Review

Stroke–heart syndrome: clinical presentation and underlying

mechanisms
Jan F Scheitz, Christian H Nolte, Wolfram Doehner, Vladimir Hachinski, Matthias Endres

Cardiac complications are a frequent medical problem during the first few days after an ischaemic stroke, and patients Lancet Neurol 2018
present with a broad range of symptoms including myocardial injury, cardiac dysfunction, and arrhythmia, with Published Online
varying overlap between these three conditions. Evidence from clinical and neuroimaging studies and animal research October 26, 2018
http://dx.doi.org/10.1016/
suggests that these cardiac disturbances share the same underlying mechanisms. Although the exact cascade of
S1474-4422(18)30336-3
events has yet to be elucidated, stroke-induced functional and structural alterations in the central autonomic network,
Klinik und Hochschulambulanz
with subsequent dysregulation of normal neural cardiac control, are the assumed pathophysiology. This dysregulation für Neurologie (J F Scheitz MD,
can promote myocardial necrosis, microvascular dysfunction, coronary demand ischaemia, and arrhythmogenesis. Prof C H Nolte MD,
These stroke-associated cardiac alterations can be summarised as a distinct so-called stroke–heart syndrome. Prof M Endres MD), Department
of Cardiology (Prof W Doehner),
Independent cohort studies have shown a strong association between this syndrome and unfavourable short-term
and Berlin-Brandenburg Center
prognosis; however, long-term consequences, including secondary cardiac events and death, are less well described for Regenerative Therapies
and specific therapeutic targets are scarce. An integrated view of stroke–heart syndrome will offer opportunities to (Prof W Doehner),
expedite research and inform clinical decision making. Charité-Universitätsmedizin
Berlin, Berlin, Germany; Berlin
Institute of Health, Berlin,
Introduction mechanisms, and derive implications of the concept Germany (J F Scheitz,
Cardiac complications represent a major medical for research and practice. We will focus on ischaemic Prof C H Nolte, Prof M Endres);
challenge during acute stroke care.1–3 Severe adverse stroke, although similar occurrences of neurocardiogenic German Centre for
Cardiovascular Research
cardiac events including acute coronary syndrome, heart injury can be observed in other acute brain disorders,
(J F Scheitz, Prof C H Nolte,
failure, and cardiac arrhythmia are reported in approxi­ including subarachnoid haemorrhage, haemorrhagic Prof W Doehner, Prof M Endres)
mately 20% of patients with ischaemic stroke in stroke, traumatic brain injury, and seizures.16 The pop­ and German Center for
randomised controlled trials, occurring predominantly ulation of patients with ischaemic stroke, however, differs Neurodegenerative Disease
(Prof C H Nolte, Prof M Endres),
within the first 3 days after the event.3 In addition, a markedly from that of patients with other acute brain
Deutsches Zentrum für Herz-
broad range of oligosymptomatic, early (first few days disorders, regarding age and cardiovascular co­morbidities; Kreislauf-Forschung, partner
to weeks) cardiac complications can be observed with furthermore, brain dysfunction due to ischaemic stroke site Berlin, Berlin, Germany;
contemporary diagnostic measures.4–8 Patients with entails a distinct time course and vascular distribution and Department of Clinical
Neurological Science,
ischaemic stroke are particularly prone to cardiac injury, location. Cerebral consequences of impaired cardiac University Hospital, University
because of the advanced age at which strokes generally function have been reviewed elsewhere.17 of Western Ontario, London,
occur, prevalence of cardiac comorbidities, and vascular ON, Canada
risk factors. Importantly, cardiac complications after Cardiac complications associated with stroke (Prof V Hachinski MD)

ischaemic stroke are associated with a poor functional The concept of stroke–heart syndrome (ie, cardiac mani­ Correspondence to:
Prof Matthias Endres,
prognosis and are the second leading cause of death in festations induced by an ischaemic stroke) as a direct
Klinik für Neurologie,
the first few weeks after the event.1–4 consequence of brain ischaemia implies that cardiac Charité-Universitätsmedizin
The clinical observation that ischaemic stroke is often distur­bances occur after the onset of neurological deficits. Berlin, 10117 Berlin, Germany
accompanied by electrocardiogram (ECG) alterations or by Strong evidence suggests that the frequency and severity matthias.endres@charite.de

an increase of unspecific cardiac blood biomarkers was
first described in the 1950s and 1960s.9,10 In the past
10 years, animal studies, clinical cohort studies, and neuro­
imaging studies have provided increasing evidence that
the varying cardiac disturbances appearing after stroke
probably share the same underlying mechanisms.11–15
Although stroke-induced alterations of physiological
autonomic cardiac control seem to have a crucial role,
the underlying pathological mechanisms are unclear
and therapeutic targets are unknown. This insufficient
evidence might be due to the fact that each cardiac
complication has been individually studied in some detail,
but not as a distinct and whole clinical entity.
In this Review, we outline the most recent evidence
suggesting that these cardiac events can be summarised as
a distinct so-called stroke–heart syndrome. Moreover, we
aim to provide an overview of the clinical manifestations of
stroke–heart syndrome, summarise presumed underlying
of stroke–heart syndrome peak within the first 3 days after
the event.3,5,18 Most of these stroke-associated cardiac
disturbances are transient, but a subgroup of patients
show poor short-term and probably long-term out­
come.4,6,8,19–21 Stroke–heart syndrome must be distinguished
from cardiac disturbances secondary to systemic disease,
such as sepsis, anaemia, or poor oxygenation (panel).
Distinguishing stroke–heart syn­drome from concomitant
or preceding acute coro­nary syndrome (ie, due to coronary
plaque rupture or thrombosis) can be especially chal­
lenging, although algorithms for diagnostic pathways
have been suggested.13
Studies in animals and humans have convincingly
shown that stroke-related factors, such as ischaemic
lesion location (especially involvement of the [right]
insula) and stroke severity, correlate with the extent
of subsequent cardiac injury and dysfunction.4,14,15,22
Although stroke-related cardiac dysfunction can occur

www.thelancet.com/neurology Published online October 26, 2018 http://dx.doi.org/10.1016/S1474-4422(18)30336-3 1

