Journal of the American Heart Association

CONTEMPORARY REVIEW

Stroke–­Heart Syndrome: Recent Advances

and Challenges
Jan F. Scheitz , MD; Luciano A. Sposato , MD; Jeanette Schulz-­Menger, MD; Christian H. Nolte , MD;
Johannes Backs, MD; Matthias Endres , MD

ABSTRACT: After ischemic stroke, there is a significant burden of cardiovascular complications, both in the acute and chronic
phase. Severe adverse cardiac events occur in 10% to 20% of patients within the first few days after stroke and comprise a
continuum of cardiac changes ranging from acute myocardial injury and coronary syndromes to heart failure or arrhythmia.
Recently, the term stroke– ­heart syndrome was introduced to provide an integrated conceptual framework that summarizes
neurocardiogenic mechanisms that lead to these cardiac events after stroke. New findings from experimental and clinical
studies have further refined our understanding of the clinical manifestations, pathophysiology, and potential long-­term conse-
quences of the stroke–­heart syndrome. Local cerebral and systemic mediators, which mainly involve autonomic dysfunction
and increased inflammation, may lead to altered cardiomyocyte metabolism, dysregulation of (tissue-­resident) leukocyte pop-
ulations, and (micro-­) vascular changes. However, at the individual patient level, it remains challenging to differentiate between
comorbid cardiovascular conditions and stroke-­induced heart injury. Therefore, further research activities led by joint teams
of basic and clinical researchers with backgrounds in both cardiology and neurology are needed to identify the most relevant
therapeutic targets that can be tested in clinical trials.

Key Words: brain–­heart axis ■ heart ■ inflammation ■ outcomes ■ stroke

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I
schemic stroke patients are at substantial risk of heart acute and long-­ term cardiovascular complications
disease, and, vice versa, heart disease increases after stroke.
the risk of ischemic stroke. Randomized controlled Within the past years, it is increasingly recognized
trials and observational studies reported severe ad- that the interactions between heart disease and isch-
verse cardiac events in ≈10% to 20% of patients with emic stroke are more than a mere consequence of tradi-
acute ischemic stroke.1–­7 These clinically severe car- tional vascular risk factors that affect both organs. Based
diac complications are more common in patients with upon the evidence from preclinical and clinical studies
severe stroke and may even occur in patients without that acute ischemic stroke can have immediate deleteri-
known comorbid cardiac disease.1,2,4,6 Stroke patients ous effects on the heart, the concept of a distinct stroke–­
with early severe cardiac complications are at a 2-­to heart syndrome was introduced in 2018 (see Box and
3-­fold increased risk of short-­term mortality.1,8 Beyond Figure 1 for definition).1,3,12–­15 The intention of the concept
these acute neurocardiogenic alterations, the occur- was to provide an integrated view of stroke-­related car-
rence of cardiovascular events and cardiac death are diac complications to increase the clinical awareness,
the main drivers of long-­term prognosis after stroke.9,10 generate a common mechanistic framework, and fa-
Nearly one-­third of deaths in stroke survivors can be cilitate the development of research collaborations and
attributed to a cardiac cause.10,11 Both short-­term and clinical management pathways. The stroke–­heart syn-
long-­term cardiac events after stroke happen despite drome concept summarizes the full spectrum of car-
contemporary secondary prevention measures. Thus, diac changes newly observed within the first 30 days
there is a medical need to reduce the burden of both after an acute ischemic stroke.3,7 Its pathophysiological

Correspondence to: Matthias Endres, MD, Department of Neurology, Charité-­Universitätsmedizin Berlin, Charitéplatz 1, Berlin 10117, Germany.
Email: matthias.endres@charite.de
For Sources of Funding and Disclosures, see page 14.
© 2022 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creative
Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use
is non-commercial and no modifications or adaptations are made.
JAHA is available at: www.ahajournals.org/journal/jaha

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 Scheitz et al Stroke–Heart Syndrome: Advances and Challenges

longer-­term effects of ischemic stroke on the heart. In

Nonstandard Abbreviations and Acronyms the late 1980s and early 1990s, there was an initial pe-
riod of flourishing animal research on deleterious heart–­
AFDAS AF detected after stroke brain interactions following stroke. Ground-­ breaking
BDNF brain-­derived neurotrophic factor experiments in cats and rats demonstrated that stroke
CaMKII Ca2+/calmodulin-­dependent kinase II can impair physiological autonomic cardiac function
CAN central autonomic network and provoke proarrhythmogenic electrocardiographic
CORONA-­IS Cardiomyocyte Injury Following changes.16,17 In recent years, several well-­ designed
Acute Ischemic Stroke experimental studies have helped to refine our knowl-
MACE major adverse cardiovascular edge of the stroke–­heart syndrome phenotype in ro-
events dent models (Figure 2).18–­24 To study the acute cardiac
MCAo middle cerebral artery occlusion effects of stroke, Veltkamp and colleagues induced
an experimental ischemic stroke via transient (60 min-
NLRP3 NLR family pyrin domain
containing 3 utes) filament occlusion of the left middle cerebral ar-
tery (MCAo) in mice.18 This paradigm resulted in large
Nr4a1 nuclear receptor subfamily 4
group a member 1 cerebral infarcts and was paralleled by early cardiac
dysfunction and damage. Serial echocardiographic
PPARα peroxisome proliferator-­activated
receptor α measurements showed that MCAo reduced left ven-
tricular (LV) ejection fraction and LV fractional shorten-
PRAISE Prediction of Acute Coronary
Syndrome in Acute Ischemic ing by 10% to 15% as compared with sham-­operated
Stroke animals. These effects began on the first day after
SICFAIL Stroke-­Induced Cardiac Failure in experimental stroke and persisted for up to 14 days.
Mice and Men These findings were accompanied by myocardial injury
TTS Takotsubo syndrome as reflected by transiently 3-­to 5-­fold increase in levels
of high-­sensitivity cardiac troponin (hs-­cTn), bradycar-
dia, rapid cardiomyocyte atrophy, and cardiac weight
model views ischemic stroke as a specific event trigger- loss.18 Vornholz and colleagues were able to reproduce
ing neurocardiogenic heart injury and is based on both this phenotype of acute cardiac dysfunction also after
right-­sided MCAo.19 A similar study in rats demon-
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preclinical and clinical data suggesting a strong overlap

