Review
Acute stress-induced (takotsubo)
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Correspondence to
Dr Dana K Dawson, School
of Medicine and Dentistry,
University of Aberdeen and
Aberdeen Royal Infirmary,
Aberdeen, UK; ​dana.​dawson@​
abdn.​ac.​uk
Received 5 June 2017
Revised 11 July 2017
Accepted 20 July 2017
Published Online First
20 August 2017
To cite: Dawson DK. Heart
2018;104:96–102.
96   Dawson DK. Heart 2018;104:96–102. doi:10.1136/heartjnl-2017-311579
cardiomyopathy
Dana K Dawson
Abstract
Acute stress-induced (takotsubo) cardiomyopathy
has a dramatic clinical presentation, mimicking an
acute myocardial infarction and is triggered by intense
emotional or physical stress. In this paper, we review
the current state of knowledge of the mechanistic
physiology underlying the left ventricular ballooning.
The pathophysiology of the recovery from this acute
heart failure syndrome is presented. The short-term
and long-term outlook puts this new syndrome on a
different perspective compared with recently held views.
Current knowledge on susceptibility and predisposition
already define distinctive characteristics of patients
with takotsubo compared with myocardial infarction.
Gaps in knowledge and future directions of research are
identified in order to best direct efforts for identifying
specific therapies for this condition, in the acute
setting, to mitigate postacute symptoms or to prevent
recurrences, none of which exist.
Introduction
Acute stress-induced (takotsubo) cardiomyopathy
has a dramatic clinical presentation, mimicking
acute myocardial infarction (MI).1 The hallmark of
this increasingly recognised condition is the associ-
ation with a major emotional or physical stress that
appears to precipitate the onset. The former are
primary takotsubo presentations, whereas the latter
are secondary (complicating any other coexisting
medical condition or its treatment). It is usually
diagnosed when invasive cardiac catheterisation
demonstrates unobstructed coronary arteries, and
ventriculography shows characteristic left ventricle
(LV) ballooning leading to various degrees of acute
LV dysfunction.
Brief history and terminology
As the youngest diagnostic entity in cardiology,
takotsubo has made a rapid transition from an
initial curiosity proposed in Japan by Sato in 1990
to a reasonably frequent diagnosis in any cardiology
department. Although referred to initially as ‘apical
ballooning’, the term acute stress-induced cardio-
myopathy is probably most accurately reflecting this
neurocardiac condition. Its description by analogy
with the peculiar LV shape resembling a Japanese
octopus-fishing pot (figure 1) gave it the name of
‘takotsubo’, and it has also been widely presented in
the media by the resonant layman term of ‘broken
heart syndrome’.
Incidence, acute presentation pathways
and mechanistic pathophysiology
As the typical symptoms of takotsubo are sudden
onset of chest pain, breathlessness or collapse, these
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patients have an initial belief that they experience
an MI—so do most ambulance crews and front-
door physicians as the similarities of symptoms,
presenting ECG, and biomarkers between the two
conditions continue to raise difficulties in distin-
guishing them on presentation. In most cases the
diagnosis is established at coronary catheterisation
that shows unobstructed coronary arteries and one
of the typical patterns of LV ballooning. However,
delays in imaging investigations or concurrent pres-
ence of coronary artery disease introduce a degree
of uncertainty in establishing a clear diagnosis. A
diagnostic algorithm for these clinical scenarios has
been summed up by the European task force on
takotsubo in a recent position paper.2 In this decade
of growing awareness among clinicians and patients
alike, our own (unpublished) data as well as other
centres’3 demonstrate that ~7% of all patients with
presumed MI are in fact takotsubo.
