ISCHAEMIC HEART DISEASE
Definitions of acute
coronary syndromes
Retesh Bajaj
Ajay K Jain
Charles Knight
Abstract
The Third Universal Definition of myocardial infarction (MI) and the clin-
ical use of high-sensitivity troponins have resulted in an increase in pa-
tients recognized with a diagnosis of MI. Although the most common
cause of MI remains acute coronary syndrome (ACS) caused by
atherosclerotic coronary artery disease, it is increasingly important
to be aware of other causes of ACS, which are likely to be seen with
greater frequency as recognition of MI increases. It is essential to
define the cause of ACS resulting in MI as it has profound implications
for treatment strategy and prognosis.
Keywords Acute coronary syndrome; MRCP; myocardial infarction;
troponin
Background
The definition of acute coronary syndrome (ACS) has evolved in
recent years. Early insights identified the clinical syndrome as
resulting from an ischaemic insult to the myocardium caused by
thrombosis and vessel occlusion related to obstructive athero-
sclerotic coronary artery disease; this then causes cardiomyocyte
necrosis or myocardial infarction (MI).1 Later studies focused on
identifying ever more sensitive markers of this myocardial ne-
crosis, which led to the identification of cardiac troponins. Their
use is now commonplace in clinical practice in identifying MI
and, in the correct clinical context, ACS.
Research over the last two decades has delineated that
although coronary artery disease remains the major cause of an
acute rise in troponin identifying MI, there are myriad other
pathological processes other than ACS that can lead to MI. As
troponin biomarkers increase the incident detection of MI, the
cause of MI, be it ‘classic’ ACS recognized as a ‘heart attack’,
rarer causes of ACS or non-coronary causes, should be sought to
accurately define the diagnosis.
The Third Universal Definition of MI published in 2012 re-
flected this.2 It divided acute MI into five types based on heter-
ogenous pathological causes, with the classic (and most
Retesh Bajaj MB BS BSc MRCP is a Cardiology Registrar at Barts
Health, London, UK. Competing interests: none declared.
Ajay K Jain BSc MRCP MD is a Consultant Cardiologist at Barts Health,
London, UK. Competing interests: none declared.
Charles Knight MD FRCP FESC is Director of the Cardiovascular
Clinical Academic Unit at Barts Health, London, UK. Competing
interests: none declared.
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Key points
C Recognition of myocardial infarction (MI) has improved and
become more frequent with high-sensitivity troponins
C MI simply implies myocardial necrosis, and does not neces-
sarily implicate causality
C MI can be caused by epicardial coronary plaque disease (acute
coronary syndrome (ACS)) or rarer causes
C MI is most commonly caused by ACS and clinically classified
into ST elevation and non-ST elevation ACS to guide treatment
strategy based on clinical risk
C Rarer causes include coronary vasospasm, embolization,
dissection and Takotsubo’s cardiomyopathy
C Defining the cause of the MI is essential for identifying the
appropriate treatment strategy
common) cause resulting from thrombotic vessel occlusion being
just one type. Hence, it is useful to note that although the terms
ACS and MI have evolved to be used interchangeably, the cause
of troponin leak or MI may not necessarily be strictly ACS, and
ACS may not strictly be occlusive epicardial coronary artery
disease. This distinction and specificity in pathophysiology is
essential as it has significant implications for long-term treatment
plans: for example, a patient with no significant coronary artery
disease noted to have a rise in troponin in the context of sepsis
would be treated quite differently from a patient with an
occluded coronary artery treated with angioplasty and percuta-
neous coronary intervention (PCI).
As rates of diagnosis of MI increase, partly because of high-
sensitivity troponins improving the recognition of myocardial
necrosis, the definition of ACS will become ever more critical to
guide treatment.
Types of MI (based on the Third Universal Definition)
MIs can be divided into five types based purely on pathological
causes, as characterized by the Third Universal Definition pub-
lished in 2012 (Table 1).2
Type 1 MI is caused by the classically recognizable clinical
entity of ACS related to atherosclerotic plaque rupture or erosion,
or coronary dissection. A decrease in epicardial blood supply to a
region of myocardium results in hypoxic damage and, ultimately,
tissue necrosis and infarction. Type 1 MI is clinically subdivided
based on symptoms, electrocardiogram (ECG) changes and
biomarker evaluation to expedite appropriate triage and man-
agement. This can include early invasive coronary angiography
and intervention with angioplasty and coronary stent insertion.