between the continuum of clinical phenotypes and un- strated that embolic strokes resulting in large brain in-
derlying mechanisms.1,3 The biggest controversy around farcts and severe neurologic deficits induced early and
this concept relates to the underlying pathophysiologic persistent reduction in LV fractional shortening.23
mechanisms: Is cardiac dysfunction following ischemic Beyond these immediate cardiac effects, there
stroke caused by vascular comorbidity along the cardio- is evidence that ischemic stroke produces a chronic
vascular risk continuum, is it a specific event triggered by heart failure phenotype. Bieber and colleagues per-
the stroke, or both? On an individual patient level, phy- formed short-­term, right-­sided MCAo in mice resulting
sicians are challenged by the clinical problem whether in small ischemic lesions in the basal ganglia and the
acute cardiac injury in a patient with stroke represents rodent analogue of the insular cortex.21 Eight weeks
a critical event requiring urgent cardiac diagnostics and after surgery, MCAo resulted in a significant reduction
potentially harmful intervention. of LV ejection fraction of about 15% compared with
In this review, we aimed to provide an updated sham-­operated and control animals. This was accom-
overview of the experimental phenotype and clinical panied by a significantly higher heart rate, increased LV
manifestations of the stroke–­heart syndrome, and to end-­systolic and end-­diastolic volumes, cardiac hyper-
extend the existing pathophysiological model, focusing trophy, and adverse cardiac remodeling as measured
on the most relevant stroke characteristics, key medi- by increased LV collagen content.21 Similarly, in several
ators, as well as downstream cardiac signaling path- murine stroke models that induced right-­sided small
ways. Finally, we aimed to derive the most challenging to intermediate cortical lesions, a progressive 10% to
questions and promising directions for future research. 25% reduction in LV ejection fraction was found over a
3-­day to 4-­week period along with cardiac interstitial fi-
brosis.20,22,24 There is evidence that cardiac alterations
MANIFESTATIONS OF STROKE–­HEART are not limited to the left ventricle, but also include the
SYNDROME left atrium. In a rat model with selective ischemic le-
sions of the left and right insular cortex stroke by local
Evidence From Animal Models endothelin-­1 injection, stroke resulted in left atrial re-
Rodent models of experimental stroke provide a unique modeling and fibrosis, particularly in atrial regions with
opportunity to study both the immediate short-­term and rich autonomic innervation.25

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 Scheitz et al Stroke–­Heart Syndrome: Advances and Challenges

BOX  Updated Criteria and Features of the Stroke–­Heart Syndrome*

Clinical definition
• New evidence of cardiac alterations or documented worsening of premorbid cardiac function after ischemic stroke.

Clinical phenotype†
• Acute myocardial injury (elevation of cardiac troponin with rise/fall pattern).
• Acute coronary syndrome (via coronary demand ischemia or coronary plaque destabilization).
• Left ventricular systolic and diastolic dysfunction including Takotsubo syndrome secondary to stroke.
• ECG changes (especially repolarization disorders like QTc prolongation), cardiac arrhythmias, and atrial fibrillation detected after stroke.
• Sudden cardiac death.

Time course
• Cardiac alterations usually peak within 72 hours after ischemic stroke onset and are considered to be part of stroke–­heart syndrome if they
occur within 30 days after the index event.
• Potential long-­term consequences of stroke–­heart syndrome occur later than 30 days after stroke.

Risk factors
• General: age, burden of cardiovascular risk factors.
• Stroke-­specific: stroke severity, involvement of central autonomic network (especially the insular cortex).
• Heart specific: preexisting coronary or structural heart disease.

Differential diagnoses
• Other systemic or cardiac conditions: in particular sepsis, chronic but stable heart failure, pulmonary embolism, pulmonary hypertension,
acute kidney injury, chronic kidney disease, myocarditis, and recent cardiac intervention.
• Causes of coronary demand ischemia not directly attributable to stroke (eg, anemia and reduced blood oxygenation).

Recent key advances

• Animal models established and characterized an acute and chronic phenotype of stroke-­induced cardiac dysfunction.
• More clinical evidence supports a time-­dependent trajectory of poststroke cardiac events with a highest prevalence (10%–­20%) within the
time-­frame of 30 days after stroke.
• More evidence supports the role of systemic and local cardiac inflammation as drivers of stroke–­heart syndrome.
• More clinical evidence supports that patients with stroke–­heart syndrome are at increased risk of long-­term major cardiac events.

*Adapted from Scheitz et al and Sposato et al.1,3 †Note that manifestations may overlap in the individual patient.

A potential drawback of animal research is that ex- systolic and diastolic LV dysfunction including Takotsubo
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perimental stroke models usually use young, male, and syndrome (TTS), (4) cardiac arrhythmias including atrial
healthy animals.18,25,26 This may hamper translation into fibrillation (AF) and relevant ECG changes, and (5)
clinical practice, because ischemic stroke is typically neurogenic sudden cardiac death (Box, Figure  2).1,3
a disease of the elderly with a high burden of chronic Importantly, these categories are not mutually exclusive,
cardiovascular comorbidities.27,28 To improve clinical and there is substantial overlap between these manifes-
translation, international guidelines recommend re- tations.1,31,32 Established risk factors include older age,
peating experiments in aged and animals of both sexes premorbid cardiac disease, and stroke characteristics
as well as animals with comorbidities such as diabetes such as stroke severity, infarct size, and lesion site in
or hypertension.29 Of note, there is evidence that the the insular cortex.1,2 The stroke–­heart syndrome appar-
stroke–­heart syndrome is more pronounced in diabetic ently affects women and men equally, although certain
mice and similar in young and aged mice.20,21,30 This phenotypes, such as TTS secondary to stroke, mainly
underscores the notion that modeling the stroke–­heart affect women.33–­35 In the original description of the
syndrome in rodents can be achieved under clinically stroke–­heart syndrome, we proposed the differentiation
relevant conditions. If these aspects are further con- of stroke–­ heart syndrome from myocardial ischemia
sidered in the future, streamlined rodent models will because of coronary plaque rupture or plaque throm-
remain highly valuable tools to probe neurocardiogenic bosis (ie, type 1 MI). Recent evidence from experimen-
mechanisms of stroke–­heart syndrome, identify causal tal studies in humans and mice, however, suggest that
mediators, and test promising interventions. acute mental stress and neuroinflammation may lead to
destabilization of atherosclerotic plaques via activation
of the neuroendocrine axis and subsequent uptake of
Spectrum, Severity, and Time Course of inflammatory leucocyte populations.36,37 Thus, we now
Clinical Manifestations propose that also type 1 MI may occur as part of the
The stroke–­ heart syndrome encompasses a broad spectrum of the stroke–­heart syndrome. Given the high
clinical spectrum of cardiovascular changes including frequency of atypical clinical presentation of ACS in the
(1) acute myocardial injury (as evidenced by acute eleva- elderly, especially those with neurological deficits (such
tion of hs-­cTn), (2) acute coronary syndromes (ACS; in- as aphasia), the accurate diagnosis of ACS has to rely
cluding type 1 and type 2 myocardial infarction [MI]), (3) on strict and systematic clinical examination, typical

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 Scheitz et al Stroke–Heart Syndrome: Advances and Challenges

The Stroke-Heart Syndrome – Recent Advances and challenges

Stroke-Heart Syndrome Prognosis:

2-3 fold increased risk of short-
Definition: term mortality
New evidence of cardiac 1.5-2 fold increased risk of
alterations or documented MACE during long-term
worsening of premorbid
cardiac function after Risk factors:
ischemic stroke Age, pre-morbid heart disease,
stroke-specific factors (severity,
Manifestations: insular cortex)
ECG changes, arrhythmia
Myocardial injury, ACS Pathophysiology:
Heart Failure, Takotsubo Autonomic dysbalance
Sudden cardiac death and inflammation
Stroke-induced ‚cardiac
Frequency: stress test‘
10-20% cardiac SAE
within 30 days Perspectives:
Join forces to identify treatments
Time-Course: (basic/ clinical scientists;
Peak within 72 hours neurologists/ cardiologists/
up to 30 days. immunologists)
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Figure 1.  Summary of key criteria and of the stroke–­heart syndrome.