 Review
Panel: Proposed criteria for stroke–heart syndrome by the
Center for Stroke Research Berlin
Clinical description
Evidence of acute myocardial injury, cardiac dysfunction, or
cardiac arrhythmia following ischaemic stroke.
Clinical characteristics
There are a broad range of clinical presentations including
repolarisation changes; cardiac arrhythmia; cardiac
autonomic imbalance with blood pressure alterations;
exacerbation of heart failure; takotsubo syndrome secondary
to acute stroke; myocardial injury with cardiac biomarker
changes; and acute myocardial infarction.
Time course
Begins early after ischaemic stroke; cardiac alterations usually
peak within 72 h after ischaemic stroke onset. Cardiac injury
or dysfunction are either newly detected after the ischaemic
stroke event, or clear evidence shows worsening of cardiac
function after stroke.
Risk factors
The occurrence and severity of stroke–heart syndrome
depends on premorbid cardiac disease, age, and vascular risk
factors, but also on stroke-related factors, such as stroke lesion
site within the central autonomic network and stroke severity.
Differential diagnoses
There must be conceptual distinction from other causes of
See Online for appendix cardiac injury or dysfunction including: systemic diseases,
such as sepsis; chronic but stable heart failure; pulmonary
embolism; pulmonary hypertension; acute kidney injury;
chronic kidney disease; myocarditis; and recent cardiac
intervention. There must be distinction from causes of
coronary demand ischaemia not attributable to stroke
(eg, anaemia and reduced blood oxygenation). There must be
distinction from myocardial ischaemia due to coronary
plaque rupture or plaque thrombosis (type 1 myocardial
infarction)
even in the absence of overt heart disease,9,12,19 the
individual threshold to develop stroke–heart syndrome
probably depends on pre-existing structural and coronary
heart disease, indicating individual cardiac vulner­
ability.3,4,22 Not surprisingly, findings from prospective
cohort studies show that age and burden of cardio­
vascular risk factors correlate with the individual
propensity to develop stroke–heart syndrome and with
its severity.4,23 Furthermore, factors promoting electrical
cardiac instability and arrhythmia (eg, electrolyte
imbalances and drugs that prolong QT time), and
comorbidities that promote autonomic failure (such as
diabetes and obstructive sleep apnoea syndrome)
probably influence the occurrence of stroke–heart
syndrome. Finally, although not yet studied in patients
with stroke, individual vulnerability to psychological
stress shows a wide variability and also relates to
2 www.thelancet.com/neurology Published online October 26, 2018 http://dx.doi.org/10.1016/S1474-4422(18)30336-3
epigenetic modification of stress-related genes.24,25 There­
fore, genetic and epigenetic factors might modify the
individual phenotype of stroke–heart syndrome (figure 1).
A continuum of clinical manifestations of stroke–
heart syndrome occurs, ranging from oligosymptomatic
or even asymptomatic ECG alterations or cardiac bio­
marker elevations to worsening of left ventricular function,
malignant cardiac arrhythmia, or stroke-induced myo­
cardial infarction. Importantly, several of these cardiac
disturbances have been observed to occur together and can
overlap in an individual patient.8,22,26
Cardiac biomarkers
Elevations in cardiac biomarkers (ie, cardiac troponin and
brain natriuretic peptide) are among the best-studied
manifestations of stroke–heart syndrome. Cardiac
troponin is the preferred biomarker to detect myocardial
injury and diagnose myocardial infarction.27 High-
sensitivity cardiac troponin assays enable detection of this
biomarker in more than 90% of patients with ischaemic
stroke, with approximately 30–60% of these patients
showing at least one cardiac troponin value above the
upper reference limit in serial measurements (ie, cardiac
troponin elevation).4,18,21 In community-based studies of
otherwise healthy individuals (adults or without prior
heart failure) from the general population, cardiac
troponin concentrations were found to be generally lower
than in studies including patients with ischaemic stroke
(appendix).28,29 Even minor elevations of this biomarker
after stroke are independently associated with poor
functional outcome.4,8,21,30 Importantly, in two cohort
studies of 1016 and 834 patients with ischaemic stroke,
approximately 5–20% showed a rise or fall pattern in
cardiac troponin amount, suggesting acute and not
chronic myocardial injury.4,31 Patients with such dynamic
cardiac troponin concentrations following stroke have
a more than three-times increased risk of in-hospital
mortality (table).4 In 250 consecutive patients with
ischaemic stroke, N-terminal pro b-type natriuretic pep­
tide concentrations rose within 2 days after ischaemic
stroke and fell subsequently.34 A meta-analysis of 16 studies
(n=3498) showed that N-terminal pro b-type natriuretic
peptide measured within 5 days after stroke is on average
255 pg/mL lower among survivors of stroke than in non-
survivors.35
Cardiac arrhythmia
Pathological ECG findings upon hospital admission can
be observed in 70–90% of patients with ischaemic stroke if
abnormalities indicating pre-existing heart disease—such
as Q waves or signs of left ventricular hypertrophy—are
included.32,36 The most frequently observed ECG changes
early after stroke are changes in repolarisation, and include
prolonged rate corrected QT (QTc) time (in 20–65% of
patients), ST segment changes (in 15–25% of patients),
and inverted T waves with altered amplitude and width (so-
called cerebral T wave, in 2–18% of patients).26,32,36,38 Most of

