy in patients with STEMI; if PCI cannot be performed
within 120 minutes of STEMI diagnosis, fibrinolysis therapy should be administered to dissolve
the occluding thrombus. The initiation of networks to provide around-​the-clock cardiac
catheterization availability and the generation of standard operating procedures within hospital
systems have helped to reduce the time to reperfusion therapy. Together with new advances
in antithrombotic therapy and preventive measures, these developments have resulted in a
decrease in mortality from STEMI. However, a substantial amount of patients still experience
recurrent cardiovascular events after STEMI. New insights have been gained regarding the
pathophysiology of STEMI and feed into the development of new treatment strategies.

*e-​mail: Roxana.Mehran@
mountsinai.org
https://doi.org/10.1038/
s41572-019-0090-3
Coronary artery disease (CAD) most of the time refers to
coronary atherosclerotic disease that results in severe coro-
nary artery narrowing, leading to inadequate blood supply
to the heart muscle (myocardium). Acute coronary syn-
dromes (ACSs) comprise the acute manifestations of CAD,
including unstable angina (myocardial ischaemia without
necrosis), non-ST-segment elevation myocardial infarc-
tion (NSTEMI) and ST-segment elevation myo­cardial
infarction (STEMI). Myocardial infarction (MI) is com-
monly defined as cardiomyocyte death caused by substan-
tial and sustained ischaemia due to an imbalance of oxygen
supply and demand. On the basis of the electro­cardiogram
(EKG or ECG) trace, MI is differentiated between STEMI
and NSTEMI. STEMI is the result of transmural ischaemia
(that is, ischaemia that involves the full thickness of the
myocardium) (Fig. 1), whereas NSTEMI does not spread
through all the myocardial wall. With the introduction
of highly sensitive cardiac biomarkers, new definitions of
MI that include biochemical and clinical aspects have
been developed. The fourth universal definition of MI1 is
based on a classification system with five subcategories.
This Primer focuses mostly on type 1 MI, which is caused
by atherothrombotic CAD and usually precipitated by
rupture or erosion of the atherosclerotic plaque.
In most STEMI cases, the transmural myocardial
ischaemia results from a total occlusion of an epicardial
coronary artery caused by a thrombus (a blood clot) that
developed on a coronary atherosclerotic plaque. STEMI
is suspected when a patient presents with chest pain and
persistent ST-​segment elevation in two or more anatom-
ically contiguous ECG leads (Fig. 1). In addition, STEMI
should be suspected if the clinical presentation is com-
patible and the ECG trace shows left bundle branch block
(LBBB) and no ST-​segment elevation, as in some cases
total coronary occlusion manifests as LBBB2. By contrast,
ECG findings of ST-​segment depressions, T wave inver-
sions or transient ST-​segment elevations are suggestive of
non-​ST-segment elevation ACS and may reflect NSTEMI
or unstable angina3.
STEMI is the most acute manifestation of CAD, with
substantial morbidity and mortality. Early reperfusion
(re-establishing the blood flow in the occluded artery)
is the most effective way to preserve the viability of the
ischaemic myocardium and limit infarct size. Early diag-
nosis of STEMI is crucial to initiate appropriate treatment
and should ideally be made within 10 minutes of first
medical contact2. Initiatives have raised awareness on the
importance of minimizing time to reperfusion with early

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Primer

Author addresses study found that acute MI occurred at a signifi­cantly

younger age in individuals living in south Asian
1
The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine countries than in individuals from other countries12.
at Mount Sinai, New York, NY, USA. These results were largely explained by higher prev-
2
Department of Cardiovascular Medicine, Saint Luke’s Mid America Heart Institute,
alence of risk factors at younger ages in south Asia.
Kansas City, MO, USA.
This higher prevalence of risk factors may also be the
3
University of Missouri-​Kansas City, Kansas City, MO, USA.
4
Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, reason for the markedly high prevalence of ischaemic
Newcastle upon Tyne, UK. heart disease in central and eastern European coun-
5
Department of Medicine III, Institute for Cardiomyopathies Heidelberg (ICH), University tries13. Although tobacco smoking (one of these risk
of Heidelberg, Heidelberg, Germany. factors) occurs worldwide and in many countries is
6
Division of Cardiovascular Medicine, Department of Medicine, Beth Israel Deaconess declining, its prevalence seems to be high in eastern
Medical Center, Harvard Medical School, Boston, MA, USA. European and Asian countries and is increasing in the
7
Department of Medicine (Cardiology), Tokai University School of Medicine, Isehara, WHO Eastern Mediterranean Region and the African
Kanagawa, Japan. Region14. Overall, low socioeconomic status is associ-
8
Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University,
ated with higher risk of and an earlier occurrence of
Kyoto, Japan.
acute MI, and similar results were observed in black and
9
Cardiothoracic Centre, Freeman Hospital, Newcastle upon Tyne NHS Foundation Trust,
Newcastle upon Tyne, UK. Hispanic patients compared with white patients within
10
Division of Cardiology, Richard A. and Susan F. Smith Center for Cardiovascular the United States15.
Outcomes Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Regardless of country or ethnicity, STEMI tends
Boston, MA, USA. to occur at a younger age in men than in women owing to
11
FACT, French Alliance for Cardiovascular Trials, Paris, France. the protective effect of oestrogen before menopause16–19.
12
Université Paris-​Diderot, Paris, France. Of note, women presenting with STEMI before the age of
60 have been shown to have worse outcome than their
diagnosis and immediate transfer to a facility with the male counterparts16.
option for cardiac catheterization and subsequent pri-
mary percutaneous coronary intervention (PCI)4. Studies Mortality
on the detection of atherosclerotic plaques at increased Developments in reperfusion therapies and preventive
risk of being associated with a future cardiac event have measures have contributed to a reduction in mortality
resulted in a more-​comprehensive view on the patho- from STEMI20. However, mortality seems to have pla-
physiology of acute MI and support the concept of the teaued, and a substantial amount of patients still expe-
‘vulnerable patient’ rather than the ‘vulnerable plaque’5–7.
rience recurrent cardiovascular events after STEMI21.
New treatment strategies including treatment that tar- Post-​STEMI complications (see below) are decreasing22,
gets inflammation are under investigation and may help a reduction that is probably related to improved systems
to further reduce the risk of recurrent cardiovascular of care and use of guideline-​directed therapy. In a nation-
events. This Primer on STEMI summarizes these new wide Swedish registry of almost 200,000 patients admit-
developments and provides a general overview of epide- ted with STEMI from 1996 to 2008, the incidence of
miology, alternative coronary causes, diagnosis and pre- heart failure decreased from 50% to 28%23. Several large-​
vention of STEMI, as well as post-STEMI complications scale registries suggest an increase in unadjusted mor-
and quality of life. tality after STEMI over time but a decrease in adjusted
mortality. In one report using data from the United
Epidemiology States Nationwide Inpatient Sample, between 2004
Disease burden and risk factors and 2012, in-​hospital mortality increased from 3.9% in
The epidemiology of patients with STEMI continues to 2004 to 4.7% in 2012 (ref.24) (Fig. 2). Data from another
evolve. The Global Registry of Acute Coronary Events analysis showed no changes over time in unadjusted in-​
(GRACE)8 documented that STEMI accounted for ~36% hospital mortality after STEMI in patients treated with
of ACS cases. Similar findings have been reported in a primary PCI (3.40% to 3.52%) or coronary artery bypass
developing country, with STEMI accounting for ~37% graft (CABG) surgery (5.79% to 5.70%)25. However, in-​
of ACS cases enrolled in the Jakarta Acute Coronary hospital mortality increased for patients who did not
Syndrome (JAC) Registry database 9. According to receive PCI or CABG surgery (12.43% to 14.91%)25.
an analysis of a large United States database, the age-​ These findings are probably related to the increased age
adjusted and sex-​adjusted incidence of hospitalizations and prevalence of multiple comorbidities at presenta-
for STEMI significantly decreased from 133 per 100,000 tion, which is becoming more common in patients with
person-years in 1999 to 50 per 100,000 person-years in STEMI. The proportion of patients with three or more
2008 (ref.10). These results reflect the situation in the comorbidities significantly increased (14.8% to 29.0%),
Western world, whereas the prevalence and incidence of as did the proportion of patients who were intubated
cardiovascular disease (CVD) in developing countries are or experienced cardiac arrest on presentation (3.2%
increasing11. Reasons for this increase include expand- to 7.8%)24. After multivariable adjustment for these
ing life expectancy, changing lifestyles and the adoption factors, risk-​adjusted in-​hospital mortality decreased
of a Western diet (which is typically rich in saturated between 2004 and 2012 (ref.24). Other studies have simi-
fats and refined sugars) in these regions. In addition, larly demonstrated that, after multivariable adjustment,
CVD occurs at a younger age in developing countries in-​hospital mortality decreased26. Furthermore, assum-
than in developed ones. For example, a case–control ing similar comorbi­dities, the odds of dying within

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 Primer

1 year after discharge are estimated to be 50% lower
among patients with STEMI in 2005 than they were
in 1997 (ref.22).
Mechanisms/pathophysiology
The predominant underlying mechanism of the total
coronary occlusion in STEMI is thrombosis developing
on a coronary atherosclerotic plaque27. A few exceptions
exist and include spontaneous coronary artery dissec­
tion (Box  1) , coronary spasm (Box  2) and coronary
embolism (Box 3).
Beyond the concept of the vulnerable plaque
A vulnerable plaque can be described as an atheroscle-
rotic lesion that has a high risk of rupture and is charac­
terized by a large lipid-​rich or necrotic core that is
separated from the vessel lumen by a thin fibrous cap
(also called thin-​capped fibroatheroma)28. Disruption
of a so-​called vulnerable plaque has been reported as
the most common cause of acute MI29,30. The underlying
mechanism is based on the atherosclerotic progression
through expansion of the lipid core and accumulation
of macrophages at the edges of the plaque, leading to
plaque rupture31.
It was hypothesized that by detecting these vul-
nerable plaques, preventive measures (such as high-​
intensity statin therapy or PCI) could be implemented
to potentially prevent future cardiovascular events32.
This theory was partly supported by optical coherence
tomography studies that revealed that patients with
STEMI had atherosclerotic plaques with larger thin
fibrous cap surface area, thinner minimum fibrous cap
thickness and a larger macrophage area than plaques
observed in patients with stable angina pectoris (chest
pain due to inadequate blood supply to the heart that
mostly presents during physical exertion and is relieved
by rest or nitroglycerine administration)33. In addi-
tion, thin-​capped fibroatheromas were more frequent

a QRS complex
Ventricular depolarization
(contraction)
aVR aVL
Circumflex
artery
R
P wave T wave
Left anterior Atrial Ventricular
descending depolarization repolarization
artery (relaxation)
Right
coronary I
artery V6
P T
V5
V1 V2 V3 V4