ECG insights
Given the acute nature of takotsubo, it has been
tempting to speculate on ECG changes that may
add in the specificity of the diagnosis. However,
there is a considerable variation in the presenting
ECG, similar to that seen in acute MI. Patients
with takotsubo can present with a normal ECG
(11%), ST/T wave changes, (39%), ST-elevation
(39%), transient left bundle branch block (4%) or
arrythmias (atrial tachycardias, heart block and
ventricular arrhythmias) (7%). The head-to-head
comparison between the 12-lead ECGs of the ST-el-
evation-presenting patient groups suggests a larger
spread of ST-elevation, which is non-localising in
acute takotsubo, whereas the amplitude of ST-ele-
vation seems overall less than that of a typical MI
ECG.4 No acute ECG findings alone or in combina-
tion are specific enough to obviate or delay urgent
cardiac catheterisation. The most characteristic
takotsubo ECG feature remains the prolongation of
QT/QTc interval, seen at presentation and peaking
24–48 hours thereafter; however, larger compara-
tive studies will need to inform if this is a reliable
differentiating feature from MI after correcting for
gender differences in QTc since most takotsubo
patients are women and the reverse is the case for
MI. QTc prolongation is one of the factors consid-
ered to increase the risk of early arrhythmic compli-
cations without a direct correlation between the
magnitude of QTc and the arrhythmic risk. Takot-
subo recovery is characterised by significant repo-
larisation abnormalities (deep T-waves), which are
protracted, sometimes repeaking later5 and which
suggest that the myocardial healing process in this
condition is different from that of MI.

Figure 1  Japanese octopus fishing pot, called a ‘takotsubo’ (artwork
done by Dr David Northridge, Consultant Cardiologist, Edinburgh Royal
Infirmary).
Vascular, myocardial and humoural compartments
The coronaries’ patency together with the typical myocardial
ballooning seen at invasive angiography are the most poignant
objective findings. More recently, it has become accepted that
bystander findings of coronary artery disease do not preclude
takotsubo diagnosis2 as optical coherence tomography studies
conclusively showed a high prevalence of atherosclerotic plaques
(some of which are thin cap fibroatheromas), but a complete
absence of ruptured plaques or intracoronary thrombi.6 The dyski-
netic wall motion, exemplified in figure 2 (online supplementary
videos 1–-4), can involve the apex or midventricular cavity or
both together; much less frequently the base of the LV, and char-
acteristically dyskinesia occurs in a non-coronary distribution.7 A
focal (segmental) subtype has also been proposed.8 Concomitant
dyskinesia of the apical right ventricular myocardium has been
reported in apical and midcavity LV subtypes, ranging in inci-
dence from 15% to 50%, echocardiography typically reporting
Figure 2  End-diastolic (ED, top row) and end-systolic (ES, bottom row) frames of LV angiograms demonstrating the four types of LV ballooning seen
in takotsubo cardiomyopathy (arrows). Click on each image for cine loops (online supplementary videos 1–4). LV, left ventricle.
Dawson DK. Heart 2018;104:96–102. doi:10.1136/heartjnl-2017-311579
Review
less right ventricular involvement than magnetic resonance
studies.9–11 Cardiac biomarker release (troponin) is dispropor-
Heart: first published as 10.1136/heartjnl-2017-311579 on 20 August 2017. Downloaded from http://heart.bmj.com/ on 30 June 2018 by guest. Protected by copyright.
tionately low relative to the area of myocardial ballooning (up
to ~25× higher than upper laboratory ranges). While this points
towards a largely preserved myocardial viability, it most likely
represents stretch and non-apoptotic myocardial injury, as it
has been suggested from acute myocardial biopsies revealing
myocyte vacuolation and alteration of cytoskeletal and contrac-
tile proteins.12 Contrasting to low troponin levels, high levels
of brain natriuretic peptide and its N-terminal precursor were
reported in subgroups of patients13 14; since this is not a universal
finding, questions remain on whether they are representative of
the severity of the increased intracardiac pressures, or part of
a generalised inflammatory response, or an adaptive/protec-
tive haemodynamic mechanism. Other biomarkers have been
explored (copeptin,15 matrix metalloproteinases,16 proinflam-
matory cytokines,17 microRNAs (16 and 26a)),18 but a distinctive
biomarker pattern immediately applicable in clinical practice has
not yet emerged.
Cardiac Imaging
In most cases, further imaging is performed (figures 3–5,
online supplementary videos 5–20). Echocardiography is partic-
ularly useful in identifying systolic anterior motion of the mitral
valve leaflets in those with a hyperkinetic basal LV, or acute
mitral regurgitation, or determining the estimated pulmonary
artery pressure, all of which have been related to in-hospital
mortaliy.19 Cardiac magnetic resonance (CMR) has consistently
demonstrated intense myocardial oedema seen in both left20–23
and right11 ventricular myocardium and a relative lack of
macroscopic fibrosis.24 It is now clear that the initial reports of
late gadolinium enhancement represented a technical inability
to null the myocardium due to presence of intense oedema. This
oedema is so marked that it results in a measurable, charac-
teristic increase in LV mass in the acute phase.22 24 The acute
increase in LV mass and lack of late gadolinium enhancement
add diagnostic confidence, since takotsubo remains a diagnosis
of exclusion.