ACS indicates acute coronary syndrome; MACE, major adverse cardiovascular events; and SAE, severe adverse events.

ECG findings, and cardiac imaging showing regional that myocardial injury and prolonged QTc time are as-
wall-­motion abnormalities or coronary lesions.3,38 sociated with the incidence of more severe forms of
With the introduction of increasingly sensitive and stroke–­heart syndrome.2,4,32,39–­41 Therefore, it is rea-
specific cardiac diagnostic tests within the past de- sonable and also recommended by current guidelines
cades, it became clear that the manifestations of the to measure hs-­cTn and perform a standard 12-­lead
stroke–­heart syndrome range from oligo-­or even as- ECG to screen for subclinical early cardiac involve-
ymptomatic laboratory or ECG findings to severe clini- ment after ischemic stroke.42 In case of pathological
cal manifestations requiring urgent cardiac diagnostics findings, prolonged ECG monitoring, thorough clin-
and treatments. The most common cardiac changes ical cardiac assessment, and serial measurement of
include myocardial injury (ie, elevated hs-­ cTn levels hs-­cTn are warranted to identify patients at higher risk
above assay-­specific reference limits), ECG alterations of developing severe or fatal cardiovascular compli-
such as QTc prolongation, and LV diastolic dysfunc- cations. Data from systematic evaluations of adverse
tion, which are observed in up to 60% of patients with events documented in high-­quality randomized con-
acute ischemic stroke, typically during the initial in-­ trolled trial settings have shown that 10% to 20% of
hospital workup.8,31,38 These patients are at increased patients with acute ischemic stroke suffer a severe
risk of death and more likely to leave the hospital with cardiac adverse event requiring urgent evaluation and
more severe stroke-­ related disabilities.8,39 Because treatment.2,5–­7 These mainly include acute myocardial
the individual premorbid cardiac status is usually un- injury (characterized by a distinctive rise or fall pattern
known, thorough clinical assessment and serial di- of hs-­cTn levels),8,38,43 LV systolic dysfunction,31,40,44,45
agnostic tests are required to distinguish comorbid and arrhythmia including atrial fibrillation.4,46 In 1%
and clinically stable heart disease from stroke–­heart to 5% of patients, even more severe manifestations,
syndrome. Several observational studies documented such as myocardial infarction,5,47,48 overt heart failure

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 Scheitz et al Stroke–­Heart Syndrome: Advances and Challenges

Cardiac function
Physiological cardiac function
Acute phenotype
Chronic phenotype

LV EF ↓ LV EF ↓
LV fractional shortening ↓ Cardiac hypertrophy ↑
Myocardial injury (troponin) ↑ Interstitial cardiac fibrosis ↑
Cardiac atrophy ↑ Left atrial remodeling ↑

1d 3d 4w 8w

Physiological cardiac function

Ischemic stroke

1) Myocardial injury (troponin ↑) Incident MACE ↑

2) Acute coronary syndromes Incident HF ↑
3) ECG changes and arrhythmia Cognitive impairment ↑
4) Systolic and diastolic dysfunction Cardiovascular death ↑
5) Sudden cardiac death

1d 3d 4w 1y Time since stroke

Figure 2.  Phenotypes and time course of the stroke–­heart syndrome in rodent models and clinical practice.
(Top) Phenotype observed in rodent ischemic stroke models. The dashed blue line indicates physiological cardiac function. The red
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line indicates the severity of acute cardiac dysfunction that peaks within 24 to 72 hours and persists up to 14 days after experimental
stroke. Note that this phenotype was most consistently inducible by severe brain ischemia. The black line indicates a phenotype of
chronic cardiac dysfunction starting 4 to 8 weeks after experimental brain ischemia. Note that this phenotype was most consistently
inducible by mild, right-­sided brain ischemia. (Bottom) Spectrum and time-­course of stroke–­heart syndrome observed in human
clinical studies. The dashed blue line indicates physiological trajectory of cardiac function during aging. The blue line indicates the
trajectory of cardiac alterations after stroke observed in observational clinical studies. Note that there is large individual variability, and
that further studies are needed to predict the incidence of long-­term cardiovascular outcomes and heart failure. EF indicates ejection
fraction; HF, heart failure; LV, left ventricular; and MACE, major adverse cardiovascular events.

including TTS,1,3,7,34,45 and malignant tachycardia or this study, and the increased risk was strongly time
cardiac arrest, have to be expected.4,5,7 The spectrum dependent.9,33 Although adjusted risk of MACE was
of severe forms of stroke–­heart syndrome are associ- increased 25-­fold in the first 30 days, it remained >2
ated with a 2-­to 3-­fold increased risk of mortality or times higher during the first year after ischemic stroke.9
poor functional outcome.1,5,48 Based on this time-­dependent trajectory, it can be as-
In regard to the time course, there is evidence that sumed that MACE occurring within the first 30 days
the acute manifestations of the stroke–­heart syndrome after stroke may be directly attributable to the stroke–­
peak within the first 72 hours after brain ischemia heart syndrome.3 After this phase, incident MACE and
(Figures 1 and 2)1,2,4 but may not be limited to this early heart failure can be considered as possible long-­term
phase. A recent Canadian population-­based study of consequences of the initial cardiac injury attributable
adults aged ≥66 years, 9.1% of 21 931 patients with to stroke–­heart syndrome.
first-­ever ischemic stroke had incident major adverse
cardiovascular events (MACE) at 1 year (including ACS
and MI, coronary interventions, incident congestive Current Challenges
heart failure, or cardiovascular death).9 Compared It remains challenging to differentiate whether post-
with 71  696 matched individuals without stroke or stroke cardiac events are manifestations of stroke–­
heart disease, ischemic stroke was associated with a heart syndrome, an expression of an underlying
4.5-­times higher risk of MACE. Of note, patients with cardiac condition, or both. This is because the cardiac
known heart disease at baseline were excluded from status before the stroke is usually not known when the