Q S

III II
aVF PR interval QT interval ST segment
AV Ventricular Early
conduction depolarization ventricular
Right coronary artery time and repolarization repolarization
Left anterior descending artery
Left circumflex artery

Normal Seconds Minutes First <24 hours Days Months

to hours hours to weeks to years

Fig. 1 | Healthy and STEMI ECG traces. a | Electrocardiography (ECG) uses sensors attached to the skin (electrodes) to
record the electrical activity of the heart. A 12-lead ECG system includes 3 limb leads (bipolar), 3 augmented limb leads
(unipolar) and 6 precordial leads (unipolar). With regard to the bipolar leads, two electrodes ( + and –) are placed equidistant
from the heart, and electricity flow from the negative to the positive electrode is recorded. In the case of the unipolar leads,
electricity flow from the centre of the heart towards the positive electrode is recorded. The different segments of an ECG
trace indicate electrical events during the cardiac cycle. Each lead generates a certain pattern in the trace, corresponding
to the electrical activity in the area of the myocardium that is captured by the lead. In ST-​segment elevation myocardial
infarction (STEMI), the presence of ST-​segment elevation in certain leads may provide information on the localization of
the myocardial infarction and the culprit vessel (for example, ST-​segment elevation in leads II, III or aVF denotes inferior
infarction, with the right coronary artery as a culprit vessel in ~80% of cases265). b | Specific changes in certain segments
of the ECG trace (indicated by arrows), especially the ST segment, can be documented over time in patients with STEMI.
AV, atrioventricular; aVF, augmented vector foot; aVL , augmented vector left; aVR , augmented vector right.

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 Primer
in patients with STEMI than in patients with stable
angina pectoris34,35. The large prospective PROSPECT
study used virtual histology intravascular ultrasono­
graphy (a type of intravascular ultrasonography that
enables the identification of different plaque compo-
nents, such as fibrous tissue and necrotic lipid core)
to evaluate lesion-​related risk factors associated with
future adverse cardiovascular events5. Recurrent ischae-
mic events were equally attributable to culprit lesions
(that is, the lesions that caused the initial ACS) and
to non-​culprit lesions. Although non-​culprit lesions
responsible for a recurrent ischaemic event were fre-
quently angiographically mild at baseline (mean ± s.d.
diameter stenosis 32.3 ± 20.6%), most of them were
thin-​capped fibroatheromas characterized by a large
plaque burden, a small luminal area or both. Although
these findings are consistent with the concept of the
vulnerable plaque, the overall risk of MI associated with
thin-​capped fibroatheroma was low (Kaplan–Meier
event rate 4.9% over a median 3.4 years follow-​up time).
In addition, previous studies have suggested that many
plaques rupture without any clinical symptoms36, and
plaque morphology can change over time, which can
result in gain or loss of high-​risk features37. These find-
ings suggest that the mechanisms leading to acute MI
are more complex than previously assumed and are not
only based on the presence or absence of plaques with
high-​risk characteristics.
Several investigations support the theory of sys-
temic mechanisms that contribute to the occurrence of
an ischaemic event, and the concept of the vulnerable
patient rather than the vulnerable plaque seems appro-
priate to evaluate for the risk of MI6,7. CAD might be
considered a systemic and dynamic process with hardly
any possibility to predict which plaque could be respon-
sible for a future cardiovascular event. Consistent with
this hypothesis, studies suggested that inflammation as
a systemic process plays a major part in atherogenesis,
plaque evolution and plaque rupture (Fig. 3).
Superficial plaque erosion is another pathological
process that can lead to ACS that is receiving increasing
1.5
1.4
In-hospital mortality OR (95% CI)
1.3
1.2
1.1
1.0
0.9
0.8
0.7
0.6 Adjusted
Unadjusted
0.5
0 of the troponin subunits (troponin I, T and C) exist.
2004 2005 2006 2007 2008 2009 2010 2011 2012
Year
Fig. 2 | Trends in MI in-​hospital mortality. The overall estimated risk of in-​hospital
mortality after myocardial infarction (MI) has increased between 2004 and 2012.
However, after multivariable adjustment that accounted for the increasing trend in
intubation or cardiac arrest at ≤24 hours, risk-​adjusted in-​hospital mortality decreased.
Error bars show 95% confidence intervals. Adapted with permission from ref.24, Elsevier.
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attention38. The pathological picture of superficial ero-
sion differs substantially from the one of the thin-​capped
fibroatheroma. It seems that endothelial cells at the
plaque–thrombus interface are generally absent, lead-
ing to the term plaque erosion39. Although the plaque
morphology is not consistent with the vulnerable plaque,
simultaneous processes of endothelial cell loss, neutro-
phil recruitment and thrombosis may have a central
role39. Although data suggest that superficial plaque
erosion accounts for approximately one-​third of cases
of ACS, this mechanism is probably most frequently
associated with NSTEMI, whereas plaque rupture is
most probably associated with STEMI38. The reason for
a gain in incidence of superficial erosion and the shift in
occurrence from STEMI to NSTEMI may be associated
with the wide use of lipid-​lowering and other preven-
tive therapies. For example, in addition to low-​density
lipoprotein (LDL)-lowering properties, statins also have
anti-​inflammatory effects that potentially contribute to
plaque stabilization.
MI from total coronary occlusion
After plaque rupture, thrombogenic material residing
within the plaque is exposed to the blood and circula­
ting coagulation factors, resulting in the formation of a
thrombus on the ruptured plaque (Fig. 3). If the throm-
bus completely occludes the coronary vessel, the aero-
bic metabolism in the affected myocardium is halted,
resulting in rapid ATP depletion as well as accumula-
tion of metabolites such as lactate40. These metabolic
effects in turn lead to electrolyte changes including a
K+ shift to the extracellular space and a reduction in
the action potential duration and amplitude41. Within
seconds, these processes lead to a reduced contractil-
ity of the myocardium42. Although these effects are
completely reversible if blood flow is restored rapidly,
animal models have shown that a 20–30-minute time
interval of sustained ischaemia is sufficient to cause
irreversible damage to cardiomyocytes42–44. Necrosis
occurs first in the endocardium, which is most dis-
tal to the blood supply, before it progresses into the
subepicardial layers43.
Myocardial cell death leads to the release of creati-
nine kinase (CK) into plasma. CK exists as different
isoenzymes, of which CK-​MB has its greatest activity in
the heart muscle. Thus, elevation of CK can occur with
damage of tissues other than myocardium, especially
skeletal muscle, whereas CK-​MB is more specific for
myocardial necrosis; levels of both markers are assessed
in patients with STEMI to confirm diagnosis. In addi-
tion, the pathological degeneration of the actin and
myosin filaments of the heart muscle results in troponin
release. Both skeletal and cardiac muscle contract via a
troponin-​dependent mechanism, and different isoforms
In contrast to troponin C, troponin I and troponin T
have distinct cardiac and skeletal isoforms45, and, there-
fore, cardiac troponin I (cTnI; also known as TNNI3)
and cardiac troponin T (cTnT; also known as TnTc) are
specific for myocardial injury and can be used as bio-
markers for early diagnosis of MI (see below) and for
evaluation of prognosis.