these ECG alterations are transient and peak early after
stroke. For instance, rate of QTc prolongation upon
hospital admission was shown to decline from 45 (65%) of
69 patients to 18 (26%) patients at 48 h thereafter.37
Importantly, these ECG alterations identify individuals at
risk for clinically relevant arrhythmia.2 Prolonged QTc
time has been linked to occurrence of myocardial injury
(measured by cardiac troponin elevation), severe cardiac
arrhythmia, and sudden cardiac death after stroke.2,22,26
Cardiac arrhythmias are strongly associated with an
unfavourable outcome. Kallmünzer and colleagues5
used an automated arrhythmia detection system in a
single stroke unit and identified 139 episodes of severe
cardiac arrhythmias causing clinical symptoms or
requiring urgent clinical evaluation in 126 (25%) of
501 patients within 72 h after stroke onset. 81 (58%) of
these patients had clinically relevant episodes of atrial
fibrillation, whereas ventricular or supraventricular
tachycardia, sinus-node dysfunction, and second-degree
or third-degree atrioventricular block were detected in
the remainder. Old age and high stroke severity were
independently associated with these arrhythmias.
Tachyarrhythmia was observed more often than was
bradyarrhythmia.5
Detection of atrial fibrillation early after stroke is a
diagnostic challenge: atrial fibrillation can be newly
diagnosed in about 7–10% of patients during the first
3–5 days. Detection increases to 24% or more with
cardiac monitoring over 6–12 months.39,54 Debate is
ongoing as to whether part of these atrial fibrillation
episodes are triggered by stroke–heart syndrome and are
not the cause of the initial stroke.40,55 This debate is
ongoing because newly detected atrial fibrillation has
been linked to stroke location involving the central
autonomic cardiac control, and the data are conflicting as
to whether stroke recurrence is not as high when atrial
fibrillation is newly detected as when atrial fibrillation is
already known before the stroke.41–43,56 Part of atrial
fibrillation episodes after stroke might be triggered by
stroke–heart syndrome.7–10 Nonetheless, detection of
atrial fibrillation after stroke probably reveals cardiac
vulnerability (ie, pre-existing atrial cardiopathy) to
develop subsequent persistent or permanent atrial
fibrillation. Therefore, treatment with oral anticoagulants
should not be challenged until more evidence on
secondary stroke prevention in patients with newly
diagnosed atrial fibrillation is available. Potential patho­
physiological models of newly diagnosed atrial fibrillation
have been reviewed elsewhere.40,55
Autonomic dysfunction
Autonomic cardiac imbalance can be assessed by
alterations of heart rate variability and baroreceptor
reflex sensitivity. Heart rate variability is lower in patients
with stroke than in healthy controls and baroreceptor
reflex sensitivity is impaired during the acute phase
after stroke, especially in strokes that are severe and involve
www.thelancet.com/neurology Published online October 26, 2018 http://dx.doi.org/10.1016/S1474-4422(18)30336-3 3
Review
Stroke-specific determinants
Lesion site within the central
autonomic network
Clinical severity
Risk factors Stroke–heart syndrome Short-term outcome
Pre-existing heart disease Myocardial injury or cardiac biomarker Death
(vulnerable substrate) elevations Poor functional outcome
Age Impaired autonomic cardiac reflexes
Cardiovascular risk factors Impaired left ventricular function Long-term outcome
Individual susceptibility (Stress-)cardiomyopathy Mortality
Epigenetics Myocardial infarction* Major cardiac events†
Unknown factors Cardiac arrhythmia Stroke recurrence†
Sudden cardiac death Incident atrial fibrillation or
cardiac arrhythmia
Incidence or progression of
heart failure†
Before stroke Acute phase after stroke After stroke
Figure 1: Overview of the clinical characteristics, modifiers, and outcomes of stroke–heart syndrome
Pre-existing risk factors in an individual increase the probability of developing stroke–heart syndrome and increase
the severity of the syndrome. The acute phase after stroke refers mainly to the first 72 h after the event. Short-term
outcomes refer to the in-hospital course, and long-term outcomes refer to events occurring at 3 months or later.
*Type 2 myocardial infarction. Diagnosis of coincident myocardial infarction due to coronary plaque rupture or
thrombosis (ie, type 1 myocardial infarction) and prediction of acute coronary syndrome following stroke is
challenging. However, ischaemic stroke can induce type 2 myocardial infarction (ie, due to demand ischaemia by
hypertensive crisis or tachyarrhythmia). Data indicate that myocardial infarction with non-obstructive coronary
arteries as part of stroke–heart syndrome can be a useful working diagnosis. †Indicates that insufficient data or
indirect data only from populations without stroke (eg, patients with stable coronary disease or atrial fibrillation)
exist to support the association between stroke–heart syndrome and long-term outcomes. Results from cohort
studies have shown evidence that myocardial injury (ie, cardiac tropinin elevation) predicts heart failure,
thromboembolism, and atrial fibrillation.
the right insular cortex.6,44,45 Overall, evidence from clinical
studies indicates an average shift towards a sympathetic
predominance during the first 3 days after stroke.6 Reduced
heart rate variability after stroke has been linked to a higher
risk of short-term mortality and sudden cardiac death.6
Impairment of the baro­receptor reflex sensitivity has been
associated with acute hypertensive crises following
ischaemic stroke and might precede space-occupying
anterior infarction.6,20,46 One hypothesis is that autonomic
dysfunction after stroke is exaggerated during sleep, and
that sleep disruption with impaired autonomic re­
patterning results in early clinical deterioration due to
arrhythmias and blood pressure fluctuations.47
Until now, no routine clinical applications of heart rate
variability and baroreceptor reflex sensitivity measure­
ments have been established, which might be because
of the absence of well-known clinical cutoffs and of
methodological standardisation. However, both para­
meters could identify patients at risk of blood pressure
alterations, severe cardiac arrhythmias, and sudden
cardiac death.
Cardiac dysfunction
Impaired left ventricular function (ie, ejection fraction
<55%) after acute stroke can occur in 8–12% of patients
with mild-to-moderate stroke and, in 3–8%, left ventri­cular
 Review

Measurement Clinical findings Associated risk factors* Prognostic value Limitations