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 Scheitz et al Stroke–Heart Syndrome: Advances and Challenges

patient presents to the emergency department and International Classification of Diseases (ICD-­10) codes,
because systematic cardiac evaluations by perform- there is also evidence that more subtle manifesta-
ing serial echocardiography or cardiovascular mag- tions may entail a higher cardiovascular risk. In a clin-
netic resonance (CMR) imaging during follow-­ up of ical study of 201 ischemic stroke patients, those who
stroke are lacking. As outlined above, however, there is had evidence of autonomic imbalance (ie, lower high-­
strong evidence supporting a potential causal relation- frequency power in heart-­rate variability analysis) within
ship between stroke and subsequent cardiac compli- 48 hours after stroke had a higher risk of secondary
cations. In addition to the wealth of animal data that ischemic events within 90 days.53 However, most of
show experimental stroke can induce immediate and the events detected in this study occurred early after
chronic cardiac dysfunction,13,18,22 clinical data provide stroke, highlighting the need for more confirmative data
evidence that there is a time-­dependent occurrence with regard to the longer term. Of 220 patients with
of cardiac complications with a clear peak during the first-­ever, mild-­to-­moderate ischemic stroke and myo-
first few days after stroke.1,2,4,9,35 Major adverse car- cardial injury measured with hs-­cTn within a median of
diac events are also observed even when patients 4 days after the event, but without clinical diagnosis of
with known history of heart disease are excluded.9,49 concurrent ACS, 27.3% experienced a cumulative end
Further evidence comes from observational studies point of recurrent stroke, MI, or death within 3 years
that applied coronary angiography in stroke patients of follow-­up.54 This was significantly higher than in
with elevation of hs-­cTn, showing that the majority of the control group of 342 patients with normal hs-­cTn
these patients had no underlying obstructive coro- levels during the acute poststroke phase (10.2%; ad-
nary artery disease.47,50 Serial measurements of hs-­ justed hazard ratio, 2.0).54 Beyond the occurrence of
cTn demonstrate a rise or fall pattern in 15% to 30% cardiovascular events, there is also evidence that pa-
of patients,8,43 which means that myocardial injury is tients with (subclinical) myocardial injury in the acute
acute and not chronic in these patients. Finally, specific phase after the ischemic stroke have a higher burden
stroke characteristics like stroke severity and stroke le- of cerebral small vessel disease and cognitive impair-
sion site promote the occurrence of poststroke cardiac ment than those without.55,56 Among 555 patients with
events even when statistically accounting for premor- first-­ever ischemic stroke, global cognitive impairment
bid cardiac conditions.32,41,51,52 These stroke character- was present in 43% of patients with hs-­ cTn values
istics linked to stroke–­heart syndrome are discussed in in the highest quartile.56 This proportion was signifi-
more detail below. cantly higher than in the group of patients with hs-­cTn
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To date, it remains also challenging to determine in the lowest quartile (15%) and remained statistically
whether long-­ term vascular events and post-­ stroke significant after adjusting for potential confounders.
cognitive dysfunction are prompted by stroke–­heart Cognitive function remained worse in this group during
syndrome or whether premorbid subclinical heart the 3 years of follow-­up.56
disease, or both, accounts for the observed associ- Another challenging field of research includes the
ations. However, there is increasing evidence that this entity of AF detected after stroke (AFDAS), which may
might be the case. As described earlier, a phenotype be considered a particular expression of the stroke–­
of chronic cardiac dysfunction with myocardial fibro- heart syndrome. According to a meta-­analysis, previ-
sis can be induced 4 to 8 weeks after experimental ously unknown AF can be found in ≈10% of patients
stroke.21,24 Moreover, ex vivo experiments using rat with ischemic stroke during the initial in-­ hospital
hearts derived from animals that underwent an ex- workup and in ≈25% by sequentially combining car-
perimental stroke paradigm were more susceptible to diac monitoring methods during long-­term follow-­up.46
second ischemic hits to the heart.23 This suggests an The theoretical construct of AFDAS has evolved in re-
increased susceptibility to secondary cardiac events cent years and addresses its distinctive characteris-
poststroke. This presumption is supported by a re- tics when compared with AF known before stroke.57,58
cent retrospective analysis using a global (primarily US Conceptually, AFDAS results from the interplay of un-
based) network of 365 383 health care records of pa- derlying cardiogenic mechanisms and stroke-­related
tients with stroke and 5-­year follow-­up that compared neurogenic phenomena.58 AFDAS seems to have a
the long-­term cardiovascular outcomes of stroke pa- lower prevalence of cardiovascular comorbidities and
tients with and without manifestations of stroke–­heart less severe structural heart disease than AF known be-
syndrome (defined as new-­onset cardiovascular com- fore stroke occurrence.58,59 These findings may explain
plications within 30 days after stroke).7 Patients with why patients with AFDAS seem to have a lower risk
stroke–­ heart syndrome had a 1.5-­to 2-­ fold higher of stroke recurrence than those with a known history
odds of 5-­year mortality and MACE depending on the of AF before stroke onset.60,61 AFDAS probably en-
respective manifestation of stroke–­heart syndrome.7 compasses higher and lower risk phenotypes based
Although this study focused on substantial manifesta- on the severity of preexisting atrial cardiopathy and
tions of stroke–­heart syndrome diagnosed based on the prevalence of risk factors.58 Within the spectrum

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 Scheitz et al Stroke–­Heart Syndrome: Advances and Challenges

of AFDAS risk, patients with severe atrial cardiopathy years, further advances have been made that have
(eg, dilated left atrium) are those who may bear the helped to further elucidate the complex interplay of is-
higher risk, whereas those with structurally healthy chemic stroke-­lesion characteristics, local cerebral and
hearts and lower-­ burden AFDAS triggered by self-­ systemic mediators, and downstream cardiac mecha-
limited and short-­lasted neurogenic mechanisms may nisms leading to the stroke–­heart syndrome (Figure 3).
have a lower embolic risk.3,62,63 Studies combining bio- The next paragraphs summarize these advances and
markers, neuroimaging patterns, and cardiovascular describe promising future directions of research.
comorbidities are needed to further characterize high-
er-­and lower-­risk AFDAS phenotypes. Characterizing Impact of Stroke Characteristics
these phenotypes may help improve the selection of There is evidence that specific localizations of the is-
ischemic stroke and transient ischemic attack patients chemic lesion favor the occurrence of stroke–­ heart
who could benefit more from anticoagulation if AFDAS syndrome. A well-­studied example is the association
is found on prolonged cardiac monitoring. between ischemic lesions in the insular cortex and the
occurrence of acute myocardial injury, TTS, and ar-
rhythmia.8,34,41,51,52 In experimental studies, the extent
PATHOPHYSIOLOGY OF of histological damage in the correlate of the insula in
STROKE–­HEART SYNDROME the mouse brain damage correlated with the severity
The pathophysiological model of stroke–­ heart syn- of cardiac dysfunction and troponin elevation.19,26 The
drome considers the spectrum of clinical manifesta- insular cortex is an integral part of central autonomic
tions to be the result of neurocardiogenic mechanisms network (CAN) and is involved in both cardiac intero-
leading to stroke-­induced heart injury (stroke-­induced ception and efferent cardiovascular response to emo-
cardiac stress-­test).1,3 Of note, neurocardiogenic injury tional experience.65,66 Under physiological conditions,
is not restricted to an ischemic stroke cause and can the CAN regulates sympathetic and parasympathetic
be observed in other acute brain disorders such as neuronal outflow to the heart.3,66 Ischemic stroke may
seizures, traumatic brain injury, and intracranial hem- lead to abrupt changes in the physiological organiza-
orrhage (reviewed elsewhere).64 Within the past few tion of the CAN, resulting in autonomic dysfunction.
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STROKE-HEART Syndrome
Stroke Mediators Heart Outcome

Immunological
• Brain-bone marrow-
spleen signals
• Systemic Inflammation
• Inflammasome

High risk of
Neuronal
• Autonomic nervous
• Cardiovascular events
tone
Downstream Mechanisms • Heart failure

• Cardiac death
Humoral
Stroke characteristics Impaired coronary • Cognitive dysfunction
• Catecholamines
• Cortisol (micro-) circulation
• Lesion size, stroke severity
• Vasoactive mediators
• Central autonomic network
(e.g. endothelin-1) Macrophage
changes
• Brain derived dysfunction
death factors
• miRNAs Cardiomyocyte
• Extracellular vesicles injury

(Epi-)Genetic modification

Figure 3.  Overview about stroke-­specific characteristics, mediators, downstream cardiac mechanisms, and outcomes of
stroke–­heart syndrome.
The 4 columns describe the most promising and well-­studied stroke characteristics, mediators, cardiac mechanisms, and short-­term
and long-­term outcomes of stroke–­heart syndrome.