Box 1 | Alternative causes of STEMI: SCAD
Spontaneous coronary artery dissection (SCAD) is defined as a nontraumatic and
noniatrogenic tear within the layers of the coronary vessel wall, with intramural
haemorrhage that creates a false lumen248. This dissection can be caused by either an
intimal tear, resulting in blood from the lumen of the vessel entering the intimal space,
or a rupture of the vasa vasorum (small arterioles that provide blood supply to the vessel
wall). Both mechanisms eventually lead to the formation of an intramural haematoma
that compresses the lumen of the vessel. A multifactorial pathogenesis of SCAD has
been suggested, with associated factors including underlying arteriopathies248
(for example, fibromuscular dysplasia), genetic factors, hormonal influences and
systemic inflammatory diseases. Hormonal changes are thought to influence the
architecture of the vessel wall by altering elastic fibres and impairing collagen synthesis
and mucopolysaccharide content249. Although SCAD is rare, its prevalence in women of
<50 years of age with an acute coronary syndrome was reported to be ~10%250.
Furthermore, it is the most common cause of acute myocardial infarction in women
who are pregnant or postpartum251. It has been reported that ~50% of patients with
SCAD present with ST-​segment elevation myocardial infarction (STEMI)251. However,
the true prevalence of SCAD is still uncertain, and large prospective investigations are
needed to better understand the natural history of this disease.
Infarct size, reperfusion injury and remodelling
The infarct size depends on several factors, including
the level of coronary occlusion, the presence or absence
of collateral blood supply to the ischaemic area and the
duration of total vessel occlusion. More proximal occlu-
sion is associated with greater infarct size, as blood sup-
ply to a greater area is interrupted. The most effective
way to preserve the viability of ischaemic myocardium
and limit infarct size is early reperfusion of the occluded
vessel. However, even after successful revasculariza-
tion with PCI, cardiac tissue may still fail to perfuse
normally, a condition called ‘no-​reflow phenomenon’.
No-reflow seems to occur predominately when ischae-
mia persists for ≥90 minutes, and underlying mecha-
nisms include injury related to ischaemia, reperfusion
or distal embolization of thrombus and atheroscle-
rotic materials, with resultant coronary microvascular
dysfunction and obstruction (MVO)46,47. Coronary
microvascular dysfunction might also be a pre-​existing
condition.
Reperfusion of the occluded vessel itself can para-
doxically induce cardiomyocyte death and injury, a
phenomenon called myocardial reperfusion injury, and
can contribute to an increase in infarct size. With resto-
ration of coronary blood flow, an intense inflammatory
response occurs at the site of infarction. An influx of
leukocytes and the activation of pro-​inflammatory cas-
cades have both beneficial and detrimental effects on the
healing process and post-​MI remodelling48,49. The initial
pro-​inflammatory response aims at removing necrotic
cell debris and is followed by an anti-​inflammatory
restorative phase, which enables wound healing and
scar formation. In a mouse model, a pro-​inflammatory
subset of monocytes that express high levels of lympho-
cyte antigen 6 C (LY6Chi) seems to predominate during
the initial phase, whereas an anti-​inflammatory subset
(LY6Clow) predominates during the restorative phase
(4–7 days after the MI)50. Disturbances in the balance as
well as the transition between the two phases can con-
tribute to post-​MI ischaemia, reperfusion injury and
adverse remodelling50. Despite growing evidence from
many studies, many aspects related to MVO, ischaemia
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Primer
and reperfusion injury or the inflammatory response
in STEMI are not completely understood yet, and this
gap in our knowledge underlies the lack of co-​adjuvant
therapies for reperfusion.
Because the myocardium has negligible regener­
ative potential, the dead cardiomyocytes are replaced by
a non-​contractile collagen-​based scar tissue. If a large
myocardial area is damaged and replaced by fibrous
tissue, this change can lead to substantial alterations in
the geometry of the ventricle. Whereas infarcted areas
thin, the rest of the myocardium undergoes hypertro-
phy. The failure to normalize increased wall stresses
results in progressive ventricular dilatation51, and the
shape becomes more spherical. This adverse remodel-
ling has substantial consequences for the contractility
of the ventricle and can eventually lead to heart failure.
In the presence of myocardial wall stress, blood levels
of natriuretic peptide B (BNP, which is synthesized and
secreted mostly by myocardium), its biologically inac-
tive amino-​terminal fragment (NT-​proBNP) and atrial
natriuretic peptide (ANP) increase. As a consequence
of the increased release of these two peptides, diuresis
and vasodilatation also increase52,53. Finally, the struc-
tural changes of the ventricle may also have electrical
effects. Changes in patterns of excitation and conduc-
tion due to altered activity of ion channels and decreased
cellular connectivity have been documented54.
Diagnosis, screening and prevention
ECG and clinical presentation
Time delay to treatment is a relevant factor that has a
great effect on mortality in patients with STEMI2,20; thus,
early diagnosis is crucial. The fourth definition of MI
has updated the diagnostic criteria for type 1 MI (Box 4).
The working diagnosis is usually based on symptoms
consistent with myocardial ischaemia, that is, persistent
chest pain and new ST-​segment elevation. However, it
is important to also recognize atypical symptoms, such
as pain in neck, back or jaw as well as weakness, nausea
or fatigue, which are more frequent in women than in
men55. In the presence of persistent chest pain, a 12-lead
ECG must be recorded and interpreted as soon as pos-
sible at the point of first medical contact, with a maxi-
mum target delay of 10 minutes56,57. Field transmission
of the ECG is recommended if ECG interpretation is
not possible on site2,20. The registration of a pre-​hospital
ECG improves clinical outcomes and time to reperfu-
sion, particularly when coupled with communication of
a STEMI diagnosis and preferential transport to a PCI-​
capable hospital57–59. ST-​segment elevation is considered
persistent when not resolving before revascularization
therapy and transient in the case of resolution before
intended revascularization therapy. Atypical electrocar-
diographic presentation of STEMI in certain situations
is possible, and criteria to support the diagnosis in such
cases have been provided by guidelines2. The diagnosis
of STEMI can be particularly difficult in the presence of
left ventricular hypertrophy, LBBB, ventricular paced
rhythm, Brugada syndrome and early repolarization
patterns because these conditions interfere with the
classic ST-​segment elevation pattern in the ECG60. For
LBBB, electrocardio­graphic criteria were identified and
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Primer
Box 2 | Alternative causes of STEMI: coronary spasm
Coronary spasm is a variant form of angina252 characterized by symptoms of chest
pain at rest with ST-​segment elevation. Coronary spasm typically occurs in the early
hours of the morning during depressed vagal tone and is associated with transient
vasoconstriction of the epicardial coronary arteries, resulting in total or subtotal vessel
occlusion with consecutive myocardial ischaemia. Underlying mechanisms are a
mostly localized abnormality of a coronary artery that results in hyper-​reactivity to
vasoconstrictor stimuli and a vasoconstrictor stimulus capable of inducing the spasm.
Most common stimuli are illicit drugs, such as cocaine, but also include some
weight-​loss products, over-​the-counter drugs, chemotherapies, antimigraine
medications and antibiotics253. Mechanisms that mediate the vasoconstriction include
stimulation of the α-​adrenergic receptors in smooth muscle cells in the coronary
arteries, increased levels of the powerful vasoconstrictor endothelin 1 and decreased
production of the vasodilator nitric oxide. Endothelial dysfunction and primary
hyper-​reactivity of vascular smooth muscle cells (increased contractile response to
stimuli) have been proposed as contributing factors254. Although coronary spasm may
potentially result in total occlusion of an epicardial coronary artery, the size of the
resultant myocardial infarction (MI) is usually small, suggesting rapid reperfusion
in the early stages of MI owing to the transient nature of the spasm253. The true
prevalence of coronary spasm is uncertain, as prevalence estimates depend
very much on the population studied. The long-​term prognosis of MI caused by
coronary spasm is relatively benign when compared with that of ST-​segment
elevation MI (STEMI) caused by plaque rupture, according to several registry
studies255,256.
validated61 to assist diagnosis in those presenting with
suspected STEMI, but these criteria do not provide
diagnostic certainty62. New LBBB does not predict an
MI per se. Nevertheless, patients with a clinical suspi-
cion of ongoing myo­cardial ischaemia and LBBB should
be managed in a way similar to patients with STEMI. In
some conditions such as acute occlusion of a vein graft
or the left main coronary artery, ST-​segment elevations
may be absent. In patients with right bundle branch
block, ST-​segment abnormalities are common and con-
found the detection of ischaemia in the corresponding
leads, unless ECG changes can be proven to be new.
STEMI may occur in the absence of obstructive
CAD on angiography63–66 and is termed MI with non-​
obstructed coronary arteries (MINOCA). MINOCA that
is associated with ST-​segment elevations may be based
on atherosclerotic plaque rupture, ulceration, fissuring,
erosion or coronary dissection with non-​obstructive or
no CAD, but also myocardial disorders such as myo-
carditis and Takotsubo stress cardiomyopathy2. The
2013 European Society of Cardiology (ESC) Task
Force introduced criteria for clinically suspected myo-
carditis67. Among patients with a clinical diagnosis of
MINOCA, myocarditis had a prevalence of up to 33%
in a meta-​analysis68. The gold standard for confirma-
tion of suspected myocarditis is endomyocardial biopsy,
although its use is limited by its invasive nature67,69.
Cardiac MRI may be an alternative test, as good diag-
nostic performance has been shown at least for acute
myocarditis70. Diagnostic criteria for Takotsubo cardio­
myopathy have been published in an international
expert consensus document71.
Role of cardiac biomarkers
Blood tests for biomarkers of myocardial injury are indi-
cated as soon as possible in the acute phase, but rep-
erfusion treatment should not be delayed awaiting the
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results. The preferred biomarker for diagnosis of MI is
cTnI or cTnT owing to high myocardial tissue specific-
ity and high clinical sensitivity. However, for qualifying
patients with STEMI (with symptoms of ischaemia for
≤12 hours and persistent ST-​segment elevation), guide-
lines recommend immediate reper­fusion therapy with-
out waiting for cardiac marker results2,20. The release of
cTn over time in STEMI is distinct from the heteroge-
neous release pattern of cTn following an NSTEMI72,73.
The release kinetics of cTn following a STEMI depend
on the type (primary PCI or fibrinolytic therapy) and
success of reper­fusion therapy72,73 and several other
factors, including the type and sensitivity of the cTn
assay used and the presence of collateral flow to the
infarct-​related artery. Typically, a steep rise and subse-
quent gradual fall with a monophasic (cTnI) or biphasic
(high-​sensitivity cTnT) curve is observed following
successful primary PCI or fibrinolytic therapy72,73.
The presence and magnitude of cTn elevations after
STEMI are useful for short-​term and long-​term prog-
nosis of cardiovascular events such as recurrent MI and
death. Elevated cTn at admission 74,75, peak values76
and persistence of elevated cTn beyond the initial weeks
after STEMI77–79 have been shown to confer impor-
tant prognostic information for long-​term outcomes.
Elevated cTn concentrations return to normal levels
within days to weeks, depending on the cTn assay (cTnT
or cTnI, and conventional sensitivity or high-​sensitivity
cTn), but may also persist in 31–37% of patients for up to
weeks or months after MI77–79. The reasons for persistent
cTn elevation after an index ACS are rather multifacto-
rial77–79. However, a significant correlation between ele-
vated high-​sensitivity-cTnT levels at 7 weeks after ACS
and reduced systolic left ventricular ejection fraction
(LVEF) as well as BNP has been demonstrated78 and
suggests an association between persistently elevated
troponins and impaired left ventricular function.
Role of imaging
Emergency transthoracic echocardiography should be
performed in patients with inconclusive STEMI diag-
nosis and in patients presenting with cardiac arrest,
cardiogenic shock (a life-​threatening condition with
inadequate tissue (end-​organ) blood perfusion), haemo-
dynamic instability or suspected mechanical complica-
tions. However, it should not be routinely performed
before revascularization in order to not delay reperfu-
sion. Routine transthoracic echocardiography after PCI
is indicated in all patients with STEMI to evalu­ate left
ventricular, right ventricular and valve function and
to exclude early post-​infarction mechanical compli-
cations and left ventricular thrombus. In patients with
pre-​discharge LVEF <40%, echocardiography should
be repeated 6–12 weeks after MI, after complete revas-
cularization and optimal medical therapy have been
achieved, to assess the potential need for implantation
of an implantable cardioverter–defibrillator for primary
prevention of life-​threatening arrhythmias2,20. Although
assessment of left ventricular function by transthoracic
echocardiography has been considered as one of the
most important prognostic factors in patients after
STEMI, the prognostic value of left ventricular function