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Heart: first published as 10.1136/heartjnl-2017-311579 on 20 August 2017. Downloaded from http://heart.bmj.com/ on 30 June 2018 by guest. Protected by copyright.
Figure 3  Cardiac magnetic resonance (CMR) (A, B, E and F) and echocardiography (C, D, G and H) of end-diastolic and end-systolic four-chamber
view (top row) and three-chamber view (middle row) of an acute mid-to-apical ballooning. Click on all end-diastolic images for online cine loops:
A and E correspond to online supplementary videos 5 and 6. C and G correspond to online supplementary videos 7 and 8. Bottom row: (I–J)
corresponding four-chamber and three-chamber late gadolinium images demonstrating no macroscopic fibrosis. Spectrally adiabatic inversion
recovery with fat saturation (T2W-SPAIR) imaging shows high signal intensity (K) indicating myocardial oedema and native T1 mapping (L) shows
colour-coded high T1 values also indicative of oedema and able to quantify its extent (scale bar). All CMR imaging performed at 3T.

Invasive haemodynamics
However, despite this distinctively different pathophysiology of
the takotsubo heart, invasive heamodynamic studies have been
unable to identify any differences in indices of systolic (preload
recruitable stroke work and ventricular elastance) or diastolic
(end-diastolic pressure/volume relationship) performance
between takotsubo and acute MI.25 This is quite surprising given
that analyses of large, representative cohorts of patients have
shown that the LV ejection fraction at presentation is compa-
rably lower in acute takotsubo than in acute MI.8
A different patho-physiology
Thus, there are some unprecedented pathophysiological disso-
ciations in the clinical presentation of patients with takotsubo:
first, takotsubo appears to affect the entire ventricular myocar-
dium in the sense that there is a striking degree of panmyocardial
98
oedema, but despite this oedematous spread there is only local-
ised—although severe—myocardial impairment; second, there
appears to be a dissociation between the large extent of func-
tional involvement and the less affected haemodynamic status.
Third, there is a different resolution dynamic compared with
classical ‘stunned’/hibernating myocardium: in stunning/hiber-
nation the ECG and wall motion abnormalities resolve in tandem
once coronary blood flow is restored. In contrast, in takostubo,
there is a protracted, continuously evolving abnormal ECG
despite quick restoration of wall motion and relatively preserved
coronary blood flow reserve. Further  data is needed to fully
characterise the takotsubo coronary flow and microcirculation.
It is tempting to speculate that the largely preserved myocar-
dial viability (although not necessarily accompanied by functional
integrity) is likely to play a part in these differences. Few studies
attempted to explain the mechanistic pathophysiology seen in
Dawson DK. Heart 2018;104:96–102. doi:10.1136/heartjnl-2017-311579

Figure 4  CMR (A–C) and echocardiography (D–F) images of midcavity ballooning. The left-hand side columns represent end-diastolic frames;
the right side columns represent end-systolic frames of 2, 4 and 3 chamber views. Click on end-diastolic images for cine loops: A–C correspond to
online supplementary videos 9–11 and D–F correspond to online supplementary videos 12–14. CMR, cardiac magnetic resonance.
acute takotsubo and herein the complexity lies in what findings
are causative versus consequential. There remains intense debate
on the trigger pathway and mechanism of myocardial injury. The
most accepted theory to date is an exaggerated sympathetic stim-
ulation resulting in a cardiotoxic discharge of circulating cate-
cholamines (epinephrine, norepinephrine and dopamine).26 Not
all investigators were able to replicate these findings,27 which if
present do not clarify if catecholamines are truly causative or a
simple epiphenomenon or perhaps a consequence of takotsubo
physiology. Anecdotally, takotsubo patients do not demonstrate
unusual tachycardia or high blood pressure at initial contact
with emergency services. Whatever the stressor that impacts so
dramatically on the heart, there are several studies that probed
into mechanistic pathways by examining the acute and early
post-recovery phase of the condition.