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 Scheitz et al Stroke–Heart Syndrome: Advances and Challenges

Importantly, the occurrence of the stroke–­heart syn- of stress response and function of the CAN well be-
drome is not limited to ischemia within the insular fore the stroke increase the individual’s susceptibility
cortex. Both in clinical and experimental settings, a to develop stroke–­heart syndrome. Moreover, further
phenotype of poststroke cardiac dysfunction can also clinical studies (eg, using lesion-­network mapping ap-
be observed when the insular cortex itself is not af- proaches) are needed to determine the specificity of
fected.22,24,67 Other relevant regions of the CAN with CAN dysfunction (beyond the insula and brain stem) for
documented impact on cardiac function include the the occurrence of the stroke–­heart syndrome.
amygdala, anterior cingulate cortex, ventromedial pre- Beyond specific lesion sites, observational clinical
frontal cortex, hypothalamus, mediodorsal thalamus, data provide compelling evidence that stroke severity
hippocampus, and brainstem regions.3,66,68–­70 With re- is associated with the occurrence of virtually all mani-
gard to the latter, QTc prolongation on ECG upon hos- festations of the stroke–­heart syndrome.1 This associ-
pital admission was found in 9 out of 12 patients with ation has been shown most consistently in relation to
acute medullary infarction.71 Lesion mapping revealed the occurrence of myocardial injury, cardiac arrhyth-
that QTc prolongation correlated with lesions in the mia, and impaired LV function after stroke.4,8,60,67 In line
right or left dorsal vagal nucleus. Remarkably, QTc time with this data, animal studies provided evidence that
partially normalized during the in-­hospital stay, sug- the severity of acute and chronic cardiac dysfunction
gesting a causal relationship with the stroke event. In correlates with the size of brain ischemia.18,21,26 Larger
addition, lateral medullary infarction can occasionally ischemic brain injury not only increases the likelihood
result in central sleep-­ related hypoventilation, which of CAN dysfunction, but also leads to more profound
may lead to secondary cardiac injury (eg, via endothe- disruption of the blood–­brain barrier and damage to
lial dysfunction) or coronary demand ischemia.72,73 Of the neurovascular unit. As a result, danger signals and
note, stroke lesion sites in the insula and brain stem extracellular vesicles enter the bloodstream, which re-
are associated with sleep-­disordered breathing during sults in a systemic activation of the immune system.80
the early poststroke phase.74 In turn, sleep-­disordered This is in line with the notion that the extent of cerebral
breathing after stroke was linked to impaired cardiac injury and inflammation correlate with detrimental ef-
autonomic dynamics, endothelial dysfunction, ECG al- fects on the heart. Whether this can be targeted by
terations like sinus brady-­or tachycardia, and reduced therapeutic interventions remains to be proven.
LV function.73–­75 Therefore, the interplay between the
CAN and sleep-­disordered breathing and its potential
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impact on the occurrence of the stroke–­ heart syn- Key Mediators

drome deserves further study. The knowledge about critical mediators of the stroke–­
Recent evidence from patients with TTS (synony- heart syndrome is rather scarce. However, the way
mous with stress cardiomyopathy) highlights the role toward mechanistic studies is paved by combin-
of the CAN in the occurrence of cardiac dysfunction. ing experimental animal models such as MCAo with
Compared with healthy controls, a surface-­and voxel-­ deeper cardiac phenotyping. Sympathetic overdrive
based morphometry study revealed that patients and reduced parasympathetic activity as a cause for
with TTS related to emotional stress but unrelated to cardiac dysfunction in the stroke–­heart syndrome are
acute stroke have reduced cortical thickness in both among the most consistently discussed mediators.1,3,81
insulae and reduced amygdala volume.76 Moreover, a MCAo-­induced cardiac dysfunction in mice was asso-
functional magnetic resonance imaging study demon- ciated with higher levels of norepinephrine in serum
strated altered parasympathetic and sympathetic net- and the heart and linked to peripheral sympathetic
work activity in TTS patients versus matched controls.77 overactivity.21,26 Seemingly contradicting, cardiac nor-
In a case–­control study of 104 individuals undergoing epinephrine stores were enhanced 3 days after MCAo
positron emission tomography–­ computed tomogra- in the study of Veltkamp and colleagues, which could
phy imaging, higher activity in the amygdala was as- be interpreted as a decrease in sympathetic activity
sociated with the occurrence of TTS during a median 3 days after stroke.18 However, unbiased RNA microar-
follow-­up of 2.5 years.78 Interestingly, individuals with ray analyses showed massive changes in expression
the highest activity within the amygdala developed TTS of catecholamine-­driven genes in the latter experimen-
up to 2 years earlier than those with relatively lower ac- tal setup. This suggests an early sympathetic overac-
tivity.78 Of note, higher resting activity of the amygdala tivation in the heart persisting for at least 1 but not for
and higher perceived stress was associated with ar- 3 days after MCAo. In line with these considerations,
terial inflammation, bone marrow activity, and incident it has been shown that already 2 hours after cerebral
cardiovascular events in patients without known car- embolism in rats, circulating catecholamines were in-
diovascular or cerebrovascular disease.79 However, it creased along with a reduction in cardiac function.23
remains challenging to determine whether inherited or Therefore, local cardiac catecholamine homoeostasis
acquired (eg, by epigenetic mechanisms) disturbance should, in particular, be examined and targeted in the