has been mainly derived from studies of the pre-​PCI
era. In patients who have undergone primary PCI, this
parameter is heavily influenced by post-​ischaemic
stunning (a state of prolonged contractile dysfunc-
tion of post-​ischaemic myocardium in which normal
myocardial function is gradually restored after a given
recovery period)80.
Cardiac MRI is an excellent tool for tissue character-
ization and enables the documentation of the different
pathophysiological processes after STEMI, including
myocardial oedema and intramyocardial haemorrhage,
as well as MVO and changes in the remote myocardial
interstitial space (in the zone opposite to the infarct
zone) in patients developing adverse left ventricular
remodelling81. Several studies evaluated these param­
eters as prognostic factors. In 810 patients, MI size, MVO
and left ventricular volumes and function were evaluated
by early post-​MI MRI (median of 4 days after STEMI).
In contrast to left ventricular function, MVO (shown
as a dark hypo-​intense core within the areas of hyper-​
enhancement on early or late gadolinium enhancement
MRI images) was shown to be a strong independent
prognostic factor in patients after STEMI82. MVO was
confirmed as a strong prognostic factor by another study
of 1,688 patients83. In addition, cardiac MRI-​derived MI
size has been frequently used as a surrogate end point
in randomized controlled trials for novel cardioprotec-
tive therapies aiming to reduce MI size84. Cardiac MRI
is well suited to have an important role in the evalua-
tion of patients with STEMI owing to its capability to
provide quantitative multiparametric characterization
of the infarcted myocardium along with comprehensive
assessment of left ventricular function and morphol-
ogy82. However, efforts are needed to achieve standardi-
zation of the technique (timing of MRI acquisition, dose
of contrast and time elapsed between contrast admin-
istration and acquisition of late gadolinium enhance-
ment imaging) and to improve accessibility for patients
(techniques that do not require breath hold and reducing
scan time and costs) in order for it to become a tool rou-
tinely used in clinical practice to evaluate prognosis and
guide treatment.
Echocardiography and cardiac MRI but also single
photon emission CT (SPECT) and PET are useful to
detect residual ischaemia and evaluate myocardium via-
bility in patients with multivessel disease (that is, with
one or more additional coronary arteries with a substan-
tial atherosclerotic burden, in addition to the culprit ves-
sel) who received treatment only of the infarct-​related
artery or in patients who present days after the acute
event with completed MI2.
Box 3 | Alternative causes of STEMI: coronary embolism
The reported prevalence of coronary embolism as the cause of ST-​segment elevation
myocardial infarction (STEMI) ranges from 4% to 13% according to angiographic and
autopsy studies257–260. However, evaluation of the true prevalence is difficult owing to
the acute clinical setting of the disease. In a report on data derived from an observational
cohort study257, the most frequent cardiac causes of coronary embolism were atrial
fibrillation, followed by dilated cardiomyopathy, endocarditis and intracardiac tumour,
whereas among systemic diseases, malignancy, systemic autoimmune disease and
antiphospholipid syndrome were present.
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Screening
Screening in the context of STEMI is mostly focused on
detecting cardiovascular risk factors and atherosclerosis.
The descriptive INTERHEART study enrolled patients
from 52 countries and identified nine potentially modi-
fiable factors (abnormal blood levels of lipids, smoking,
hypertension, diabetes mellitus, abdominal obesity, psycho-
social factors, consumption of fruits and vegetables, con-
sumption of alcohol and regular physical activity) that
account for >90% of the population-​attributable risk
of a first MI85. An analysis of the National Health and
Nutrition Examination Survey (NHANES) revealed that
five modifiable risk factors for CVD (elevated choles­terol,
diabetes mellitus, hypertension, obesity and smoking)
accounted for one-​half of CVD deaths in US adults of
45–79 years of age from 2009 to 2010 (ref.86).
As atherosclerosis is usually the result of several risk
factors, guidelines recommend comprehensive cardio-
vascular risk assessment87. Risk assessment models based
on pooled cohort equations such as Framingham88, the
ASCVD89 or SCORE87 can help to evaluate the 10-year
risk of atherosclerotic CVD and guide preventive meas-
ures. However, data from cardiac imaging cohorts sug-
gest that the value of these models to assess the risk of
an individual might be limited. Studies that evaluated
coronary artery calcium with CT have shown that
many individuals who are deemed to be at high cardio­
vascular risk on the basis of assessment with risk mod-
els have in fact no atherosclerosis and are at very low
risk of cardio­vascular events90. Coronary artery calcium
scoring seems to be an excellent tool for guiding pre-
ventives therapies (especially statin and/or aspirin use)
and can add valuable prognostic information beyond the
traditional risk factors91.
Prevention
As the majority of STEMI cases result from thrombus
formation on a ruptured coronary atherosclerotic plaque,
prevention aims at reducing the burden of athero­
sclerosis. Several strategies have been recommended in
the primary prevention of CVD. All individuals should
be offered lifestyle modification advice to reduce CVD
risk regardless of risk score values.
Smoking is one of the major risk factors for the
development of atherosclerotic conditions including
MI92 and worsens outcomes after intervention. Patients
who smoke are at a higher risk of mortality and mor-
bidity following PCI93. Several mechanisms by which
cigarette smoking leads to CAD have been proposed,
including oxidative damage to the endothelium, lead-
ing to endothelial damage and accelerating atheroscle-
rosis, platelet activation and thrombosis, reduced oxygen
availability and sympathetic nervous system activation,
resulting in coronary vasoconstriction94–97.
Obesity prevalence has increased globally98. In the
United Kingdom, the prevalence increased from 15% in
1993 to 27% in 2015 (ref.99), and more than half of the
population could have obesity by 2050. Obesity and over-
weight increase the risk of developing MI by adversely
contributing to risk factors including hypertension, dys-
lipidaemia, chronic inflammatory state, type 2 diabetes
mellitus and metabolic syndrome. The mechanisms by
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which excessive body weight worsens these risk factors
have been reviewed elsewhere100,101.
An unhealthy diet (based on food high in sodium,
refined sugar and fat) is associated with an increased risk
of MI by inducing weight gain. It also has an adverse
effect on other risk factors for MI including hyper-
cholesterolaemia, hypertension and type 2 diabetes
mellitus102–104. High sodium intake has been shown to
increase blood pressure, whereas sodium reduction has
been shown to decrease CAD, and in particular, elderly
patients or individuals with underlying elevated blood
pressure may benefit the most from it105. One of the main
forms of sugar in diet is sweetened beverages, and a sys-
tematic review has demonstrated a positive association
between sweetened beverages and CAD106. Excessive
consumption of saturated and trans-​fat is also considered
to be a risk factor for coronary heart disease107,108. Not
all types of fat have an adverse effect on cardiovascular

a
Red blood cell Activated platelet • Inflammation
• Matrix degradation
• Expansive remodelling
Endothelial cell Fibrin
T cell Collagen
Lumen

Cholesterol
LDL Monocyte crystal
Adhesion Apoptotic
molecule body
Necrotic core
LDLR
Apoptotic
Intima

body
Oxidized Macrophage Foam cell
LDL Smooth muscle cell
Media

b
Platelet tethering Platelet activation Inside-out signalling
Platelet
P2Y12 Fibrinogen
GPIb–IX–V
GPIIb/IIIa (high affinity)
ADP

vWF GPIIb/IIIa (low affinity)

Blood flow Microparticle

release Prothrombin

Thrombin

Endothelial cell

Fig. 3 | Atheromatous plaque development, plaque rupture and thrombus formation. a | Retention of low-​density
lipoprotein (LDL) particles within the subendothelial layer results in recruitment of monocytes to the growing athero­sclerotic
plaques, where they differentiate into macrophages48,266,267. Macrophages perpetuate inflammation and destabilize the
extracellular matrix and the endothelial layer266. Inflammation results in stimulation of procoagulant factors that trigger
thrombus formation, resulting in acute coronary syndrome38. Furthermore, it increases the production of fibrin, one of the
main components of thrombus, and of plasminogen activator inhibitor 1 (PAI1), the major endogenous inhibitor of
fibrinolysis38. Mechanisms such as recurrent intraplaque haemorrhage have been suggested to contribute to the accelerated
plaque progression268,269. Intraplaque bleeding was reported to increase the deposition of free cholesterol and macrophage
infiltration, resulting in rapid necrotic core expansion270. An ongoing vicious cycle of inflammation, extracellular matrix
degradation and expansive remodelling may lead to accelerated growth and eventually to acute plaque disruption271.
b | The rupture of the atherosclerotic plaque causes endothelial damage and triggers thrombus formation. Platelets start
to adhere to the exposed subendothelial matrix; initial adhesion of platelets is mediated by the platelet membrane protein
glycoprotein (GP) Ibα, a binding protein making up part of the GPIb–IX–V complex on the platelet cell, binding to von
Willebrand factor (vWF)272,273. After activation, platelets change their shape and release various bioactive substances
including ADP274,275. Locally released ADP further activates platelets through continuous stimulation of P2Y purinoceptor 12
(P2Y12) ADP receptors276. After platelet activation, inside-​out signal transduction mechanisms trigger a conformational
change in the fibrinogen receptor GPIIb/IIIa to a high-​affinity ligand-​binding state. The GPIIb/IIIa receptors mediate the final
common pathway of platelet aggregation. Excessive platelet activation overcomes regulatory haemostatic mechanisms
and leads to generation of unwarranted levels of thrombin277. Several thrombin receptors that are located on the surface of
the platelet are efficiently activated by thrombin, which further activates the platelets277,278. In the presence of an increased
thrombogenic and inflammatory milieu, the process of thrombus formation is also regulated by the fibrinolytic system,
which may be inhibited by inflammation. LDLR , LDL receptor. Part a adapted from ref.279, Springer Nature Limited.