Type 2 MI results in myocardial necrosis and troponin leak
caused by an imbalance between myocardial oxygen demand
and supply. The underlying pathological mechanisms are
528 Ó 2018 Published by Elsevier Ltd.
 ISCHAEMIC HEART DISEASE
Types of myocardial infarction (MI)
C Type 1 e spontaneous MI related to ischaemia caused by a pri-
mary coronary event, such as plaque fissuring or rupture
C Type 2 e MI secondary to ischaemia resulting from an imbalance
between oxygen supply and demand
C Type 3 e sudden death from cardiac disease with symptoms of
myocardial ischaemia, accompanied by new ST elevation or left
bundle branch block, or verified coronary thrombus at angiog-
raphy and/or autopsy
C Type 4 e MI associated with percutaneous coronary intervention
C Type 5 e MI associated with coronary artery bypass grafting
Table 1
heterogenous and include anaemia, tachy- or brady-arrhythmia,
hypertension or hypotension, coronary artery spasm, coronary
endothelial dysfunction and respiratory failure.
A rise in troponin concentration caused by myocardial ne-
crosis is also recognized in critically ill patients and patients
undergoing major non-cardiac surgery; here it may be related to
cell dysfunction and damage caused by toxins, sepsis syndrome
or pharmacological agents. Notably, in these patients, the
epicardial vessels may be patent, but there is a ‘supply and de-
mand’ mismatch leading to myocardial necrosis. Coronary artery
disease may be worsening this mismatch, so a careful assessment
of risk factors, cardiac symptom history and current clinical
context is essential in guiding management.
Type 3 MI is defined as a typical presentation of myocardial
ischaemia/infarction in which the patient dies before it is
possible to detect biomarker elevation.
Two types of type 4 MI have been described: 4a, in which
serum troponin rises after PCI, and type 4b, which relates to
acute stent thrombosis.
Finally, critical elevation of troponin in association with cor-
onary artery bypass surgery is known as type 5 MI.
The impact of ACS
Coronary artery disease causing ACS and MI remains one of the
leading causes of death worldwide, irrespective of socioeconomic
status. World Health Organization statistics estimate that 13% of
the 57.1 million global deaths recorded in 2015 resulted from
coronary artery disease, with over three-quarters of these taking
place in low- and middle-income countries.3 This agrees with
British Heart Foundation statistics from 2015 suggesting that
14% of all deaths in men and 9% in women in the UK resulted
from coronary artery disease.4
Troponins in recognizing MI versus diagnosing ACS
It is difficult to overstate the key role that troponins, especially
high-sensitivity troponins, have played as sensitive and specific
biomarkers of myocardial necrosis in recognizing MI; this has led
to their incorporation as key to its definition (Table 2).5 Apart
from being needed for governance and epidemiological accuracy,
the correct diagnosis of MI is essential to guide appropriate pa-
tient management and indicate risk, as myocardial necrosis as a
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risk factor adversely affects morbidity and mortality across all
patient groups.
However, even though positive troponins help in identifying
MI, correlation with ACS or an alternative cause can be clinically
challenging. MI can be the first presentation of significant coro-
nary artery disease and the result of an ACS; alternatively, it can
be a coincidental finding in an alternative pathology and unre-
lated to ACS.
The clinical presentation of ACS is known to be variable and
can include so-called ‘silent’ events (without overt chest pain)
and classic anginal chest pains at rest through to sudden death
from catastrophic cardiac ischaemia causing heart failure or
cardiac arrest.
Clinical diagnosis of ACS: ST and non-ST elevation
As occlusive coronary artery disease is the most common cause
of ACS, clinical classification aims at rapid identification and
treatment, informed by established data and guidelines to mini-
mize morbidity and mortality.