Cardiac Myocardial injury, Detectable in about 90% of Old age, (right) insular Associated with poor Causes of myocardial injury other than acute
troponin4,8,13,14,18, sensitive marker for patients; elevated in about cortex lesions, stroke short-term and long-term coronary syndrome are possible (eg, hypertensive
19,21,22,28,29,30,32,33
acute coronary 30–60% of patients severity, heart failure, outcomes; incident heart crisis, tachyarrhythmia); premorbid concentration
syndrome (high-sensitivity assay); coronary artery disease, failure; secondary is uncertain; chronic mild elevations are present in
acute elevation in about impaired kidney function cardiovascular events about 85% of patients (high-sensitivity assay)
5–20% of patients (rise or without substantial change in serial measurements
fall in repeated
measurements)
Brain natriuretic Released in response to Elevated in patients with Old age, female sex, Associated with poor short- Premorbid concentration is uncertain
peptide (including myocardial wall stress, stroke compared with stroke severity, atrial term outcome; cardioembolic
N-terminal pro monitor treatment of controls; increased during fibrillation stroke origin
b-type natriuretic heart failure the first 48 h
peptide)34,35
Corrected QT Repolarisation changes, Corrected QT time Pre-existing heart disease Myocardial injury (cardiac Certain drugs (eg, antidepressants) can prolong
time26,32,36,37 risk for malignant prolonged in about 20–65% troponin elevation); severe corrected QT; premorbid corrected QT time is
arrhythmia of patients; frequency cardiac arrhythmia; mortality† unknown; cause of ST segment changes is
declines within 48 h after unspecific (eg, co-medication, electrolyte amount)
stroke onset
T wave9,26,36,38 Repolarisation changes Inverted, cerebral T wave Pre-existing heart disease Myocardial injury (cardiac Certain drugs (eg, antidepressants) can prolong
in about 2–18% of patients troponin elevation); severe corrected QT; premorbid corrected QT time is
cardiac arrhythmia; mortality† unknown; cause of ST segment changes is
unspecific (eg, co-medication, electrolyte amount)
ST segment Repolarisation changes, Present in about 15–25% of Pre-existing heart disease Myocardial injury (cardiac Certain drugs (eg, antidepressants) can prolong
changes26,36 myocardial ischaemia patients troponin elevation); severe corrected QT; premorbid corrected QT time is
cardiac arrhythmia; mortality† unknown; cause of ST segment changes is
unspecific (eg, co-medication, electrolyte amount)
Arrhythmia Disturbance of Clinically significant Old age, stroke severity Worsening of left ventricular High frequency with monitoring longer than 72 h
(including atrial depolarisation or arrhythmia in about 25% of function; mortality
fibrillation) repolarisation patients‡
Atrial Disturbance of About 10% episodes of Old age, insular cortex Worsening of left ventricular High frequency of newly detected atrial fibrillation
fibrillation5,39,40–43 depolarisation or previously unknown atrial stroke, high amount of function; mortality with monitoring longer than 72 h; whether newly
repolarisation fibrillation detected during cardiac troponin at detected atrial fibrillation after stroke is the cause
in-patient baseline or consequence of stroke is unknown; whether the
electrocardiogram risk of stroke recurrence after newly detected atrial
monitoring fibrillation is equal to the risk of stroke recurrence
in patients with known atrial fibrillation is
unknown
Baroreceptor reflex Response to short-term Impaired Stroke severity, right Hypertensive crisis; space- Absence of established cutoff values and
sensitivity6,20,44–46 blood pressure insular involvement occupying infarction; methodological standardisation; previous use of
variations mortality β blockers or antihypertensive drugs can affect
results; baroreceptor reflex sensitivity
measurements not applicable in clinical routine
Heart rate Autonomic cardiac Reduced; shift towards Stroke severity, right Mortality; sudden cardiac Absence of established cutoff values and
variability6,44,47 balance sympathetic predominance insular involvement death methodological standardisation; previous use of
β blockers or antihypertensive drugs can affect
results; heart rate variability measurements not
applicable in clinical routine
Reduced left Left ventricular Present in about 8–12% of Old age, high stroke Poor short-term outcome, Premorbid cardiac function unknown
ventricular ejection dysfunction patients severity, history of heart high risk of stroke
fraction disease, high baseline
(<55%)8,17,23,48–50 cardiac troponin and
brain natriuretic peptide
Regional wall Left ventricular Present in about 10% of Old age, male sex, high Stroke recurrence Premorbid cardiac function unknown
motion dysfunction patients burden of cardiovascular
abnormalities23,49,50 risk factors, heart disease
(including coronary artery
disease), stroke severity,
inflammatory markers
Secondary Left ventricular Present in about 1% or less Old age, female sex, Poor short-term outcome Atypical types of takotsubo syndrome are probably
takotsubo dysfunction of patients insular cortex stroke, underdiagnosed with echocardiography
syndrome7, 51–53 stroke severity,
inflammatory markers
*Risk factors independently associated with the respective biomarker in observational and cohort studies. †Strongest evidence for prolonged corrected QT time. ‡Defined as arrhythmia causing symptoms or
requiring urgent evaluation and treatment.5

Table: Biomarkers and measurements of cardiac dysfunction within the first few days of acute ischaemic stroke

4 www.thelancet.com/neurology Published online October 26, 2018 http://dx.doi.org/10.1016/S1474-4422(18)30336-3