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health; mono-​unsaturated or polyunsaturated fatty acids
such as omega-3 have been demonstrated to be cardio­
protective. For a healthy and balanced diet, eating at
least five portions of fruit and vegetables a day is rec-
ommended, along with at least two portions of fish
weekly109. Adherence to dietary recommendations has
been shown to lower the risk of fatal and non-​fatal acute
MI110. If LDL cholesterol is elevated, lifestyle modifica-
tion plays a crucial part in lowering the cardiovascular
risk. However, certain patient groups need additional
pharmacological treatment with statins to lower LDL
cholesterol. Statins reduce LDL cholesterol levels by
inhibiting the activity of HMG-​CoA reductase, a key
enzyme in the synthesis of cholesterol. Patients who
might need statins for primary prevention include indi-
viduals with baseline LDL cholesterol levels of ≥190 mg
per dl, patients with diabetes mellitus and patients with
increased atherosclerotic CVD risk resulting from the
presence of risk factors such as arterial hypertension,
smoking and increased age111. As mentioned above, coro­
nary artery calcium scoring may also provide valuable
information on which patient may benefit from statin
therapy. Different guidelines in the United Kingdom112,
United States111 and Europe113 provide slightly different
recommendations.
The beneficial effect of physical exercise on coronary
heart disease has long been recognized114. Many studies
have strongly supported the protective effect of physical
activity on CAD, with the incidence of CAD halved in
the most physically active individuals compared with the
most sedentary115,116. The mechanisms by which exercise
exerts its protective effect are probably by reducing the
risk factors associated with the development of CAD,
such as lowering blood pressure117 and triglycerides118,
and improving endothelial function, enhancing nitric
oxide bioavailability and promoting collateral vessel
development119,120. The current recommendation is to do
physical activity for 150 minutes per week and strength
exercises on ≥2 days on a weekly basis121.
Management
The acute treatment of STEMI is centred around pro-
viding emergency effective reperfusion of the myocar-
dium via recanalization of the occluded coronary artery.
Compared with fibrinolysis, primary PCI has shown
beneficial outcomes in patients with STEMI if performed
within 120 minutes of diagnosis and, therefore, became
the preferred reperfusion strategy2,20. PCI is a catheter-​
based technique to dilate the narrowed vessel with an
inflatable balloon (a procedure known as balloon angio­
plasty) and keep it open by consecutive implantation of
a stent (a small tube made of metal mesh). The initi-
ation of STEMI networks to provide around-​the-clock
cardiac catheterization availability and the development
of standard operating procedures within hospital sys-
tems have helped to reduce the time to reperfusion and
resulted in improved clinical outcomes122,123. Data from
the National Cardiovascular Data Registry (NCDR)
ACTION Registry–Get With the Guidelines (GWTG)
showed that 60% of >37,000 patients with STEMI used
emergency medical services (EMS) to reach the hospital.
Elderly adults, women, adults with comorbidities and
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Box 4 | Criteria for type 1 MI1
Detection of a rise and/or fall in cardiac troponin values
with at least one value above the ninety-​ninth percentile
upper reference limit and with at least one of the
following:
• Symptoms of acute myocardial ischaemia
• New ischaemic electrocardiogram changes
• Development of pathological Q waves
• Imaging evidence of new loss of viable myocardium
or new regional wall motion abnormality in a pattern
consistent with an ischaemic aetiology
• Identification of a coronary thrombus by angiography
including intracoronary imaging or by autopsy
MI, myocardial infarction.
individuals with cardiogenic shock and heart failure
used EMS more frequently. Hospital arrival time was
shorter for those who used EMS (89 minutes) than for
those who did not (120 minutes)124.
If primary PCI is not available within 120 minutes of
diagnosis, then fibrinolysis should be performed unless
contraindicated. Fibrinolytic therapy aims to dissolve
the thrombus by activating plasminogen, resulting in the
formation of plasmin, which cleaves the fibrin crosslinks
within the thrombus. Alteplase, tenecteplase and
reteplase are fibrin-​specific agents, which means that
they preferentially bind to fibrin in a thrombus and cat-
alyse cleavage of entrapped plasminogen to plasmin125,
resulting in localized fibrinoly­sis with limited systemic
proteolysis. Conversely, streptokinase is a nonfibrin-​
specific agent and causes an indirect conformational
change in the plasminogen molecule, which then acts
as plasmin125. The role of CABG surgery is generally
limited to indications such as complicating mechani-
cal defects, coronary anatomy not suitable for PCI and
failed PCI (Fig. 4). Additional pharmacological thera-
pies are recommended, and treatment is well codified
in practice guidelines2,20 and fairly standardized126.
Reperfusion therapy
In-​hospital mortality after STEMI has dramatically
decreased to <10% because of establishment of coronary
care units, improvements in medical therapy and wide-
spread use of early reperfusion therapy127,128. The current
clinical guidelines for STEMI in the United States and
Europe recommend primary PCI over fibrinolysis if pri-
mary PCI can be initiated promptly2,20, and algorithms
for the selection of reperfusion therapy are available in
clinical guidelines (Fig. 4). The large-​scale United States
National Registry of Myocardial Infarction (NRMI)
reported that the mortality advantage of primary PCI
over onsite fibrinolysis disappeared when the delay from
first medical contact to PCI exceeded 120 minutes129.
Thus, guidelines recommend the use of fibrinoly­
sis for patients with STEMI who present within 12 hours
of symptom onset in whom PCI cannot be performed
within 120 minutes. Treatment should then be started within
30 minutes of first medical contact, after careful assess-
ment for contraindications. Guidelines generally give pref-
erence to fibrin-​specific fibrinolytic agents (tenecteplase,
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Symptoms suggestive of STEMI

Patient presenting to a PCI centre EMS Patient presenting

to a non-PCI centre

STEMI diagnosis

Yes
STEMI diagnosis Time to PCI centre ≤120 min?
No

CABG surgery Primary PCI Fibrinolysis

• Anticoagulation therapy needs • Anticoagulation therapy during • Anticoagulation therapy until

to be discontinued for surgery
• Antiplatelet therapy:
- Aspirin as soon as possible
without cessation for surgery
- P2Y12 antagonist as
soon as possible; consider
discontinuation for surgery
the PCI procedure
• Antiplatelet therapy:
- Aspirin as soon as possible
- P2Y12 antagonist
(prasugrel or ticagrelor) at
the time of the PCI procedure
at the latest
revascularization (if performed) or
during hospital stay for at least 48 hours
and up to 8 days
• Antiplatelet therapy:
- Aspirin as soon as possible
- P2Y12 antagonist (clopidogrel)
as soon as possible

<50% ST-segment resolution at 60–90 min?

Yes and/or one or more of the following:
• Heart failure and/or shock
• Haemodynamic or electrical instability
• Worsening ischaemia
No

Emergency PCI Routine PCI strategy

• Emergency PCI performed • Coronary angiography, with PCI if
as soon as possible in indicated, performed between 2 and
case of failed fibrinolysis 24 hours after successful fibrinolysis

Additional drugs for secondary prevention if indicated

Reperfusion therapy In the case of mechanical complication, If coronary anatomy is not suitable for PCI,
Pharmacological therapy CABG surgery is recommended CABG surgery is recommended

Fig. 4 | Management algorithm for STEMI. At first medical contact, the diagnosis of ST-​segment elevation myocardial
infarction (STEMI) should be made within 10 minutes. After the diagnosis is confirmed, the decision on the reperfusion
strategy (percutaneous coronary intervention (PCI), fibrinolysis or coronary artery bypass graft (CABG) surgery) has to
be made. Depending on the reperfusion strategy , the choice of antithrombotic and anticoagulant therapy may differ.
Additional pharmacological therapies should be given as indicated. EMS, emergency medical services; P2Y12, P2Y
purinoceptor 12.

alteplase or reteplase), with specific dosing according
to age and body weight2,20. It is important to note that
even if fibrinolysis is performed as the primary therapy
approach, it should always be followed by coronary angi-
ography and potentially PCI. The timing of coronary
angiography is dependent on the success of fibrinolysis
on the basis of certain criteria (Fig. 4). In patients who pres-
ent late (>12 hours from symptom onset), a PCI is indi-
cated in the presence of ongoing symptoms suggestive of
ischaemia, haemodynamic instability or life-​threatening
arrhythmias2,20.
Depending upon the population evaluated, the use of
the different reperfusion strategies and the proportions
of patients eligible to receive them vary. In general, the
use of fibrinolysis is steadily declining, whereas primary
PCI is increasingly performed23,127,130. For individuals
directly admitted to centres with PCI facilities, ‘door
to balloon time’ (time from presenting at the hospital to
inflation of the balloon during primary PCI to reperfuse
the occluded artery) declined significantly. Of note, an
analysis of data from a Swedish registry evaluated sex
disparities and documented that women were less likely
than men to receive reperfusion therapy131.
Despite differences in the studies, it is clear that
patients with STEMI are more frequently being treated
with primary PCI and that reperfusion times are shorter
than in the past. Of note, the management of patients
with multivessel disease by culprit-​only or multivessel
PCI is still a matter of debate (Box 5).
Trans-​radial intervention. Compared with traditional
trans-​femoral intervention (TFI), trans-​radial inter-
vention (TRI) is less invasive and has proved to be a
safer approach in emergency PCI for ACS132,133. With
TRI, access to the occluded coronary artery is gained
through the radial artery, which is a smaller artery than