ACS can usually be identified clinically by a patient’s history,
ECG findings and highly sensitive cardiac biomarkers. Rapid
diagnosis allows for earlier identification of high-risk patients
and revascularization to minimize MI. Classically, patients pre-
senting with persistent (>20 minutes) cardiac-sounding chest
pain at rest who have persistent ST segment elevation in two or
more contiguous leads are designated as having ‘ST elevation
ACS’ or ‘ST elevation MI’ (STEMI). The degree of ST elevation
depends on age and sex. Acute or evolving changes in the STeT
waveforms can be highly valuable in locating the responsible
artery and the timing of the event, and in estimating the pro-
portion of myocardium at risk. ACS maybe the result of plaque
rupture and thrombosis (most commonly) impairing coronary
blood supply to the myocardium, with myriad causes that can
include coronary vasospasm caused by cocaine or coronary
dissection, which can effectively do the same. Rarer causes
include embolization of clot or septic embolization down a cor-
onary artery related to infective endocarditis.
Patients diagnosed with STEMI are treated as a medical
emergency, ideally with primary PCI; rapid intervention aiming
to restore blood flow is the gold standard of treatment, unless
contraindicated.5
Patients presenting with continuing cardiac chest pains
without persistent ST elevation are designated as having non-ST
elevation ACS. Where biomarker values indicating car-
diomyocyte necrosis are raised, patients are said to have had a
non-STEMI (NSTEMI). In these patients, new ST depression or T
wave changes can occur, or alternatively the ECG can be normal.
Patients with high-risk features such as significant increases in
troponins and dynamic ECG changes are generally treated with
an early interventional approach. Continuing chest pain re-
fractory to medical therapy, for example intravenous nitrates, is
treated with emergency angiography and PCI, if appropriate (see
Further reading). Patients without elevated biomarkers and
symptoms at rest are labelled as having unstable angina. With
the advent of high-sensitivity troponins, this group has become
smaller, but current research indicates that, compared with
NSTEMI patients, it has a substantially lower risk of death (see
Further reading).
529 Ó 2018 Published by Elsevier Ltd.
 ISCHAEMIC HEART DISEASE
Criteria for acute myocardial infarction (MI)
C Detection of a rise and/or fall of cardiac biomarkers (preferably
troponin (cTn)) with at least one value above the 99th percentile
of the upper reference limit (URL) together with evidence of
myocardial ischaemia (at least one of the following):
e Symptoms of ischaemia
e New or presumed new significant ST-segmenteT wave (STeT)
changes or new left bundle branch block (LBBB)
e Development of pathological Q waves in the ECG
e Imaging evidence of new loss of viable myocardium or new
regional wall motion abnormality
e Identification of an intracoronary thrombus by angiography or
autopsy
C Cardiac death with symptoms suggestive of myocardial ischaemia
and presumed new ischaemic ECG changes or new LBBB, but
death occurred before blood samples could be obtained or before
cardiac biomarker values would be increased
C Percutaneous intervention (PCI)-related MI is arbitrarily defined
by elevation of cTn values (>5  99th percentile URL) in patients
with normal baseline values (99th percentile URL) or a rise of
cTn values >20% if the baseline values are elevated and are
stable or falling. In addition, either (i) symptoms suggestive of
myocardial ischaemia or (ii) new ischaemic ECG changes or (iii)
angiographic changes consistent with a procedural complication
or (iv) imaging demonstrating new loss of viable myocardium or
new regional wall motion abnormality are required
C Stent thrombosis associated with MI detected by coronary angi-
ography or autopsy in the setting of myocardial ischaemia and a
rise and/or fall of cardiac biomarker values with at least one value
above the 99th percentile URL
C Coronary artery bypass grafting (CABG)-related MI is arbitrarily
defined by elevation of cardiac biomarkers (>10  99th percentile
URL) in patients with normal baseline cTn values (99th percentile
URL). In addition, either (i) new pathological Q waves or new LBBB,
or (ii) angiographic documented new graft or native coronary artery
occlusion, or (iii) imaging evidence of new loss of viable myocar-
dium or new regional wall motion abnormality
Adapted from Thygesen et al.2
Table 2
It is important to interpret ECGs within the clinical context
and, where possible, compare them with previous ECGs as ST
deviation can be observed in other conditions, including left
ventricular hypertrophy, Brugada syndrome, acute pericarditis,
myocarditis, Takotsubo’s cardiomyopathy and early repolariza-
tion e some of these mimics are discussed below.
Clinical classification of ACS allows triaging and selection of
the first investigative step, namely coronary angiography, to
potentially define the ACS and, with atherosclerotic disease,
allow potential treatment.