Early recovery pathways
A fundamental characteristic of takotsubo is the spontaneous
recovery of the LV ejection fraction, which returns to normal or
near normal in all patients over a variable period of time (days
to weeks). This process of recovery has been documented both
at myocyte and microvascular level.
The index of microvascular resistance (IMR; the distal coro-
nary pressure multiplied by the mean transit time of a saline
bolus during maximal coronary hyperaemia) reflects the status
of the microcirculation and has been shown to be elevated
during takotsubo presentation at comparable levels with those
seen in acute MI (well above the normal cut-off of 25 U).28 A
Dawson DK. Heart 2018;104:96–102. doi:10.1136/heartjnl-2017-311579
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Heart: first published as 10.1136/heartjnl-2017-311579 on 20 August 2017. Downloaded from http://heart.bmj.com/ on 30 June 2018 by guest. Protected by copyright.
clear time course recovery was documented, with IMR linearly
decreasing form ~60 U at presentation to 25 U after the first 4
days.29 It remains unclear if this microcirculatory dysfunction is
a vascular phenomenon per se or simply mechanical extravas-
cular obstruction due to intense myocardial oedema. Persistence
of endothelial dysfunction at variable times after an acute
episode was shown in a small number of patients.30 Concomit-
tantly, the oedematous process recovers, although it remains
detectable on CMR imaging 3–4 months after an acute episode,
at least in the areas that were dyskinetic during acute presenta-
tion.21 22 Cell swelling and widening of interstitial spaces was
documented on electron microscopy of human myocardial biop-
sies in the acute phase with attenuated findings on recovery,
in keeping with the non-invasive imaging findings.12 Cardiac
energetics (the phosphocreatine/gamma-adenosine triphosphate
ratio (PCr/γATP) ratio obtained non-invasively by 31P-magnetic
resonance spectroscopy) is severely reduced acutely and part-re-
covers by 4 months.22 Despite this energetics reduction, upreg-
ulation of cardiomyocyte survival pathways (phosphorylated
PI3K/Akt) have been clearly documented from human biop-
sies,31 which is in keeping with the lack of detection of macro-
scopic fibrosis on CMR in the vast majority of cases. However,
CMR imaging of the extracellular compartment shows that
this remains expanded,32 and LV biopsies showing an increase
in collagen-1 subfraction suggest that microscopic fibrosis may
play a part in this expansion.33 Finally, non-invasive indices of
systolic and diastolic performance (LV twist, untwist and global
longitudinal strain) continue to remain abnormal during this
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Figure 5  CMR (A–C) and echocardiography (D–F) images of basal ballooning. The left-hand side columns represent end-diastolic frames; the right
side columns represent end-systolic frames of two-chamber, four-chamber and three-chamber views. Click on end-diastolic images for cine loops: A–C
correspond to online supplementary videos 15–17 and M–O correspond to online supplementary videos 18–20 .
early recovery phase32 34 despite normalisation of LV ejection
fraction and volumes. Therefore, contrary to initial beliefs, there
is a large body of evidence that points to an incomplete recovery
3–4 months after a takotsubo episode, despite normalisation of
ejection fraction. It remains unknown at this stage whether this
recovery is just more protracted than initially assumed or if it
is exhausted and results a new clinical phenotype that remains to
be defined. Nevertheless, the EF normalisation remains clinically
useful in consolidating the diagnosis at follow-up.