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the femoral artery that is used with TFI. The smaller size durable, biocompatible acrylic and fluorinated copol-
of the radial artery compared with the femoral artery and ymer showed significantly lower rates of repeat target
the superficial location at the hand wrist with good pos- vessel revascularization and stent thrombosis than
sibility of manual compression are associated with lower bare-​metal stents137. Considering the reduced rate of
bleeding risk. TRI was demonstrated to be superior to thrombotic events with newer-​generation DESs138, deter-
TFI in terms of reducing not only bleeding complica- mining the optimal duration of dual antiplatelet therapy
tions, particularly access site bleeding, but also mortality after DES implantation in patients with STEMI would be
in the MATRIX trial and in a meta-​analysis133,134. The an important clinical research question, particularly in
current European clinical guidelines recommend trans-​ patients with high bleeding risk.
radial access for PCI in ACS as class Ia (as a general
rule, the numeral in the class of recommendation indi- Haemodynamic support. In primary PCI for STEMI,
cates the strength of the recommendation (the lower the haemodynamic support is frequently needed for patients
numeral the higher the strength), and the letter indicates with high-​risk PCI and/or cardiogenic shock. However,
the quality of the supporting evidence (from strongest haemodynamic support using an intra-​aortic balloon
to weakest))2. pump (IABP) did not lead to a benefit in 30-day mor-
tality compared with control in the IABP-​SHOCK II
Stent technology: new generation drug-​eluting stents. trial139. Newer left ventricular assist devices such as
Stent implantation for the culprit lesion in STEMI dur- Impella (Abiomed) and TandemHeart (LivaNova) have
ing primary PCI is the recommended treatment (class Ia theoretical advantages over an IABP by unloading the
recommendation)2,20. Compared with balloon angio- left ventricle (blood from the left ventricle or atrium is
plasty alone, PCI with bare-​metal stent implantation pulled and expelled into the ascending aorta or femoral
decreased the risk of reinfarction and subsequent target artery) and increasing cardiac output. Several previ-
vessel revascularization (that is, the need for a recurrent ous trials reported the benefits of these new devices on
revascularization with PCI or CABG surgery of the haemo­dynamic parameters compared with an IABP140,141,
initially treated vessel), although there was no signifi- but no trials have demonstrated the benefits in clinical
cant mortality benefit135. First-​generation drug-​eluting outcomes. Large-​scale randomized controlled trials are
stents (DESs) are coated with an antiproliferative agent warranted to evaluate whether these new devices could
(such as everolimus) and reduced the risk of repeat have a mortality benefit in patients with STEMI and
coronary revascularization even further136. Newer-​ cardiogenic shock.
generation DESs have several improvements compared
with first-​generation DESs, such as thinner stent struts Aspiration thrombectomy and distal protection device.
and biocompatible polymers, potentially reducing the Aspiration thrombectomy is a procedure in which the
risk of stent thrombosis. In the EXAMINATION trial, thrombus in the culprit lesion is aspirated and removed
second-​generation everolimus-​e luting stents with through the guiding catheter. However, large-​scale clini­
cal trials evaluating the efficacy of PCI with aspiration
thrombectomy reported no clinical benefits compared
Box 5 | Multivessel disease: culprit-​only or multivessel PCI
with primary PCI alone142,143. Furthermore, in the TOTAL
About half of patients with ST-​segment elevation myocardial infarction (STEMI) trial, routine aspiration thrombectomy was associated
receiving primary percutaneous coronary intervention (PCI) have multivessel with an increased rate of stroke within 30 days142. On
disease261, but the optimal management of non-​culprit substantial atherosclerotic the basis of these results, routine aspiration thrombec-
lesions is still under debate. In the PRAMI trial262, over a mean follow-​up of 23 months, tomy during primary PCI is not recommended in the
multivessel PCI with complete revascularization was superior to culprit-​only PCI in
clinical guidelines2,144.
terms of a composite end point of cardiac death, myocardial infarction (MI) or
refractory angina. Several other trials confirmed the favourable results of multivessel
Distal protection devices are used to capture debris
PCI compared with culprit-​only PCI, but these advantages must be interpreted with from the atherosclerotic plaques and thrombi to pre-
caution, as the studies had some limitations. For example, repeat revascularization was vent distal embolization and no-​reflow phenomenon
included in composite end points of most of the studies. However, the decision to during PCI, but there is no strong evidence supporting
perform subsequent revascularization procedures in patients in the culprit-​only arm their routine use during primary PCI. However, these
could have been prompted (and thereby biased) by the knowledge of the existence of devices might be beneficial in selective situations, such
other stenosed vessels, as their presence would have been detected during the initial as large thrombus burden. Notably, in the VAMPIRE
procedure263. By contrast, in the CULPRIT-​SHOCK trial173, culprit-​only PCI (with the 3 trial, use of a distal protection device was associated
option of staged PCI (a second planned PCI at a later time point) for non-​culprit with a significantly lower rate of no-​reflow phenome-
lesions) was significantly better than immediate multivessel PCI in terms of a
non in patients with STEMI with attenuated plaques
composite end point of death or severe renal failure at 30 days. An exploratory analysis
of 1-year mortality of this study did not show any significant difference between the
>5 mm in length on the basis of pre-​PCI intravascular
two groups264. A 2015 focused update of the American College of Cardiology (ACC)– ultrasonography145.
American Heart Association (AHA)–Society for Cardiovascular Angiography and
Interventions (SCAI) guidelines for PCI in patients with STEMI gave a class IIb Concomitant pharmacological treatment
recommendation to consider PCI of non-​culprit lesions in patients with multivessel In addition to early reperfusion therapy, a variety of
disease who are haemodynamically stable either at the time of the primary PCI or as a medications are recommended in patients with STEMI
planned staged procedure144. The European guidelines give a class IIa recommendation by international guidelines 2,20. The choice of anti­
to consider revascularization of non-​culprit lesions in patients with STEMI with coagulation and antiplatelet therapies is dependent on
cardiogenic shock at the time of the primary PCI and in haemodynamically stable the reperfusion strategy as well as the ischaemic and
patients routinely before hospital discharge2.
bleeding risks of the patient.

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Anticoagulation therapy. Anticoagulation therapy aims
to inhibit thrombin formation or activity, which plays
an important role in the pathophysiology of STEMI and
during primary PCI. Several options are available to
provide rapid effective anticoagulation to patients with
STEMI being treated with primary PCI. Antithrombin III
(AT3) is a peptide that inhibits several of the activated
clotting factors. Unfractionated heparin binds to and
increases the activity of AT3 and has some inhibi-
tory effect on coagulation factors IXa, XIa and XIIa.
Enoxaparin is a low molecular mass heparin and also
binds to AT3. In the setting of primary PCI, these agents
should be given intravenously2,20. Whereas the dose of
unfractionated heparin may need to be adjusted on
the basis of a measurement of the activated clotting
time (the time until a clot is formed from a fixed vol-
ume of blood under certain conditions), enoxaparin
does not need monitoring and is given as a single bolus.
Bivalirudin is a direct thrombin inhibitor and may be
used in patients at high risk of bleeding or with heparin
induced-​thrombocytopenia.
Unless there is a clear indication for continued anti-
coagulation therapy (such as atrial fibrillation, mechani-
cal prosthetic valve or intraventricular thrombus, among
others), routine full-​dose anticoagulation therapy is gen-
erally not indicated after PCI. Prophylactic doses for the
prevention of venous thrombo-​embolism may be used
in patients with prolonged bed rest2.
Patients receiving fibrinolysis should also receive
anticoagulation therapy until PCI is performed (if appli-
cable) or for the duration of hospital stay (but without
exceeding 8 days). Enoxaparin is preferred to unfrac-
tionated heparin; in patients treated with streptokinase,
fondaparinux (an anticoagulant that purely inhibits
factor Xa) should be used2.
Antiplatelet therapy. Antiplatelet agents aim to prevent
platelets from forming a thrombus and are, therefore,
crucial for the treatment of patients during and after
STEMI. The standard of care for antiplatelet therapy
in STEMI is oral dual antiplatelet therapy combining life-
long aspirin and an oral inhibitor of P2Y purinoceptor 12
(P2Y12; the predominant receptor in the ADP-​stimulated
prolonged platelet aggregation)146 for platelet aggrega-
tion, which, as a rule, should be used for 12 months147.
Detailed guidelines have been issued regarding the optimal
duration of dual antiplatelet therapy148,149.
In all patients, aspirin should be given as soon
as possible after diagnosis, and treatment should be
maintained permanently at a low dose. There are three
options for an oral P2Y12 inhibitor. Clopidogrel remains
the drug of choice in patients at high risk of bleeding,
particularly patients requiring lifelong oral anticoagu-
lation therapy, or if the newer agents are not available,
contraindicated or poorly tolerated. However, current
guidelines2,20 recommend the potent oral P2Y12 inhibi-
tors (ticagrelor or prasugrel) over clopidogrel, given the
benefits of these agents compared with clopidogrel in
large outcome trials150,151. Beneficial effects in redu­cing
ischaemic events, although with increased risk of bleed-
ing, have been documented150,151. Prasugrel is contra­
indicated in patients with a prior history of stroke or
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transient ischaemic attacks and not recommended in
patients of ≥75 years of age. In patients with a body
weight ≤60 kg, the maintenance dose should be reduced.
Intravenous antiplatelet agents include glycopro-
tein IIb/IIIa (GPIIb/IIIa; also known as integrin αIIb–
integrin β3) receptor blockers and cangrelor, a P2Y12
inhibitor. Currently, GPIIb/IIIa receptor blockers are
mostly used in the catheterization laboratory for bail-
out to manage complications arising during PCI such as
large thrombus, slow flow (delayed progression of the
injected contrast medium through the coronary tree)
or no reflow. Cangrelor has a rapid onset and offset of
action and can reduce periprocedural ischaemic compli-
cations, although it is associated with an increased risk
of bleeding compared with clopidogrel152. Cangrelor may
be considered in patients not pretreated with oral P2Y12
inhibitors at the time of PCI or in those who cannot
swallow oral agents.
In patients receiving fibrinolysis, dual antiplatelet
therapy should be restricted to lifelong aspirin and clopi-
dogrel for 12 months, as prasugrel and ticagrelor have
not been studied as adjuncts to fibrinolysis.
STEMI complications
Arrhythmia and conduction abnormality. The incidence
of ventricular tachycardia (VT) and ventricular fibrilla-
tion (VF) after STEMI has decreased since the establish-
ment of routine early revascularization and β-​adrenergic
receptor blocker therapy153. However, contemporary
studies report an almost 6% rate for the incidence of
sustained VT or VF in patients with acute MI154,155. Early
VT or VF within 48 hours after STEMI seems to be asso-
ciated with increased in-​hospital mortality but seems to
have no effect on long-​term prognosis156,157. Conversely,
VT or VF that develops after 48 hours and in the absence
of recurrent ischaemia is associated with worse progno-
sis, mandating aggressive treatment as well as evaluation
for implantation of a cardioverter–defibrillator158.
Similar to ventricular tachyarrhythmia, the occur-
rence of conduction abnormalities and bradyarrhyth-
mias associated with acute MI has decreased in the era of
early revascularization159. More specifically, new onset
of atrioventricular block in patient with STEMI has been
reported to occur in 6.9% of patients with STEMI treated
with thrombolytic therapy160, compared with a 3.2%
incidence rate in patients treated with primary PCI161.
Sinus or atrioventricular-​nodal delay is mostly associ-
ated with STEMI located in the inferior wall of the heart
and can occur within the first hours and up to several
days after the MI. Sinus bradycardia or various degrees
of atrioventricular block occurring in the early phase of
MI as a result of increased vagal tone respond well to
atropine (an anticholinergic drug) and usually resolve
within 24 hours162. Later occurrence of conduction delay
may be associated with oedema and local accumulation
of adenosine163. These abnormalities are usually asymp-
tomatic but can also result in haemodynamic instabi­lity.
In the case of haemodynamic instability, temporary pac-
ing may be required; however, most conduction abnor-
malities due to inferior STEMI resolve within 2 weeks159.
Atrioventricular block associated with anterior infarc-
tion is mostly infra-​Hisian (located further down in the