ACS defined by pathophysiology
Although it is valuable to recognize MI and clinically diagnose
ACS, it is vital to be aware of the various causes of ACS, some of
which are described below.
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Plaque disease and thrombosis: coronary atherosclerotic plaque
narrows the coronary artery lumen. Plaque rupture can become a
nidus for thrombosis and vessel occlusion, resulting in myocar-
dial ischaemia and infarction. Acute stent thrombosis is a well-
recognized phenomenon of clot formation within a previous
coronary artery stent; its incidence has markedly reduced with
the advent of newer drug-eluting stents and more advanced an-
tiplatelet therapy regimens.
Coronary artery dissection: this can result from a type A aortic
dissection involving a coronary artery and is a recognized mimic
of ACS. Clinical suspicion can be raised by differential pulses and
blood pressures in the limbs, haemodynamic instability and oc-
casionally bedside echocardiography, although the definitive
investigation is contrast-enhanced computed tomography (CT)
aortography.
Spontaneous coronary artery dissection is a recognized entity
classically affecting women who may be young with no coronary
atherosclerosis. This diagnosis is generally made on angiography,
and clinically these patients can present as having classic ACS.
Coronary vasospasm: this can be associated with cocaine abuse
and must be considered particularly in younger age groups,
although it is not exclusive to them. A thorough history is
essential. b-Adrenoceptor blockers must be avoided in this
group, and treatment with nitrates is indicated.
Prinzmetal’s or variant angina: this results in coronary vaso-
spasm and is diagnosed angiographically with ST elevation
revealed using intracoronary acetylcholine. It is treated with
calcium channel blockers and nitrates.
Coronary embolization: this very rare condition can be either
septic embolization from infective endocarditis, resulting in
vessel occlusion and STEMI, or clot embolization related to a
patent foramen ovale or atrial septal defect. The result can be
coronary occlusion, and clinically it can be indistinguishable
from STEMI because of this e the clinical context (e.g. sepsis in
infective endocarditis) and single vessel isolated disease/occlu-
sion should raise suspicion.
Takotsubo’s cardiomyopathy: this can present as STEMI and is
recognized in postmenopausal women predominantly after
physical or emotional stress. The exact cause is unclear and has
been speculated to be multivessel epicardial spasm,
catecholamine-induced myocardial stunning or microvascular
spasm. A classic picture of left ventricular contraction seen on
invasive angiography is said to resemble an ‘octopus pot’ (its
name being a direct translation from the Japanese for this), and is
pathognomonic. Troponin concentrations are likely to be
elevated. The acute phase can involve dramatic and life-
threatening heart failure that requires supportive management
and sometimes critical care. However, myocardial recovery and
prognosis are excellent.
Mimics of ACS
The following conditions can present to hospital acutely and be
mistaken clinically for ACS. However, they are strictly speaking
530 Ó 2018 Published by Elsevier Ltd.
 ISCHAEMIC HEART DISEASE
not coronary syndromes even though they can result in ECG
changes and myocardial necrosis. Some of them also result in
troponin leak and therefore show evidence of myocardial ne-
crosis or MI. The following classic findings are noted.
Pericarditis: widespread saddle-shaped ST elevation. PR
depression, particularly in leads II and V1 (and reciprocal PR
elevation in aVR), is relatively specific for this. Troponin con-
centrations may increase if there is coexisting myocarditis.
Myocarditis: the umbrella term for heterogenous conditions that
can be mild and self-limiting or catastrophic, resulting in severe
and rapid heart failure with a large increase in troponins.
Specialist input to guide management of these often complex and
unwell patients should be sought early.
Normal variant/benign early repolarization: sometimes
referred to as a ‘high take-off’ pattern. This is associated with a
lack of cardiac symptoms and normal troponin concentrations.
Brugada syndrome: ST elevation in a pathognomonic shape
only in leads V1eV3, related to a channelopathy. The ST eleva-
tion may only be precipitated during a fever, and a lack of chest
pain should arouse suspicion in these patients. Troponin con-
centrations should not be elevated.