Insights from experimental models
Due to the likely complexity of takotsubo and the lack of knowl-
edge of the precise mechanistic pathophysiology, it is hard to
replicate this condition in animal models. However, it is possible
to generate a non-ischaemic, non-pathogenic myocardial stress
status, which is probably the closest approximation to a takot-
subo-like model. Important insights can be derived from such
experimental set-up; however, the findings must be interpreted
and translated with the required caution into clinical interven-
tions. Table 1 summarises the model constructs, the most rele-
vant data and how these can be beneficially used in the human
disease.35–38
The aftermath of a takotsubo episode
Establishing a correct diagnosis is important since it has become
clear that takotsubo is not harmless. There is a recognised
early, in-patient mortality of 3%–5%, with the mode of death
attributed to ventricular arrhythmias, intractable pump failure,
cardiac rupture or thromboembolic stroke.7 There is also a
100
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recognised recurrence rate, of 10%–15%, where the trigger is
typically different and the interval of time to a recurrence is
unpredictable.39 However, the two studies that challenged the
way we viewed the prognosis of takotsubo until recently were
the data emergent from the international takostubo registry8
and the Swedish cardiac catheterisation registry,40 which inde-
pendently showed that the subsequent long-term morbidity
and mortality of takotsubo is comparable with that of MI. The
long-term takotsubo mortality is attributed to both cardiac and
non-cardiac causes with the former having a significant contribu-
tion.8 The localisation of acute LV ballooning (basal, mid-cavity
or apex) does not seem to impact differently on outcomes.41 In
contrast, there have been some clear identifiers of poor in-hos-
pital prognosis: a low LV ejection fraction,8 19 raised pulmo-
nary artery pressure,9 10 severe mitral regurgitation19 and right
ventricular involvement in an inverse McConnell pattern.42
To date, there is no specific therapy known to help the short-
term recovery and protect against the early in-hospital mortality.
Having said that, standard pharmacological and/or mechanical/
electrical support to assist cardiogenic shock/arrhythmias should
be promptly initiated according to local guidelines, with two
notable exceptions: catecholamines should probably be best
avoided until further evidence becomes available and intra-aortic
balloon pump should be avoided in those with severe LV outflow
obstruction due to systolic anterior motion of the mitral valve,
as it can inadvertently lower the cardiac output. Equally there
is no medication that is able to prevent recurrences or to miti-
gate the symptoms that a proportion of these patients continue
to experience34 after they recover from their acute illness.
Dawson DK. Heart 2018;104:96–102. doi:10.1136/heartjnl-2017-311579
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Table 1  Experimental models of takotsubo-like disease.

Model construct Signalling Histology Beta-blocker therapy effect

Heart: first published as 10.1136/heartjnl-2017-311579 on 20 August 2017. Downloaded from http://heart.bmj.com/ on 30 June 2018 by guest. Protected by copyright.
Paur et al35 i.v. single bolus of 4×10–8 mol Switch of β2AR to Gi pathways at high – Prior selective β2-AR blockade
adrenaline per 100g; male rat epinephrine concentrations may be increased in vivo mortality; β1-
responsible for the cardio-depression as a AR blockade prevented cultured
protective strategy myocyted cell death
Shao et al36 i.p. single injection of 50 mg/kg Gi-pathway inhibition (pertussis) Akinetic areas are characterised by β2AR blockade improved
isoprenaline; male rat significantly prevented development of an intramyocellular lipid accumulation and function but increased mortality
akinetic area but also increased mortality reduced glycogen content
Shao et al37 i.p. single injection of 400 mg/ Downregulation of myocyte Intramyocellular lipid accumulation –
kg isoprenaline; male mouse transmembrane lipid transporters (CD36)
and increase in glucose metabolism
proteins (PPARγ), the former possibly via an
ApoB lipoprotein mechanism
Sachdeva et al38 i.p. single injection of 100 mg/ – Swollen mitochondria with visible membrane Pretreatment with propranolol
kg isoprenaline; male rat damage, intracytoplasmic lipid droplets, or metoprolol improved survival
large oedematous interstitial spaces, but did not protect against the
neutrophil and macrophage infiltration in magnitude of akinesia or the
areas of subendocardial myocyte necrosis histological changes
ApoB; apolipoprotein, B,i.p.;intra-peritoneal, i.v.;intra-venous.

Retrospective registry data suggest that beta-blockers are not
useful in preventing acute in-hospital mortality43 or recurrences.
However, randomised clinical trials with prespecified end-points
in takotsubo have not taken place and remain premature until a
more clear mechanism of disease is elucidated in humans. In the
absence of this available evidence, some centres, such as ours,
chose to not prescribe any medication to these patients on the
basis of primum non nocere principles.