function can be severely impaired (ie, ejection fraction of
<40%).8,23,48 These findings are limited by the fact that the
prevalence of impaired left ventricular function before
stroke is not known.8,23,48,49 Old age, high stroke severity,
history of heart disease, and high base­line cardiac troponin
are predictors of impaired left ventricular function.8,23
Impaired left ventricular dysfunction or left ventricular
wall motion abnormalities after stroke have been
associated with poor functional outcome (two-times
increased risk of modified Rankin Scale score >2).23,50
Takotsubo syndrome is a particular type of left ventri­
cular dysfunction that can be observed in acute
ischaemic stroke. It is an acute heart failure syndrome
with most patients showing a characteristic pattern of
left ventri­ cular dysfunction (apical ballooning) that
resembles a Japanese octopus trap called takotsubo.51,57
Clinical consensus recommends coronary angiography
to rule out acute coronary syndrome and show left
ventricular dysfunction, especially in patients with ST
segment elevation.51 Echocardiography should be
considered to identify regional wall motion abnor­
malities in patients with stroke. Clinicians should be
aware that besides the apical ballooning type,
midventricular, basal, and focal types of takotsubo
syndrome can be differentiated. The focal type of
takotsubo syndrome can resemble focal wall motion
abnormalities seen in acute coronary syndrome; in
these cases, cardiovascular MRI can be useful to
diagnose takotsubo syndrome.51 This syndrome predom­
inantly affects postmenopausal women and is often
preceded by stressful physical or emotional triggers.57
Although the left ventricular dysfunction recovers
markedly over time, in an inter­ national cohort of
1750 patients with takotsubo syndrome, long-term
prognosis at 10-year follow-up was similar to that of
myocardial infarction.58 Acute neurological disorders
(ie, ischaemic stroke, intracranial haemorrhage, and
seizures) are also common triggers of takotsubo
syndrome.51 The syndrome has been reported in
0·5–1·2% of patients after acute stroke7,52 and, when
secon­ dary to acute stroke, can occur without the
presence of emotional or psychological stress.7,53
Transient myocardial impairment occurs typically
within the first 10 h after stroke onset, with full or partial
recovery within 3 weeks.7 Notably, although echo­
cardiographic and electrocardiographic signs along
with elevations of cardiac troponin can clearly indicate
acute contractile impairment, patients often remain
asymptom­atic (or might be unable to report symptoms
because of neurological deficits). Still, takotsubo syn­
drome secondary to acute stroke has been linked to a
three-times or more increase in in-hospital mortality.7
Mechanisms and pathophysiology
The evidence strongly suggests that the broad range of
clinical presentations of stroke–heart syndrome probably
originate from stroke-induced structural or functional
www.thelancet.com/neurology Published online October 26, 2018 http://dx.doi.org/10.1016/S1474-4422(18)30336-3 5
Review
alterations within the central autonomic network—a
network of brain structures modulating physiological
adaptation of cardiovascular function via regulation of
the sympathovagal outflow to the heart.59,60 Current
understanding of the neural control of cardiac function
was pioneered by rigorous experiments done from 1970s
to early 2000s by Clifford B Saper (USA), David Smith
(UK), David Cechetto (Canada), Eduardo E Benarroch
(USA), and Stephen Oppenheimer (UK).12,38,59,61
Meta-analyses of functional MRI studies confirmed the
insular cortex, prefrontal cortex, cingulate cortex,
amygdala, hypothalamus, and hippocampus formation
as important factors in the central autonomic network
(figure 2A).60,62 Evidence suggests that sympathetic and
parasympathetic cardiovascular function might
be lateralised.2,38,61 Sympathetic activation seems to be
mainly located within the prefrontal cortex, anterior
cingulate cortex, left amygdala, and right anterior insular
and left posterior insular cortices.60
Of the brain regions aforementioned, the insular
cortex is frequently affected in patients with ischaemic
stroke because of its blood supply by the middle
cerebral artery. The insular cortex constitutes a
cortical re­presentation of interoceptive awareness and
emotional processing of the current cardiovascular
state (eg, heart beat awareness).63 A study of 228 patients
who had an MRI scan after ischaemic stroke used voxel-
based lesion symptom mapping to investigate whether
localisation of the ischaemic stroke precipitated
myocardial injury. Although single cardiac troponin
values did not show any relation to stroke lesion
location, relative dynamic changes in this biomarker
concentration were statistic­ally significantly associated
with right anterior insular lesions (especially the
dorsal subregion, figure 2B).14 With this methodo­
logical approach, a similar correlation was observed in
150 patients with ischaemic stroke between lesion
location and occurrence of post-stroke cardiac arrhyth­
mias.64 Although several studies suggest an association
between right insular stroke and several manifestations
of stroke–heart syndrome (eg, myo­ cardial injury or
cardiac arrhythmia), the clinical implications of these
findings are yet to be explored. The insula is strongly
connected to the anterior cingulate cortex, which is
involved in producing blood pressure and heart rate
responses to stress.59 The amygdala is another
important region within the central autonomic network
that modulates cardio­ vascular response to severe
emotional stimuli and has a role in processing emotions
such as fear and anxiety.59,61,62 Activity within the
amygdala on ¹⁸F-fluoro­deoxyglucose PET/CT scans of
293 participants undergoing cancer screening was
associated with high perceived stress, arterial inflam­
mation, and incidence of cardiovascular events.65 These
conditions highlight the notion that altered response
to stress has important consequences on cardio­vascular
function.
 Review
A
Anterior cingulate cortex
Posterior cingulate cortex
Insular cortex
Prefrontal cortex
Hypothalamus
Amygdala
Hippocampus
B function play a crucial part in the occurrence of mental-
Z-values
0 2 4 6
* network are present in patients who had a takotsubo
Figure 2: Forebrain components of the central autonomic network
(A) Overview of brain regions involved in neural control of the heart. (B) Voxel-based lesion symptom mapping
analysis of 228 patients with anterior circulation stroke showing a statistically significant association of relative
change in cardiac troponin levels with lesions of right anterior insular cortex (especially its dorsal portion), frontal
operculum and, to a lesser spatial extent, of dorsal posterior insular cortex. Reproduced from Krause et al,14
by permission of John Wiley and Sons. *Z-values indicate statistical significance (significant if ≥3).
Cardiac response to mental stress
Studies exploring the link between cardiovascular
function and mental stress provide important insights
into the pathophysiology of stroke–heart syndrome. As
with ischaemic stroke, strong emotions, such as fear and
anxiety, and unexpected happiness might lead to an
overshoot activation or dysregulation within the central
autonomic network.66–68 This dysregulation can even
result in cardiovascular events and sudden cardiac death.
A popular example of how emotionally moving events
affect cardiac function is the 2·66-times increase in
cardiac events in 4279 people in a metropolitan area of
Germany, on match days when the German team played
during the Fédération Internationale de Football
Association World Cup in 2006.69 Stress-induced acute
coronary syndrome during the World Cup was accomp­
anied by higher concentrations of endothelin and pro­
inflammatory markers in the blood of 58 patients with
acute coronary syndrome on match days, compared with
58 matched patients who had an acute coronary syndrome
event without related emotional circumstances.70
In experimental settings, mental stress can be
simulated by the use of mental arithmetic or public
speaking tests. Exaggerated increase in heart rate
following a mental stress test has been associated with
altered activation patterns within the central autonomic
network.61 Moreover, increased sympathetic activation
with elevated catecholamine concentrations, reduced
6 www.thelancet.com/neurology Published online October 26, 2018 http://dx.doi.org/10.1016/S1474-4422(18)30336-3
baroreceptor reflex sensitivity, peripheral and coronary
vasoconstriction, release of cardiac troponin, ischaemic
ECG alterations, impaired left ventricular function, and
reduced coronary blood flow can be detected following
such mental stress algorithms.68,71–73 This event is called
mental-stress-in­ duced myocardial ischaemia.73 Major
pathophysiological features of mental-stress-induced
myocardial ischaemia are a sustained increase of
systemic vascular resistance and a reduction of
endothelium-dependent vasodila­tation.73 Therefore,
findings from some studies have suggested that
coronary demand ischaemia and micro­ vascular dys­
stress-induced myocardial ischaemia.73 Impor­tantly,
individual susceptibility probably influences the degree
of cardiovascular response to stress.25,74
Takotsubo syndrome is an example of how stress can
result in cardiac dysfunction. Findings from a neuro­
imaging study of 22 women with this syndrome and
39 healthy female controls showed that structural and
functional alterations within the central autonomic
syndrome episode.75 These findings underline that altered
stress response within the central autonomic network is
involved in the pathogenesis of takotsubo syndrome. In
support of this hypothesis, the circulating microRNAs
miR-16 and miR-26a were found to be dysregulated in a
cohort of 36 patients with takotsubo syndrome, compared
with 27 patients with ST-segment elevation acute myo­
cardial infarction and 28 healthy controls.76 In mice,
miR-16 regulates the expression of the serotonin trans­
porter, and expression of miR-26a in the frontal cortex and
hippocampus increases shortly after restraint stress.77,78
Additionally, excessive catecholamine release constitutes a
pathophysiological hallmark of takotsubo syndrome.57,79
Catecholamine concentrations are statistically significantly
higher in patients with takotsubo syndrome than in
those with myocardial infarction.80 Moreover, the cellular
response to catecholamines observed in cardio­myocytes
derived from induced pluripotent stem cells of patients
with takotsubo syndrome was higher than that found in
controls.81 Notably, in a study of 222 consecutive patients
with ischaemic stroke, high concentrations of catech­
olamines were independently associated with myocardial
injury following acute ischaemic stroke.33 On a cardio­
myocyte level, catecholamine overload results in disturbed
calcium homoeostasis, which leads to hypercontraction of
sarcomers together with increased oxidative and metabolic
stress. This process can result in myo­cardial contraction
band necrosis (typical catecholamine-mediated lesions
with hypercontracted sarcomers) and impaired coronary
microcirculation.57,79 In addition, the amount of endo­thelin
in plasma is increased, which further supports the
notion that endothelial dysfunction and micro­ vascular
con­striction play an important part in the patho­physio­
logy of takotsubo syndrome.76 Oestrogen is known to
improve microcirculation and might explain the fact that
 Review