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 Scheitz et al Stroke–­Heart Syndrome: Advances and Challenges

first hours after ischemia in the brain. Of note, MCAo-­ in cardiomyocytes, pointing to a model in which both
induced cardiac dysfunction could be attenuated by peripheral sympathetic activation along with local car-
β-­blockers.21 Moreover, different experiments found diac sympathetic activation collectively orchestrate
that monoamine oxidase inhibition resulted in both re- myocardial inflammation. Another candidate mediator
duced local cerebral neuroinflammation and reduced in this particular context is BDNF (brain-­derived neu-
catecholamine-­induced cardiac dysfunction.82,83 This rotrophic factor), a neurotrophin involved in the devel-
points to the potential of neuro-­humoral blockade as opment of (autonomic) neurons, angiogenesis, and
therapeutic target. The role of autonomic dysfunction is maintenance of endothelial function.96,97 It has been
supported by clinical evidence of impaired autonomic demonstrated that BDNF improves cardiac muscle
reflexes, and variability of blood pressure and heart contraction and relaxation via the before-­mentioned
rate in patients with ischemic stroke.84–­86 High blood CaMKII pathway.97 Circulating levels of BDNF are re-
pressure variation, especially within the first 3 hours duced after stroke, especially after severe stroke.98
in the early critical phase of autonomic disbalance is Therefore, BDNF signaling may represent a pathway
associated with increased mortality at 90 days.87 Both mediating the interplay between autonomic tone, en-
tachycardia and hypertensive blood pressure levels dothelial integrity, and myocardial dysfunction. Further
are established triggers of coronary demand ischemia, experimental stroke studies in this direction are war-
which can cause myocardial injury.88 In addition, pres- ranted in the future.
sure overload can lead to reversible LV dysfunction Both systemic inflammation and sympathetic over-
with troponin release and myocyte apoptosis even drive can result in activation of coagulation, platelet
without necrosis.89 hyperactivity, and endothelial dysfunction.99–­101 This
Recent experimental studies support an import- process of thromboinflammation has received scientific
ant role of inflammatory responses in the occurrence attention during the COVID-­19 pandemic and has been
of stroke–­heart syndrome.19,24 Stroke-­induced cardiac proposed as an important mediator of myocardial in-
dysfunction in mice was accompanied by a systemic jury, coronary microcirculatory dysfunction, and other
inflammatory response, upregulation of proinflammatory extrapulmonary manifestations of COVID-­19.101,102 The
cytokines within the myocardial tissue, and macrophage impact of thromboinflammation in the occurrence of
infiltration into the heart.19,24 Thus, besides sympathetic the stroke–­heart syndrome, however, has yet to be
overactivation, proinflammatory pathways represent in- proven.
dependent or perhaps interdependent mediators of the A potential contribution of cell–­ cell communica-
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stroke–­heart syndrome. In regard to the latter, sympa- tion in combination with proinflammatory signals
thetic activation leads to the mobilization of inflammatory have recently been shown in experimental stroke
cells from the bone marrow or spleen.90,91 In a photo- models. Stroke-­induced cardiac fibrosis and LV dys-
thrombotic stroke model, splenectomy attenuated car- function was accompanied by decreased levels of
diac dysfunction along with interstitial cardiac fibrosis the microRNA miR-­126 in the serum and the heart.22
at 4 weeks.24 This was preceded by an attenuation of Mice specifically lacking miR-­126 in endothelial cells
proinflammatory cytokines and cardiac macrophage re- showed an even more severe phenotype. This study
cruitment, suggesting that the spleen is critically involved demonstrates how a stroke-­associated reduction in
in the development of subacute and long-­term conse- miR-­126 and miR126-­target genes may mediate the
quences of stroke–­heart syndrome, eventually leading stroke–­heart syndrome via the involvement of endo-
to chronic remodeling. Beyond the brain–­bone marrow–­ thelial cells. Thus, it is possible that vascular injury
spleen axis, further interorgan cross talks that involve the after stroke might lead to long-­distance cell–­cell com-
kidney and gut may be relevant drivers of inflammation munication independent of the surrounding tissue.
and promote poststroke cardiac injury.92,93 In this regard, metabolites or extracellular vesicles
The directed recruitment of CD45+ leukocytes should also be considered.103 Of note, administration
to the heart in response to injury has been shown of exosomes derived from cluster of differentiation
to depend on cardiomyocyte-­born cardiokines that 133+ umbilical cord blood cells attenuated cardiac
serve as chemoattractant signaling molecules.94,95 dysfunction in a photothrombotic stroke model.20
Although the specific role of these cardiomyocyte-­ This was accompanied by reduced oxidative stress,
born signals in stroke–­heart syndrome remains to be reduced transforming growth factor-beta expression,
shown, similar pathophysiological roles have already and reduced recruitment of proinflammatory macro-
been described for CC-­chemokine ligands 2 (mono- phages. cluster of differentiation 133+ umbilical cells
cyte chemotactic protein 1) and 3 (macrophage in- express miR-­ 126, thereby providing a potential link
flammatory protein) in ischemia–­ reperfusion injury to the aforementioned endothelial mechanism. The
of the heart.94,95 Importantly, this cascade was me- vasculature, with its enormous surface, may thereby
diated by a catecholamine-­sensitive protein kinase, serve as an amplifier of deleterious signals as was re-
namely CaMKII (Ca2+/calmodulin-­dependent kinase II) cently demonstrated in tumor biology.104

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 Scheitz et al Stroke–Heart Syndrome: Advances and Challenges

Cardiac Downstream Pathways contribution of these epigenetic-­ metabolic signaling

The above-­mentioned mediators affect various cardiac pathways to the stroke–­heart syndrome. Supporting
cell populations via induction of coronary demand is- this notion, many of the genes acutely regulated after
chemia (eg, via coronary vasoconstriction), microvas- experimental stroke were found to depend on the ac-
cular dysfunction, metabolic switches, and cardiac tivity of the transcription factor PPARα (peroxisome
inflammation (Figure 2). Within the past years, it is in- proliferator-­activated receptor α) that regulates fatty
creasingly recognized that cardiomyocytes constitute acid storage and glucose metabolism.18
less than half of the total cardiac cell population.105 In Besides upregulation of metabolic pathways,
response to acute injury, other cardiac-­resident cells, Veltkamp and colleagues also reported that pathways
including fibroblasts as well as the vasculature and that mediate muscle wasting were regulated following
immune cell compartments, also undergo phenotype experimental stroke.18 These expression changes per-
changes that can trigger maladaptive cardiac remod- sisted over >3 days, pointing to more long-­term con-
eling. Interestingly, it has been shown that tissue-­ sequences. Likewise, heart weight was reduced in the
resident cardiac macrophages can be activated by first days after MCAo, suggesting that these changes
remote injury processes including stroke.106 Several might impact the heart, resulting in pathological at-
downstream cardiac pathways have been established rophy, a process that is also seen in muscle wasting
to mediate cardiac dysfunction.107 However, signaling diseases such as cancer-­related cachexia. However,
pathways to be potentially targeted by pharmacologic data that investigate the potential causal involvement
interventions that mediate acute cardiac dysfunction are missing but may represent another new research
after stroke are largely elusive. Previous approaches direction.
to use calcium sensitizers in stroke models failed,108
indicating that the underlying pathways may be more
complex. Evidence for an important contribution of OPEN QUESTIONS, ONGOING
pro-­ inflammatory pathways was provided by a re- STUDIES, AND DIRECTIONS FOR
cent study in which an inhibitor of NLRP3 (NLR family
pyrin domain containing 3), a key component of the FUTURE RESEARCH
inflammasome, restored cardiac function in mice after Currently, there are many unanswered questions on
MCAo.30 In a rat stroke model, increased oxidative the pathophysiology, long-­term outcomes, and spe-
cific therapeutic approaches to stroke–­ heart syn-
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stress and altered NO signaling were measured in the