Diagnosis e defining ACS
The advent of high-sensitivity troponin use and the Third Uni-
versal Definition of MI have increased the number of patients
recognized as having had an MI e most are either type 1 or type
2 MI. Most cases are diagnosed as an ACS and, given the multiple
causes of ACS, accurate diagnosis is key to the appropriate
management of this heterogenous group,. Generally, most pa-
tients with clinical ACS undergo coronary angiography inva-
sively as a diagnostic test to assess epicardial coronary blood
TEST YOURSELF
To test your knowledge based on the article you have just read, please complete the questions below. The answers can be found at the
end of the issue or online here.
Question 1
A 55-year-old man presented with a 5-hour history of chest
discomfort associated with palpitations and dizziness. He had no
significant past medical history and had a 10 packeyear smoking
history.
On clinical examination, his heart rate was 160 beats/minute,
and blood pressure 110/70 mmHg.
Investigations
 ECG showed supraventricular tachycardia
 High-sensitivity troponin 65 ng/litre (1e24)
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flow; this allows for simultaneous therapeutic treatment if there
is vessel occlusion. An alternative modality is CT coronary
angiography; this may be preferable in a subset of patients to
exclude significant epicardial coronary artery disease.
Contrast-enhanced cardiac magnetic resonance imaging is
extremely valuable if there is diagnostic uncertainty, and pro-
vides insights into myocardial damage and aetiology. It can help
to identify myocarditis and MI, and characterize cardiomyopa-
thy, with great specificity.
As MI and ACS become more widely recognized, the multiple
potential causes of ACS must be recognized, as must the mimics
of ACS, to guide appropriate management. A
KEY REFERENCES
1 Libby P. Current concepts of the pathogenesis of the acute coro-
nary syndromes. Circulation 2001; 104: 365e72.
2 Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of
myocardial infarction. Circulation 2012; 126: 2020e35.
3 World Health Organization. Cardiovascular diseases (CVDs). http://
www.who.int/mediacentre/factsheets/fs317/en/ (accessed 4 July
2018).
4 British Heart Foundation. Cardiovascular disease statistics. 2017,
https://www.bhf.org.uk/research/heart-statistics/heart-statistics-
publications/cardiovascular-disease-statistics-2017 (accessed 5
January 2018).
5 Ibanez S, James S, Agewall S, et al. 2017 ESC Guidelines for the
management of acute myocardial infarction in patients presenting
with ST-segment elevation. Eur Heart J 2018; 39: 119e77.
FURTHER READING
Roffi M, Patrono C, Collet JP, et al. 2015 ESC Guidelines for the
management of acute coronary syndromes in patients presenting
without persistent ST-segment elevation. Eur Heart J 2016; 37:
267e315.
Based on the Third Universal Definition, what type of
myocardial infarction is this?
A. Type 1
B. Type 2
C. Type 3
D. Type 4a
E. Type 4b
Question 2
A 58-year-old woman presented with collapse and chest
discomfort. She had been having an argument with a colleague
and had felt unwell before losing consciousness.
On clinical examination, her heart rate was 100 beats/minute,
and blood pressure 100/60 mmHg.
531 Ó 2018 Published by Elsevier Ltd.
 ISCHAEMIC HEART DISEASE

Investigations 2-week history of feeling feverish and unwell. He had a history of

 ECG demonstrated widespread ST elevation aortic valve replacement.
 High-sensitivity troponin 500 ng/litre (1e24) On clinical examination, his temperature was 38.8 C, heart rate
 Emergency coronary angiography showed unobstructed 120 beats/minute, and blood pressure 134/88 mmHg. There was
coronary arteries a systolic murmur to the right of the sternum. He was
 Left ventriculogram demonstrated regional wall motion commenced on antibiotics on admission, and further in-
abnormalities in the left ventricle primarily affecting the vestigations were undertaken for the chest pain.
apex with hyperdynamic wall motion near the valves
Investigations
 ECG demonstrated an anterior ST elevation myocardial
What is the most likely diagnosis?
infarction
A. Coronary dissection
B. Coronary vasospasm
C. Takotsubo’s cardiomyopathy What is the likely cause of the acute coronary syndrome?
D. Thrombotic embolization A. Coronary dissection
E. ST elevation myocardial infarction with spontaneous B. Coronary vasospasm
recanalization C. Embolic phenomena
D. Plaque rupture
Question 3 E. Plaque shift
A 48-year-old man developed acute central chest pain 6 hours
after admission to a medical ward. He had been admitted with a

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