post­menopausal women are more susceptible to develop

takotsubo syndrome.57
Ischaemic brain injury

Animal stroke models

Models of focal cerebral ischaemia in rodents (eg, middle
cerebral artery occlusion) provide an opportunity to
explore the mechanisms underlying stroke–heart
syndrome. Several groups have shown stroke-induced
cardiac dysfunction and cardiomyocyte damage in
rodents undergoing middle cerebral artery occlusion,
with an increase of cardiac troponin concentration and
contraction band necrosis.15,82–85 For example, more than
60% of mice subjected to left but not right middle
cerebral artery occlusion developed cardiac dysfunction,
which correlated with injury to the left insula and
increased concentrations of norepinephrine.15 Bleilevens
and colleagues82 showed that a subgroup of rats sub­
jected to left middle cerebral artery occlusion for
60 min developed substantial myocardial injury, which
was predicted by the extent of insular involvement.
Cardiac arrhythmia induced by middle cerebral artery
occlusion was associated with both specific brain lesions
(paraventricular nucleus) and aberration of L-type
calcium channels in cardiomyocytes.86,87 A decrease in the
amount of microRNA miR-126 might contribute to
stroke–heart syndrome: miR-126 was specifically down­
regulated after stroke, and mice deficient in endothelial
expression of miR-126 had exaggerated cardiac dys­
function after stroke.83 Additionally, brain damage might
also lead to chronic cardiac dysfunction: mice showed
worsening of left ventricular ejection fraction and an
increase in left ventricular volumes during 8 weeks after
right, but not left, transient middle cerebral artery
occlusion, which was mediated by chronic autonomic
dysfunction and ameliorated by β blockers.88 Overall,
animal models offer us the advantage of dissecting
neurocardiogenic effects directly without any cardiac
comorbidity or atherothrombotic burden, and to identify
causal humoral or nervous factors.
Unifying hypothesis
Altogether, available data provide compelling support for
the concept that stroke-induced structural and functional
disturbance within the central autonomic network
results in an overactivated stress response involving
the autonomic nervous system and the hypothalamic–
pituitary–adrenal axis (figure 3). As a consequence,
excessive catecholamine and cortisol concentrations reach
the heart, leading to an altered calcium homo­eostasis with
exaggerated cytosolic calcium influx in cardiomyocytes.
This altered calcium homoeostasis stimulates cardio­
myocyte contraction, disturbs muscle relaxation, affects
electrical stability, impairs energy metabolism, and
thus, promotes oxidative and metabolic stress. In turn,
stress metabolites impair endothelial function with
endothelin release and subsequent vaso­ constriction—
predominantly within the micro­circu­lation. On a vascular
Functional or structural alteration within the central autonomic network
Additional
(unknown)
mediators
Sympathetic nervous system activation Activation of the HPA axis
Catecholamine storm Proinflammatory cytokines Cortisol Neurohumoral factors
Cardiomyocyte Coronary (micro)vessel
Vasoconstriction,
Increased calcium influx (microvascular) spasm
Electrical Hypercontraction Metabolic stress Endothelial
instability Reduced relaxation Oxidative stress dysfunction
Arrhythmogenesis
Contraction Microvascular Coronary
band necrosis dysfunction demand ischaemia
Variable clinical manifestations
of the stroke–heart syndrome
Figure 3: Presumed pathomechanisms underlying stroke–heart syndrome
Ischaemic stroke results in activation or dysregulation of the central autonomic network and the
hypothalamic–pituitary–adrenal (HPA) axis. Excessive release of catecholamines, proinflammatory cytokines,
cortisol, and other neurohumoral factors impair physiological cardiomyocyte and (micro)vascular function.
This impairment promotes arrhythmogenesis and causes contraction band necrosis, microvascular dysfunction, and
coronary demand ischaemia. These mechanisms can co-occur, ie, more than one can contribute to the patient’s
condition. As a consequence, the broad clinical manifestations of stroke–heart syndrome, such as cardiac
arrhythmia, myocardial infarction, hypertensive crisis, and takotsubo syndrome secondary to stroke might emerge.
level, catecholamines, cortisol, and neurohumoral factors
(eg, endothelin, angiotensin II, and vasopressin) lead to
an increased vasoconstriction and increased systemic
vascular resistance that promote coronary demand
ischaemia and microcirculatory dysfunction.
These processes might explain the different phenotypes
of stroke–heart syndrome: coronary demand ischaemia
caused by both epicardial and microvascular vaso­
constriction probably promotes stroke-induced myo­cardial
injury in some patients with stroke. Secondary to demand
ischaemia, cardiac wall motion abnormalities and
takotsubo syndrome-like myocardial stunning can occur.
Myocardial stunning is a reversible wall motion
abnormality in patients with focal ischaemia after
reperfusion, but can also be induced by an acute brain
injury.12,79,80 Both cardiac reperfusion following myocardial
ischaemia and direct catecholamine toxicity can result in
contraction band necrosis (also called coagulative
myocytolysis). Histo­ pathologically, these lesions are
characterised by hyper­contracted sarcomeres with myo­
fibrillar break.12 In animals, contraction band necrosis can
be provoked following experimental catecholamine
exposure, and can be induced by middle cerebral artery
occlusion.12,80,82 Therefore, contraction band necrosis could

www.thelancet.com/neurology Published online October 26, 2018 http://dx.doi.org/10.1016/S1474-4422(18)30336-3 7