left atria. This was accompanied by the recruitment of drome, with many of them being addressed in ongoing
neutrophils, T and B lymphocytes into the left atrium, studies (Table).40,67,112–­120 Because elevation of serum
as well as atrial fibrosis.25 A detailed analysis of the markers of myocardial injury is associated with all other
recruitment of proinflammatory cells, receptor-­ligand clinical categories of stroke–­heart syndrome,4,32,40,41 it
binding studies in combination with single cell, or even seems reasonable to measure hs-­cTn in all patients
single nucleus sequencing may add to a better mecha- to screen for early cardiac involvement after ischemic
nistic understanding of these processes and their role stroke and identify patients who are at risk for a more
in reducing the burden of stroke–­heart syndrome. severe clinical course and further specific cardiac di-
In addition, recent discoveries highlight the role of agnostics. As described above, it is currently not clear
the interface between metabolic and epigenetic pro- how to differentiate causes of myocardial injury at the
cesses. Nr4a1 (nuclear receptor subfamily 4 group a individual patient level and identify patients at high risk
member 1) is a catecholamine-­ sensitive nuclear re- of ACS requiring timely coronary revascularization. It
ceptor that integrates cytokine signaling in inflamma- is therefore crucial to refine diagnostic algorithms to
tory disorders by acting in nonmyocytes.109 Nr4a1 was identify the corresponding underlying pathophysiology
found to be upregulated 1 day after MCAo in the heart.18 in the respective patient, in the future ideally without in-
Interestingly, Nr4a1 was also enhanced in cardiomyo- vasive diagnostics. This question is currently being an-
cytes derived from induced pluripotent stem cells of swered by the PRAISE (Prediction of Acute Coronary
TTS patients,110 suggesting an overlapping molecular Syndrome in Acute Ischemic Stroke) study, in which
signature of these 2 brain-­dependent forms of acute stroke patients with relevant hs-­cTn elevation undergo
cardiac dysfunction. Interestingly, Nr4a1 was shown coronary angiography in addition to standardized
to be a key target of an epigenetic axis affecting car- electrocardiography and echocardiographic assess-
diomyocyte calcium handling in response to stress.111 ment.119 In the future, other suitable diagnostic meas-
Mechanistic experiments revealed that this process ures may routinely involve contrast-­enhanced multislice
was causative for exercise-­ induced cardiac fatigue, cardiac computed tomography and/or comprehensive
which is reminiscent of the stroke–­heart syndrome. CMR to differentiate cardiac pathologies.121,122 In par-
Thus, it will be interesting to explore the potential ticular, CMR offers opportunities to distinguish causes

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 Downloaded from http://ahajournals.org by on September 3, 2022

Table.  Ongoing Clinical Studies Exploring the Pathophysiology or Targeting of Long-­Term Consequences of Stroke–­Heart Syndrome

Title of study Target no. of Outcomes of

Scheitz et al

Study (registration) Design City, country Target population patients interest Measures Progress

1 Atrial Prospective, Copenhagen, Ischemic stroke 150 (originally Extent of LA fibrosis Gadolinium-­ Active, recruiting
Cardiomyopathy observational, Denmark (≤30 d before estimated incidence of silent enhanced CMR
in Patients case–­control-­study inclusion) without enrolment=225) brain lesions, LA imaging
With Stroke of (healthy age-­and atrial fibrillation volume, LAEF
Undetected sex-­matched
Mechanism112 controls)
(NCT03830983)
2 BEHABIS (The Bern Prospective, Bern, Switzerland Acute ischemic 220 TTS (prevalence of CMR (gadolinium-­ Active, recruiting
Heart and Brain observational, stroke (<12 h after neurogenic stunned enhanced with or
Interaction Study)67 single-­center symptom onset) myocardium), without perfusion)
(NCT03720522) cohort study without severe renal subacute MI
failure (GFR <40)
3 BeLOVE (Berlin Prospective, Berlin, Germany Hospitalization for: 10 000, 2000 each MACE Clinical Active, recruiting
Long-­Term observational, acute ischemic study arm (cardiovascular assessment, CMR,
Observation of multicenter cohort stroke; acute mortality, nonfatal MRI (head), ECG,
Vascular Events)113 study coronary syndrome, stroke, nonfatal 3-­dimensional
(DRKS00016852) acute heart failure, myocardial echocardiography,
acute kidney injury infarction, ocular coherence
(4 study arms) hospitalization tomography
because of heart
failure)
4 CONVINCE Randomized Several countries in Noncardioembolic 2623 Recurrence of Clinical assessment Active recruiting
(Colchicine controlled trial Europe ischemic stroke nonfatal ischemic
for Prevention (colchicine vs without major stroke, nonfatal
of Vascular placebo) disability major cardiac
Inflammation in event, vascular
Non-­CardioEmbolic death
Stroke)115
(NCT02898610)
5 CORONA-­IS Prospective, Berlin, Germany Acute ischemic 300 Quantify autonomic Multimodal CMR, Active, recruiting
(Cardiomyocyte observational, stroke with hospital dysfunction echocardiography,
Injury Following single-­center admission <48 h and decipher autonomic
Acute Ischemic cohort study after symptom downstream ECG markers,
Stroke)116 onset cardiac biobanking
(NCT03892226) mechanisms
leading to
myocardial injury
6 Heart and Brain Prospective, Oxford, United Retired British civil 775 Brain atrophy, Vascular Recruitment
Study–­Substudy observational, Kingdom servants cognitive decline ultrasound, MRI completed,
of Whitehall II cohort study (head) extended follow-­up
Imaging cohort117
(NCT03335696)

(Continued)

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Stroke–­Heart Syndrome: Advances and Challenges
 Downloaded from http://ahajournals.org by on September 3, 2022

Table.  Continued

Title of study Target no. of Outcomes of

Scheitz et al

Study (registration) Design City, country Target population patients interest Measures Progress