conduction pathway), with new bundle branch block or
hemiblock usually indicating extensive anterior MI2,159.
In-​hospital mortality and 30-day mortality have been
reported to be higher in patients with atrioventricular
block than in those who do not develop it, regardless of
infarct location, whereas outcomes beyond 30 days seem
similar across groups164.
Left ventricular thrombus. Data on the incidence of
left ventricular thrombus detected by optimal imaging
modalities range from as high as 15% in patients with
STEMI to up to 25% in patients with anterior MI165.
Although standard transthoracic echocardiography
has low sensitivity, contrast echocardiography or car-
diac MRI should be used if pre-​test probability is high.
Once left ventricular thrombus is detected, anticoagu-
lation therapy (in addition to dual antiplatelet therapy)
is essential, although it increases the bleeding risk.
Mechanical complications. Mechanical complications
after acute MI include papillary muscle rupture and
dysfunction, left ventricular aneurysm, ventricular sep-
tal rupture and free wall rupture. These complications
have become rare events in the era of primary PCI,
with the current incidence reported to be <1%. A report
from the APEX-​AMI study documented rates of 0.51%
for free wall rupture, 0.17% for ventricular septal rupture
and 0.26% for papillary muscle rupture166. Nevertheless,
these complications constitute a life-​threatening emer-
gency scenario mandating early diagnosis and urgent
surgical referral. Initial symptoms range from dyspnoea
to fulminant heart failure, cardiogenic shock and sud-
den cardiac death. Any of these symptoms as well as the
occurrence of a new heart murmur (an unusual sound
caused by abnormal blood flow) should always prompt
immediate echocardiography, which is the gold standard
for the diagnosis of mechanical complications. In addi-
tion, transfer to the intensive care unit is mandated.
Once the diagnosis is confirmed, further treatment and
timing of surgery should ideally be evaluated by a multi-
disciplinary team. In case of haemodynamic instability
or cardiogenic shock, the insertion of an IABP may be
considered, whereas refractory circulatory failure should
prompt percutaneous initiation of extracorporeal mem-
brane oxygenation as a bridging therapy to manage the
patient until definitive treatment is applied167,168.
Cardiogenic shock occurs in ~5–15% of patients, is
one of the most powerful predictors of short-​term and
long-​term outcomes after STEMI169–171 and remains the
leading cause of death after acute MI171. Mechanical
complications are rare causes of cardiogenic shock, as
the most common underlying cause is left ventricular
dysfunction. Evidence from randomized controlled
trials in patients with cardiogenic shock is limited. Long-​
term follow-​up of the SHOCK trial has shown that early
revascularization was associated with increased sur-
vival compared with initial medical stabilization172. In
patients with multivessel disease presenting with STEMI
and cardiogenic shock, culprit-​only PCI was associated
with a lower rate of the composite end point of death or
severe renal failure leading to renal-​replacement therapy
than immediate multivessel PCI173. A beneficial effect in
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terms of 30-day mortality of the insertion of an IABP in
patients with STEMI with cardiogenic shock and
planned early revascularization could not be confirmed
by a trial that randomized 600 patients139. Thus, further
randomized controlled trials are needed to evaluate
optimal treatment strategies in patients with STEMI and
cardiogenic shock.
Routine secondary prevention therapies
In addition to anticoagulation and antiplatelet thera-
pies, several pharmacological therapies should be con-
sidered and established before discharge in patients
with STEMI2.
The use of angiotensin-​converting enzyme (ACE)
inhibitors after MI was associated with a significant
reduction in all-​cause mortality and a significant reduc-
tion in incidence of reinfarction174. However, data on
ACE inhibitors in patients treated with primary PCI
are scarce. The mechanisms by which ACE inhibitors
reduce adverse events after MI include reducing ven-
tricular remodelling after STEMI, decreasing sympa-
thetic activity and increasing vagal tone, which may
reduce the incidence of sudden death175.
The widespread use of β-​adrenergic receptor block-
ers (a class of antihypertensive drugs) after MI is based
on several large clinical trials176–178, and a systematic
review supports their use, showing reduced mortal-
ity and morbidity179. β-​Adrenergic receptor blockers
after MI also improved survival and reduced non-​fatal
MI180,181. However, in a recent observational study,
β-​adrenergic receptor blocker therapy was not associ­
ated with a reduction in all-​cause mortality in patients
with MI without heart failure or systolic dysfunction.
This result suggests that not all patients presenting with
MI would benefit from β-​adrenergic receptor blocker
treatment, especially those without heart failure or
systolic dysfunction. Randomized controlled trials are
necessary to confirm this finding182.
Lipid-​lowering therapy is one of the most important
parts of secondary prevention. Statins, which reduce cir-
culating levels of cholesterol, are a well-​established treat-
ment for secondary prevention of CVD, as demonstrated
by several randomized controlled trials183–186. A meta-​
analysis of >90,000 individuals in 14 randomized trials
confirms the benefit of the use of statins after hospital
admission with MI, with reductions in total mortality
as well as further coronary events187. Further evidence
is provided by a study of >105,000 patients who began a
moderate-​intensity or high-​intensity statin therapy after
hospitalization for MI; overall, 1.7% of patients had sta-
tin intolerance, and 52.8% had high adherence to statin
therapy. Results suggested an incidence of recurrent MI
that was 36% higher in patients with intolerance and a
43% higher risk of CAD in patients with statin intoler-
ance than in those with high statin adherence188, whereas
the risk of mortality was similar across the groups over a
median follow-​up of 1.9–2.3 years.
Genetic studies have shown lower levels of LDL cho-
lesterol and a reduced risk of CVD in individuals with
loss-​of-function mutations in PCSK9 (which encodes
proprotein convertase subtilisin/kexin type 9, a protein
that promotes the catabolism of LDL receptors, thereby
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increasing circulating levels of LDL particles)189. Drugs
targeting PCSK9 include monoclonal antibodies (evo-
locumab and alirocumab) and small interfering RNAs
(inclisiran) and are associated with impressive reduc-
tions (40–60%) of LDL cholesterol when combined with
statin therapy190,191. A randomized placebo-​controlled
trial of evolocumab showed a 20% relative risk reduc-
tion in cardiovascular events (cardiovascular death, MI
or stroke) after a median follow-​up of 2.2 years190, and a
trial of alirocumab showed a 15% relative risk reduction
in major cardiovascular events192. However, these drugs
are currently not routinely prescribed to patients with
STEMI owing in large part to their high cost.
Cardiac rehabilitation typically includes assessment
of motivation to change lifestyle, education on goal plan-
ning, referrals to other services (for example, dietary
and smoking cessation advice), exercise with individual
programmes and advice on relaxation and stress man-
agement193. Systematic reviews have shown the benefit
of cardiac rehabilitation in patients after MI, showing
a reduction in all-​cause and cardiovascular mortality
between 13% and 25%194–196. However, the role of car-
diac rehabilitation has been debated recently, after the
RAMIT trial showed no significant beneficial effects
of cardiac rehabilitation on survival following MI197.
A recent study attempted to address the issue and
showed a 46% lower mortality at 10 years in patients
who completed rehabilitation than in those who did not
complete it after treatment with primary PCI198.
Pre-​discharge risk stratification
Patients with STEMI should have an evaluation of early
and long-​term risk of adverse cardiovascular events
before hospital discharge, including assessment of the
LVEF, severity of CAD and completeness of coronary
revascularization2,20. Guidelines encourage the use of
clinical scores such as the thrombolysis in myocardial
infarction (TIMI) or GRACE scores for STEMI to assess
early and long-​term risk2,20,199. Both scores seem to per-
form comparably for prediction of in-​hospital death200,
and the GRACE score for STEMI also provides progno­
stic information for 6 months after discharge201. By con-
trast, compared with non-​ST-segment elevation-acute
coronary syndrome (NSTE-​ACS) guidelines, STEMI
guidelines do not emphasize prognostication using
biomarkers3,199. Several biomarkers have been reported
to confer independent or complementary prognostic
information after STEMI, including cTn76,202, BNP203,
NT-proBNP204, midregional pro-​ANP205, growth and
differentiation factor 15 (ref.206), IL-1 receptor-​like 1 (also
known as ST2)207, glycated haemoglobin A1c (HbA1c)208 or
biomarker panels209. However, besides the measurement
of metabolic risk markers, such as LDL cholesterol and
glucose, and renal function, no explicit recommenda-
tions are given for the routine measurement of additional
prognostic biomarkers after STEMI.
Quality of life
The major goals of treating patients with CAD are to
reduce the risk of major adverse cardiovascular events,
prolong life and improve patients’ symptoms, func-
tional status and quality of life. In the setting of STEMI,
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treatments are often directed towards improving sur-
vival and preservation of viable myocardium to avert
the development of heart failure. However, the effect
of the MI on quality of life and the effect of treatments on
recovery are also of great importance to patients. Real-​
world studies (studies with no or broad selection criteria
with no specific intervention compared with randomized
controlled trials with a generally well-​specified popula-
tion and treatment) have shown that ~20% of patients
who were hospitalized for a STEMI have some degree
of residual angina 1 year after their MI — a rate that is
similar to that of patients recovering from NSTEMI and
coronary revascularization in general210,211. Importantly,
there is substantial variation in the risk of having resid-
ual angina after an MI, with young age, CABG surgery,
a high burden of pre-​MI angina and depression as inde-
pendent predictors of residual angina211 and poorer
quality of life after MI212. Residual angina may have a
particularly negative effect on the quality of life of young
patients recovering from a STEMI, as it can impair the
ability to work and fulfil everyday tasks. The transition
from being completely healthy to being a patient with
heart disease after MI may be especially difficult, and
depression after acute MI, which is strongly associated
with residual angina after an MI, is also more common
in young patients and women213.
Historically, compared with balloon angioplasty
alone, PCI with stenting decreases the risk of residual
angina — at least in the intermediate term — probably
through reduction in restenosis. In the Stent Primary
Angioplasty for Myocardial Infarction trial — one of
the few STEMI trials to examine quality of life — 21%
of patients in the stent arm reported angina at 6 months
after STEMI compared with 43% in the angioplasty
arm214. In patients with STEMI and multivessel coro-
nary disease, observational data suggest that complete
revascularization (either during index hospitalization or
staged) is associated with less angina and better quality of
life than culprit-​only PCI215. Smoking cessation after an
MI is also associated with less angina and better quality
of life at 1 year after MI, with residual angina rates of 29%
in persistent smokers compared with 21% in those who
quit after MI and 18% in patients who never smoked
or quit before their MI216. Interestingly, participation in
cardiac rehabilitation, which improves survival, has not
been associated with better quality of life217.
Optimal medical therapy with antiplatelet agents,
statins, β-​adrenergic receptor blockers and ACE inhibi-
tors has an important role in reducing the risk of recur-
rent ischaemic events and improving survival. However,
medical therapy has not been shown to reduce the risk
of residual angina or improve quality of life211. Clearly,
there is a role for antianginal medications in the post-​MI
patient who has residual angina, but a strategy of pre-​
emptive antianginal medications has not been tested in
patients with STEMI.
Outlook
The development of novel antithrombotic strategies and
percutaneous devices, combined with decreased delay
from first medical contact to the catheterization lab­
oratory, has led to a progressive and consistent reduction