 Review
be considered classic neuro­ cardio­genic heart damage.
Electrical instability of cardiomyocytes together with
excessive adrenergic stimu­lation of the conductive network
can lead to cardiac arrhythmia. Finally, impaired autonomic
cardiac reflexes result in disturbed blood pressure
regulation and hypertensive crises. Both tachyarrhythmia
and hypertensive crisis can further precipitate coronary
demand ischaemia leading to myo­cardial infarction. In
other individuals, increment of para­ sympathetic tone
following stroke can promote brady­arrhythmia and sub­
sequent demand ischaemia.
Stroke-induced systemic alterations
Ischaemic stroke can induce systemic alterations that can
in turn affect cardiac function and promote myo­cardial
injury. Impaired baroreceptor reflex sensitivity and
increased sympathetic activity might result in activation of
the renin–angiotensin–aldosterone system, which can
further sustain endothelial dysfunction, increased systemic
vascular resistance, and blood pressure alterations.89
Furthermore, ischaemic stroke is followed by a systemic
proinflammatory response that might impair cardiac
function. Proinflammatory cyto­kines released by damaged
neuronal cells have been shown to alter sympathetic
output of the hypothalamic–pituitary–adrenal axis and
could, thereby, further drive excessive catecholamine
release.11 Findings from one study have suggested that
ischaemic stroke could induce gut dysbiosis, which in turn
can foster cardiac dysfunction.11 Additional research is
needed to clarify the effect of these processes on the
severity of stroke–heart syndrome.
Concomitant acute coronary syndrome
In a study of 405 consecutive patients presenting with
acute cerebral infarction, patients had a high prevalence of
cardiovascular risk factors and a substantial pro­portion
had underlying (known or silent) coronary artery disease.90
Therefore, evidence of stroke–heart syndrome inevitably
raises the suspicion of a concomitant or preceding acute
coronary syndrome. Importantly, classic presentation of
acute coronary syndrome can be concealed by neurological
deficits such as aphasia, anosognosia, or impaired
consciousness. This setting poses a clinical dilemma since
diagnostic criteria that allow a reliable differentiation
between stroke–heart syndrome and comorbid acute
coronary syndrome have not been established. Data
regarding the frequency of an underlying acute coronary
syndrome are scarce. In the prospective Troponin
Elevation in Acute Ischemic Stroke (TRELAS) study
of 2123 consecutive patients with ischaemic stroke, 29 with
an elevated cardiac troponin concentration (above a clinical
cutoff to rule-in myocardial infarction in patients with
typical chest pain) had a diagnostic coronary angiography
to evaluate coronary vessel status.91 Coronary culprit
lesions, suggesting acute coronary artery disease, were
present in seven (24%) of 29 patients. Conversely, coronary
angiography showed no coronary artery disease in 14 (48%)
8 www.thelancet.com/neurology Published online October 26, 2018 http://dx.doi.org/10.1016/S1474-4422(18)30336-3
of 29 of patients. This finding was in contrast with the age-
matched and sex-matched controls with non-ST elevation
acute coronary syndrome, despite similar baseline cardiac
troponin concentrations (figure 4).91 This particular
combination of non-obstructed coronary arteries despite
acute elevation in cardiac troponin has been defined as an
own entity of myocardial infarction (myocardial infarction
with non-obstructed coronary arteries),92 which is used as a
working diagnosis to prompt further evaluation of its
underlying causes. Echocardiography and cardiovascular
MRI are useful to identify the underlying mechanisms
(eg, takotsubo syndrome, coronary spasm, coronary
microvascular dys­ function, and spontaneous coronary
emboli).93 Clinicians should also be aware that a relevant
proportion of patients with stroke and elevated cardiac
biomarkers might have type 2 myocardial infarction.13,94
Type 2 myocardial infarction is due to coronary demand
ischaemia, unlike classic type 1 myocardial infarction that
is caused by coronary plaque rupture or thrombosis.
Hypertensive crisis and tachyarrhythmia are important
causes of type 2 myocardial infarction that have to be
considered and treated.94
Currently, no strong data are available to support
diagnostic criteria for simultaneous acute coronary
syndrome in patients with acute stroke, or to identify
those in need of coronary interventions. Measurement of
cardiac troponin can be helpful, since both absolute
concentrations and relative change in are higher in acute
coronary syndrome than in other conditions causing
myocardial injury, but a cutoff to distinguish between
myocardial injury due to stroke–heart syndrome and
acute coronary syndrome has not been established.13,27
Both the ongoing PRediction of Acute Coronary
Syndrome in Acute Ischemic StrokE (PRAISE,
NCT03609385) and Bernese Heart and Brain Interaction
in Acute Stroke studies will bring light on this issue.
Until data are available, evidence of acute myocardial
infarction (ie, increase or decrease by >20% of cardiac
troponin in repeated measurements) should prompt
non-invasive cardiac imaging (ie, echo­ cardiography,
cardiac MRI, and coronary CT). In patients with high
probability of an acute coronary syndrome (typical
complaints, ECG alterations, and premorbid coronary
artery disease), coronary angiography should be
considered on an individual case basis.
Conclusions and future directions
In this Review, we have described the broad clinical
characteristics and underlying mechanisms of cardiac
complications following acute ischaemic stroke. Clinicians
should be aware that about 20% of patients with ischaemic
stroke will reveal signs of an ongoing stroke–heart
syndrome. The extent of pre-existing cardiac disease and
underlying vascular risk factors increases an individual’s
vulnerability to develop stroke–heart syndrome and
moderates its severity. Stroke-specific determinants, such
as stroke severity and lesion location within the central