Susceptibility and predisposition
The causative association with a type of emotion or stress has
been widely accepted as the hallmark of this condition (mostly
as a negative experience but in a minority a positive one,44 with a
few remaining unable to recognise a trigger). Many triggers have
been described, for example, bereavement, near-miss road traffic
accident, arguments, conflict, divorce, public speaking, a severe
fright, protracted stress and hardship or any physical illness such
as cancer, administration of chemotherapy, infections, diarrhoea/
vomiting, routine general anaesthesia, cardioversions and many
others. There is also a clear gender predilection towards women
(in proportion of 9:1—prompting speculation about a neuroen-
docrine predisposition or a significant under-diagnosis in men),
and although takotsubo was initially thought to affect mostly post-
menopausal women,3 it has become clear that younger patients are
equally vulnerable. Data from single centre cohorts and registries
suggest that takotsubo presenters are less burdened by the usual
risk factors associated with coronary heart disease but in exchange,
a self-declared history of mental health or neurological disorders
appears to decorate the medical history of these patients.8 24 45
Since neither the acute onset nor the more persistent morbidity
post-takotsubo cardiomyopathy can be immediately explained
by any occult or intrinsic cardiac pathology that may be concur-
rent or predating the acute event, it is implicit to speculate that
other predeterminants may be causally involved in subjects who
develop this condition. Despite initial enthusiasm about a high
surge of catecholamines,26 small isolated genetic studies failed
to identify significant causative variants with a filtering process
focused mainly on the adrenergic pathway.46–48 However, these
studies are difficult to interpret as with a range of 28–95 patients
studied, they were almost certainly underpowered to address this
question. There remains therefore a need to describe the epidemi-
ology of this condition in nationwide population studies in order
to precisely define the characteristics of those susceptible. This
Dawson DK. Heart 2018;104:96–102. doi:10.1136/heartjnl-2017-311579
would subsequently inform on the type of genetic studies needed
to probe into a genetic predisposition, if any.
Research potential and future directions
There remain many unanswered questions in this complex
syndrome. Perhaps the most urgent of all is to describe the  clin-
ical physiology of the EF-recovered takotsubo patient in order
to firmly establish what type of care these patients require
long term, if at all.
The dynamic interplay of the microvascular abnormalities
and the myocyte survival and recovery certainly deserves further
attention. Small studies appear to suggest that microvascular
perfusion remains functional in the malfunctioning myocardium
at least to the degree where it does not jeopardise myocyte integ-
rity both in the acute state and at 4 months follow-up. However,
both reduced49 and increased50 glucose uptake has been reported
in the ballooning segments, raising the possibility that the takot-
subo myocyte may either have different degrees of insulin sensi-
tivity or a swift ability to switch between substrates. If either or
both should be the case, this may be exploited from a therapeutic
standpoint. Furthermore, the unprecedented extent of myocar-
dial oedema together with initial reports of cellular infiltrates12
questions whether inflammation could be either a cause or an
effect in this pathology. Many intracellular and intercellular
processes remain undefined and this type of information can be
derived form a takotsubo-like experimental model. Both auto-
nomic and central nervous system are likely to be involved. For
example, studies suggest that 123I-metaIodoBenzyl-Guanidine
(123I-mIBG), an analogue of norepinephrine, is reduced in takot-
subo hearts shortly after presentation. However, norepineph-
rine is stored in presynaptic vesicles and released through an
acetycholine-dependent mechanism located in the preganglionic
neurons; it remains therefore unclear if the 123I-mIBG abnormal-
ities are seen as a result of sympathetic overstimulation or vagal
incompetence or both. The gender predilection requires further
probing into cardiac–endocrine pathways to ascertain why this
condition appears to afflict mostly women. Finally, large patient
epidemiological studies are needed to define the physical and
mental illnesses/personality profiles of this population and
their families as this may provide important clues on patterns
of genetic/environmental susceptibilities. Much remains to be
uncovered before a mechanistic-guided therapeutic approach
can be recommended.
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Acknowledgements  The cardiovascular research unit team at the University of
Aberdeen and the NHS Cardiology Department at Aberdeen Royal Infirmary.
Competing interests  None declared.
Provenance and peer review  Commissioned; externally peer reviewed.
© Article author(s) (or their employer(s) unless otherwise stated in the text of the
article) 2018. All rights reserved. No commercial use is permitted unless otherwise
expressly granted.
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