7 InsuCor (Insular–­ Prospective, Würzburg, Acute ischemic 180 (New) systolic Echocardiography, Active, recruiting
Noninsular Stroke observational, Germany stroke (onset <3 d; cardiac blood biomarker
Underlying case–­control study with and without dysfunction, stroke,
Cardiac Failure involvement of the vascular events
(DRKS00012454) insular lobe) within 3 mo
8 MIRACLE (MR Prospective, London, Ontario, Acute ischemic 44 NT-­proBNP, NT-­proBNP, Active, recruiting
Evidence of Cardiac observational, Canada embolic stroke systemic inflammatory
Inflammation Post-­ cohort study of undetermined inflammation, markers,
Stroke Study) source myocardial gadolinium
infarction, LV enhanced CMR
function, LA fibrosis imaging
9 Multifactorial Risk Prospective, Tübingen, Germany Ischemic stroke 878 Any stroke, Clinical follow-­up Active, not
Stratification in observational, or TIA admitted to mortality, ischemic recruiting
Patients With single-­center hospital stroke, TIA,
Ischemic Stroke cohort study systemic embolism,
or Transient myocardial
Ischemic Attack infarction,
and Structural, intracranial
Inflammatory, or hemorrhage, major
Arrhythmogenic bleeding
Cardiac Disease118
(NCT04352790)
10 PRAISE (Prediction Prospective, Multicenter, Acute ischemic 251 Presence of Coronary Recruitment
of Acute Coronary observational, Germany stroke (<72 h) with acute coronary angiography, completed.
Syndrome After multicenter cohort troponin elevation syndrome, deaths, echocardiography, Follow-­up ongoing
Acute Ischemic study functional outcome, ECG
Stroke)119 cardiovascular
(NCT3609385) events
11 Predicting the Prospective, Columbus, Ohio, Female patients 10 Stress-­induced ST-­T changes Active and
Development observational USA with acute ischemic cardiomyopathy on ECG, recruiting
of Myocardial single-­center stroke or patients echocardiography
Depression in cohort study with SAH, >50 y, and measurement
Acute Neurological predicted to be of catecholamines
Patients on norepinephrine and troponin
(NCT03801694) infusion for at least
48 h
12 PROSCIS Prospective, Berlin (PROSCIS-­B); First ever acute 627 with first-­ever Composite of Clinical follow-­up Recruitment
(Prospective Cohort observational, Munich stroke (including ischemic stroke stroke, myocardial including cerebral completed (Berlin);
With Incident hospital-­based (PROSCIS-­M), intracerebral (Berlin), 850 infarction, and MRI, cognitive active (Munich).
Stroke)120 cohort study Germany hemorrhage in (Munich) vascular death testing
(NCT01363856, Berlin) (within 3 y)
NCT01364168)

(Continued)

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Stroke–Heart Syndrome: Advances and Challenges
 Scheitz et al Stroke–­Heart Syndrome: Advances and Challenges

of myocardial injury after stroke and investigate long-­

CMR indicates cardiovascular MRI; LA, left atrium; LAEF, left atrial ejection fraction; LV, left ventricle; MACE, major adverse cardiovascular events; MI, myocardial infarction; MR, magnetic resonance; MRI, magnetic
term cardiac remodeling. The localization, pattern, and

results published.
completed. First
estimated reversibility of myocardial tissue changes

Recruitment
enables the differentiation of ischemic and nonis-
Active and
Progress

recruiting
chemic injury. Focal fibrosis, as detected by CMR, may
reflect unrecognized MI and has a prognostic impact
in suspected ischemic heart disease.123 Beyond focal
fibrosis, diffuse fibrosis can be quantified by CMR and

echocardiography
conditioning (brief
and transient limb

Follow-­up by mail
Remote ischemic

strongly correlates with histopathological findings of

or telephone,
collagen content in the myocardium.124 Diffuse fibro-
Measures

ischemia)

and ECG
sis on CMR is associated with ventricular remodeling
and event-­free survival in patients aortic stenosis.125

resonance imaging; NT-­proBNP, N-­terminal pro-­B-­t ype natriuretic peptide; SAH, subarachnoid hemorrhage; TIA, transient ischemic attack; and TTS, Takotsubo syndrome.
The role of CMR to differentiate mechanisms of my-
ocardial injury after stroke is being addressed in the
CORONA-­ IS (Cardiomyocyte Injury Following Acute
cerebrovascular
ischemic events

manifestation of
cardiovascular
Any death and
Outcomes of

recurrence of

Heart failure,

Ischemic Stroke) study.116

cardiac and

within 3 mo

Further open questions concern in particular the

interest

disease

longer-­term outcomes of stroke patients with stroke–­

heart syndrome, especially with regard to chronic car-
diac function and vascular end points. At present, it is
not clear if the high frequency of systolic and diastolic
Target no. of

dysfunction detected in stroke patients is transient and

recovers over time or whether this will result in clinically
patients

manifest heart failure. Approximately one-­third of pa-

696
80

tients with early poststroke cardiac dysfunction have

known heart failure before the stroke.45 More longitudi-
plus acute coronary

treatment on stroke
stroke (onset <24 h)
Target population

nal clinical studies are needed to determine the time-­

syndrome (onset
Acute ischemic

Acute ischemic
patients (≤60 y)

course, reversibility, and progression of heart failure in

<24 h), elderly

stroke with

stroke patients. Among others, the SICFAIL (Stroke-­

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Induced Cardiac Failure in Mice and Men) study aims

unit

to characterize and provide mechanistic understand-

ing for long-­term cardiac dysfunction after stroke.40
The biggest task for the future will be to prove how to
specifically treat stroke–­heart syndrome and its long-­
City, country

Beijing, China

term consequences. From our point of view, it seems

Würzburg,
Germany

conclusive that stroke patients with ACS should pri-

marily be treated with coronary revascularization.126,127
In contrast, patients with other manifestations of
controlled, double-­

stroke–­heart syndrome may benefit from a pathophys-

blind, trial (sham

iologically oriented drug therapy. This could consist

observational,
Randomized,

single-­center
cohort study
Prospective,

of targeting the sympathetic nervous system (eg, with

procedure)

β-­blockers), heart rate control, and improvement of

Design

blood pressure variability (eg, β-­blockers, ivabradine,

renin–­angiotensin system inhibitors), anti-­inflammatory
of Remote Ischemic

approaches (eg, inhibition of the inflammasome or in-

Failure in Mice and
Elderly With Acute
(Protective Effects

SICFAIL (Stroke-­

(DRKS00011615)
Induced Cardiac

flammatory cytokines like interleukin-­1β with colchicine

Ischemic Stroke

(NCT03868007)
Acute Coronary
Conditioning in
Title of study
(registration)

Complicating

or canakinumab), improvement of vascular endothelial

Syndrome)
RIC-­ACS

function, and reduction of oxidative stress (eg, with

Men)40

statins, renin–­ angiotensin system inhibitors, antioxi-

dants, new generation monoamine oxidase inhibitors),
Table.  Continued

a combined antithrombotic medication (eg, temporary

use of dual antiplatelets or adding low-­dose anticoagu-
lation), and avoiding proarrhythmic drugs (QTc prolon-
gation). Until now, however, none of these candidates
Study

have formally been tested in appropriate randomized

13

14

and blinded therapy studies. Joint research initiatives

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 Scheitz et al Stroke–Heart Syndrome: Advances and Challenges

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Dr Scheitz reports a research grant from the Corona-­Stiftung, outside the autonomic and cardiac responses in a rat stroke model. Arch Neurol.
submitted work. Dr Sposato reports personal fees from Boehringer Ingelheim 1992;49:690– ­696. doi: 10.1001/archn​eur.1992.00530​31003​2009
and Pfizer, and grants from Bayer, outside the submitted work. Dr Backs 18. Veltkamp R, Uhlmann S, Marinescu M, Sticht C, Finke D, Gretz N,
reports personal fees from Lead Discovery Center (LDC) Dortmund, outside Grone HJ, Katus HA, Backs J, Lehmann LH. Experimental ischaemic
the submitted work. Dr Endres reports grants from Bayer and fees paid to stroke induces transient cardiac atrophy and dysfunction. J Cachexia
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J Am Heart Assoc. 2022;11:e026528. DOI: 10.1161/JAHA.122.02652817