autonomic network (especially the insular cortex), should
further alert clinicians (figure 1). From a pathophysiological
perspective, the mani­fest­ations of stroke–heart syndrome
might be regarded as the result of a stroke-induced stress-
test to the heart. At least three major causes of cardiac
dysfunction seem to have a role: direct myocardial
catecholamine toxicity, micro­ vascular dysfunction, and
coronary demand ischaemia. Importantly, these processes
are mutually dependent and can overlap in individuals.
An integrated view of post-stroke cardiac complications
as a distinct stroke–heart syndrome has the potential to
inform clinical decision making. Further data are needed
to provide evidence-based recommendations regarding
screening, diagnosis, prevention, and treatment of
cardiac complications after stroke. If patients are at risk
or if evidence of stroke–heart syndrome (table, panel),
prolonged monitoring for cardiac arrhythmia and
worsening of cardiac function, and non-invasive cardiac
imaging (eg, echocardiography or cardiovascular MRI)
seem warranted. To prevent occurrence of stroke–heart
syndrome, electrolyte disturbances should be balanced,
drugs with known QTc prolongation (such as certain
antibiotics, antidepressants, and antipsychotics) should
be avoided, and conditions promoting coronary demand
ischaemia (such as tachyarrhythmia or hypertensive
crisis) should be managed rigorously. Given the proposed
pathophysiology of stroke–heart syndrome, β blockers or
renin–angiotensin–aldosterone system inhibitors might
be considered for cardioprotection, but no strong data to
support this suggestion are available.
Several avenues for future research regarding stroke–
heart syndrome include the exact pathophysiological
pathways and therapeutic targets; a potential link
between acute stroke–heart syndrome and incidence of
long-term cardiac complications (eg, heart failure,
arrhythmias, and sudden cardiac death); and predictors
of the individual phenotype and prognosis. The proposed
criteria of stroke–heart syndrome (panel) might be
considered for the design of clinical studies and to define
a suitable target population for therapeutic interventions.
The presumed mechanisms of stroke–heart syndrome
identify the catecholamine storm, calcium homoeo­stasis in
cardiomyocytes, coronary micro­circulation, and coronary
demand ischaemia as promising targets within clinical
studies. Further key questions on the factors contributing
to stroke–heart syndrome remain, including the extent of
direct neurocardiogenic mechanisms versus microvascular
mechanisms in individual patients, and to what degree
activation the hypothalamic–pituitary–adrenal axis, direct
sympathovagal imbalance, or neurohumoral mediators
have a role. Methodologically, further con­ sideration is
needed for imaging the cardiac phenotype of stroke–heart
syndrome with modern cardio­ vascular MRI or hybrid
imaging techniques. Additionally, a thorough study of
biomarkers (eg, circulating microRNAs) and autonomic
ECG markers has the potential to identify a subgroup of
patients with stroke with relevant autonomic imbalance.
www.thelancet.com/neurology Published online October 26, 2018 http://dx.doi.org/10.1016/S1474-4422(18)30336-3 9
Review
100
CAD with culprit
lesion
Stable CAD
80
No CAD
60
Frequency (%)
40
MINOCA
20
0
NSTE-ACS Ischaemic stroke
Figure 4: Coronary angiographic findings in patients with elevated cardiac
troponin
Right column shows frequency of coronary artery disease (CAD) with acute
coronary lesions suggesting coronary plaque rupture or thrombus (ie, culprit
lesions), stable coronary artery disease (more than 50% stenosis in at least
one major epicardial vessel), absence of any obstructive coronary artery disease
in patients with acute ischaemic stroke, and cardiac troponin concentrations
above the clinical cutoff value to rule in myocardial infarction. The latter
represents a group with myocardial infarction with non-obstructive coronary
arteries (MINOCA). Left column shows coronary angiographic findings in
age-matched and sex-matched patients presenting with non-ST elevation acute
coronary syndrome (NSTE-ACS). Adapted from reference 91, by permission of
Mochmann and colleagues.
Another important aspect of future research will be
to determine whether stroke–heart syndrome is an
acute but merely transient event, or whether cardiac
disturbances persist throughout long-term follow-up.
Considering ischaemic stroke as a stress test for the
heart, acute cardiac alterations might be useful to
detect patients at risk of future cardiovascular events.
More effort is certainly needed to reassess (autonomic)
cardiac function system­ atically throughout the long-
term after the initial stroke event and monitor causes
of death. Another important gap in evidence is the
individual risk prediction of occurrence and severity
of stroke–heart syndrome. Although lesion location
within the central autonomic network, high and more
dynamic cardiac troponin con­ centrations, and pre­
morbid cardiac disease seem to be established risk
factors for stroke–heart syndrome, further contributing
aspects, such as sex issues, circadian rhythm­ icity,
and epigenetic modification of stress-related genes
linked to individual vulnerability to stress need to be
scrutinised.
 Review
Search strategy and selection criteria
We searched PubMed for papers published between
Jan 1, 2008, and Aug 15, 2018, without any language
restrictions, with the following terms: “ischaemic stroke”,”
cerebral stroke”, “acute cerebrovascular accident”, “brain”,
“central autonomic network”, “insula”, or “amgydala”
together with “cardiomyopathy”, “heart”, “myocardial
diseases”, “arrhythmia”, “troponin”, “cardiac biomarkers”,
“sudden death”, “wall motion abnormalities”, “takotsubo
syndrome”, “takotsubo cardiomyopathy”, or “cardiovascular
diseases/metabolism”. Additional references were gathered
from retrieved publications. Original research articles and,
when appropriate, high impact reviews were included.
The final reference list was generated on the basis of
originality and relevance to the topic of this Review.
Contributors
JFS wrote the first draft of the Review. All authors contributed equally to
the conception, literature search, writing, and editing of the Review.
Declaration of interests
JFS reports speaker honoraria from W L Gore & Associates and Stryker
GmbH & Co. KG, and a research grant from the Corona-Stiftung. CHN
reports speaker honoraria and travel grants from W L Gore & Associates,
Pfizer Pharma, Bristol-Myers Squibb, and Sanofi, and consulting fees
from Boehringer Ingelheim. WD reports grants and personal fees from
Vifor; personal fees from Pfizer, Boehringer Ingelheim, and Sphingotec;
and grants from ZS Pharma. VH reports no disclosures. ME reports
grant support from Bayer, the German Research Foundation, the
German Federal Ministry of Education and Research, the German
Center for Neurodegenerative Diseases, the German Centre for
Cardiovascular Research, the EU, Corona Foundation, and Fondation
Leducq; and speaking and consulting fees paid to
Charité-Universitätsmedizin Berlin from Boehringer Ingelheim,
Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Amgen, GlaxoSmithKline,
Sanofi, Covidien, Ever, and Novartis.
Acknowledgments
We thank Daniel Heppe for support with creating the figures.
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