in mortality among patients with STEMI218,219. Despite
these advances, ~20% of patients with acute MI expe-
rience recurrent cardiovascular events within the fol-
lowing year21. This observation demonstrates the need
for the development of new therapeutic targets, such
as inhibition of the inflammatory pathway, or meas-
ures to improve microvascular perfusion, which should
be coupled with techniques to identify patients who
would benefit the most from treatment. Finally, as
novel advancements begin to make their way into clin-
ical guidelines, discrepancies between guideline-​based
treatment and daily practice in STEMI are accentuated
in developing countries220. Thus, it is important to strive
to close the gap in access to life-​saving therapies, which
will be a challenge for decades to come.
New strategies that target inflammation
As discussed earlier, inflammation plays an impor-
tant part in atherogenesis and plaque evolution 221.
The CANTOS trial was the first to validate the inflamma-
tory hypothesis in a large cohort of patients with CAD:
targeting the IL-1β innate immune pathway with cana­
kinumab (an anti-​IL-1β human monoclonal antibody)
led to a clinically meaningful 15% relative reduction in
major cardiovascular events compared with placebo,
regardless of the LDL level222. The CIRT trial evaluated a
different approach to target inflammation, using a ther-
apy with low-​dose methotrexate; however, this therapy
did not result in lower IL-1β, IL-6 or C-​reactive protein
(CRP) levels than placebo. The trial was stopped early
and did not show a difference between the groups with
regard to the composite end point of non-​fatal MI, non-​
fatal stroke or cardiovascular death. Instead, methotrex-
ate was associated with elevations in the levels of liver
enzymes, reductions in leukocyte counts and haemato­
crit levels and an increased incidence of non-​basal-cell
skin cancers223. One of the explanations for the conflict-
ing results of the CANTOS and CIRT trials may be based
on the fact that CANTOS included only patients with
high residual inflammatory risk and limited the enrol-
ment to those with persistently elevated high-​sensitivity
CRP levels, whereas CIRT did not screen for CRP levels.
Both CIRT and CANTOS enrolled patients with athero­
sclerosis who were in stable condition, and there are few
data in the acute setting. Anakinra, an IL-1 receptor
inhibitor, was evaluated in two small phase II studies
among patients with acute MI, reducing high-​sensitivity
CRP levels224,225. In addition to the interleukin pathway,
T cell activation signalling, synthetic inhibitors of the
protein tyrosine phosphatase, low doses of IL-2 and
infusion of autologous regulatory T cells are in devel-
opment or represent future areas of research to target
inflammation in ACSs226.
No reflow and reperfusion injury
Some aspects of the pathophysiology of MI remain
surprisingly refractory to successful treatment. The no-​
reflow phenomenon is a complication that can occur
following coronary revascularization and is associated
with an increased risk of cardiogenic shock, recurrence
of MI and mortality227,228. Although the risk factors are
well known (such as high thrombus burden, primary
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PCI setting per se and ischaemic time), there are still
no highly effective treatment options. Use of GPIIb/IIIa
inhibitors and vasodilators has failed to demonstrate a
clinical benefit in several observational studies and ran-
domized trials229. Reducing the total ischaemic time by
bringing the patient to the cardiac catheterization labora-
tory as quickly as possible remains one of the most effec-
tive ways to prevent the no-​reflow phenomenon as well
as reperfusion injury. To this end, devices that alert the
patient to the presence of a heart attack may reduce
the time from symptom onset to hospital admission and
thereby total ischaemic time230,231. Although pharma-
ceutical trials targeting reperfusion injury did not show
any beneficial results with regard to clinical outcomes,
evidence exists that remote ischaemic conditioning (that
is, inducing ischaemia in a tissue distant from the heart)
has a protective effect on the heart and improves clini-
cal outcomes by reducing myocardial injury232. Greater
understanding of the complex pathophysiology, includ-
ing the mechanism of reperfusion injury, may identify
additional targets to prevent the loss of the microvascu-
lar integrity and increase vascular permeability. Despite
numerous failures to date, the prevention and treatment
of reperfusion injury, which directly affects infarct size,
should remain a focus of future cardiovascular research.
Stem cell therapy
Stem cell therapy has been presented as a promising
future therapeutic option over the past decade, particu-
larly in cardiology233,234. Repairing damaged tissue fol-
lowing an MI by injecting undifferentiated cells into the
myocardium is an incredibly challenging strategy that
could potentially limit the development of heart failure,
regardless of the treatment administered before the PCI.
However, there are many uncertainties with regard to
this strategy. The regulatory mechanism of stem cell dif-
ferentiation into cardiomyocytes remains unclear. Thus,
which cell types should be used for cell transplantation,
the mode of delivery, the optimal environment to guar-
antee that stem cells differentiate into cardiomyocytes
and the optimal timing for stem cell transplantation
remain unclear. In addition, recent calls for retraction of
journal articles and the pause of the related CONCERT-​
HF trial have contributed to the uncertainty about the
role of stem cell therapy in heart failure after MI235.
Personalized medicine and artificial intelligence
Regardless of the pathway targeted, one of the challenges
will be to identify and select the right population that
may derive the greatest benefit from new treatments.
Whereas trials draw inferences about populations,
machine learning explores large data sets and uses algo-
rithms that can make predictions regarding outcomes in
individual patients. In health care, global interest in the
potential of machine learning has increased236. In fact,
deep learning algorithms have already demonstrated
high accuracy in detecting left ventricular diastolic
dysfunction on ECG237,238. Personalized benefit–risk
estimates are another possible utilization of machine
learning algorithms. Further, the use of machine learning
models to define the population of interest, in everyday
practice or in clinical trials, may change the way patients
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with ACS are stratified on the basis of their risk and may
optimize the benefit–risk ratio for an individual patient.
Harmonizing the standard of care
In STEMI, therapeutic strategies may differ slightly
according to the characteristics of each population or
region239. Nevertheless, the American and European
guidelines share the same reperfusion strategy recom-
mendation based on a network of primary PCI-​capable
and non-​PCI-capable hospitals20. This consensus is the
result of years of accumulation of high-​level evidence
that has led to large-​s cale modification in national
health-​c are policy to improve access to life-​s aving
therapies. However, in the United States, more than
one-​third of the patients with STEMI transferred to a
PCI-​capable centre for primary PCI still fail to achieve
a delay time ≤120 minutes despite estimated transfer
times <60 minutes2,240.
There are many steps along the path from accu-
mulating evidence regarding new practices to their
widespread adoption241,242. For instance, educational
programmes, based on survey data evaluating the gap
between daily practice and guidelines, were crucial in
adjusting and increasing the adherence to the evidence-​
based therapy220,243. This gap is known to be influenced by
many factors, including cultural, educational, financial
and geographical aspects of each region244.
An example of the effect of these efforts is the trans-
formation of the management of ACS in Romania.
In 2004, Romania had a staggering 20% in-​hospital
mortality in patients with STEMI. Despite having the
lowest health-care budget in Europe, a 13% reduction in
in-hospital STEMI mortality was achieved through the
implementation of a modern primary PCI network
in 2011 (ref.245). Romania’s efforts serve as an example of
what can be achieved in emerging countries and demon-
strate that at least 5 years of hard work may be necessary
to implement such strategies.
Although the adherence to guideline-​recommended
therapies and devices and access to a cardiac catheteri-
zation laboratory are markedly lower among emerging
countries than in developed countries, the numbers of
patients, by contrast, continue to increase, with >70%
of the cases of STEMI projected to occur in develop-
ing regions in the next 10 years246. This estimate high-
lights the urgent need to foster an effective system to
promote and develop evidence-​based revascularization
recommendations and educational initiatives for these
countries. The 10-year success with The Stent for Life
Initiative, a nonprofit international organization of
national cardiac societies and partnering stakeholders,
is a leading example in this field220. This programme sup-
ports the implementation of European STEMI guide-
lines through a network of stakeholders, educational
programmes and awareness campaigns247.
Several decades following the advent of PCI for MI,
tremendous progress continues in the development of
novel stents and haemodynamic support devices as well
as intracoronary imaging techniques. There has been a
parallel development of new therapeutic targets in the
pharmacological field, such as improved antiplatelet and
antithrombin agents, and the inflammation pathway may
prove to be a valuable additional target to improve out-
comes as well. The development of new analytic meth-
ods may help clinical decision making and may further
optimize the benefit–risk ratio in individual patients.
Published online xx xx xxxx

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Acknowledgements
S.G. acknowledges financial support from MEXT/JSPS
KAKENHI 17K19669 and partly from 18H01726 and
19H03661. S.G. acknowledges financial support from
Bristol-​Myers Squibb from their independent research sup-
port project (33999603) and financial support from the
Vehicle Racing Commemorative Foundation and the Nakatani
Foundation of measuring technologies in biomedical
engineering.
Author contributions
Introduction (B.V.); Epidemiology (D.S.P. and B.V.);
Mechanisms/pathophysiology (R.M., B.V., S.G. and B.E.C.);
Diagnosis, screening and prevention (V.K., H.A.K., D.C.,
E.G.,B.E.C. and B.V.); Management (P.G.S., B.E.C., T.K., H.S.
and B.V.); Quality of life (D.J.C., S.V.A. and J.A.S.); Outlook
(C.M.G., M.K. and B.V.); Overview of Primer (R.M.).
Competing interests
R.M. or her spouse has received institutional research grant
support from Bayer, Beth Israel Deaconess, The Medicines
Company, Bristol-​Myers Squibb, Sanofi, CSL Behring, Eli Lilly,
Medtronic, Novartis Pharmaceuticals, OrbusNeich and
AstraZeneca; has received consulting fees from Abbott
Laboratories, Abiomed, AstraZeneca, Bayer, Boston
Scientific, CardioKinetix, Cardiovascular Systems, Medscape,
Siemens Medical Solution, Spectranetics, The Medicines
Company, Roivant Sciences, Volcano Corporation, CSL
Behring, Janssen Pharmaceuticals, Merck & Co. and Osprey
Medical; has served on a data safety monitoring board for
Watermark Research Partners; holds equity in Claret Medical
and Elixir Medical; and serves on advisory boards of Abbott
Laboratories, Bristol-​M yers Squibb, Boston Scientific
Corporation, Covidien, Janssen Pharmaceuticals, The
Medicines Company and Sanofi. S.G. received research fund-
ing from Sanofi, Pfizer and Ono; is an associate editor for
Circulation from the American Heart Association and is a
m e m b e r o f t h e S t e e r i n g C o m m i t t e e fo r E vo l v i n g
Anticoagulation in AF and VTE programme at Medscape.
J.A.S. declares ownership of the copyright to the Seattle
Angina Questionnaire. All other authors declare no
competing interests.
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