The important thing is not to stop questioning
Albert Einstein
Preamble
This constitutes an introductory
statement explaining the aims and the justification of attempting to “free
associate” on the positions taken by a recent publication [1] on all the
particulars of takotsubo syndrome (TTS); indeed, the positions taken reflect the composite of statements and
elaborations contained in the literature on TTS, a large fraction of which as of 8/27/26, consists of 8,025 reports in PubMed, accessed in response
to the MeSH search term “takotsubo” [2]. As an example, it has
almost become a cliché to refer to a big list of plausible pathogenetic
mechanisms of TTS, which in isolation or in concert are responsible for its causation.
Similarly, the position often taken by all authors on the management of TTS is
that our approach as treating physicians should be to implement supportive
therapy, while awaiting specially-designed randomized controlled trials (some
of them concluded, or currently ongoing and recruiting patients) [1], to provide the necessary scientific justification for our
therapeutic actions. Another stimulus for this composition has been spurred by
the reviewing the literature in preparation for a recently published opinion paper [3],
on the “ventricular-arterial coupling” characteristics of TTS. Of course, one
cannot claim that the following associative self brain storming exercise, resulting in arguments and
counterarguments about TTS, is all inclusive. It should be stressed in the
outset that this is not a comprehensive narrative review of TTS, in the mold of
prior such works [1]. Nevertheless,
the objective of this communication is to stir exploratory thinking among
clinicians and researchers, engaged in the recognition and management of TTS
and elucidation of its pathophysiology.
Methodology
The
approach used in the writing of this communication was based on the author’s a self
brain storming or “free association” in response to the content of the
aforementioned two papers [1,3] and the literature [2], expressing random thoughts in the form of arguments
and counterarguments, presented as “bullet-like” numbered (for easy reference) unassociated
statements, thus drastically deviating from the sequential logical and
scientific reporting format, employed in conventional publications. The reason
that these free-standing statements were not grouped under subheadings (e.g.
“Diagnosis of TTS”, “Therapy of TTS”, “Pathophysiology of TTS”, etc), is that
it was meant to enumerate them in sequence as they occurred to the author, while
he was reading the above cited recently published comprehensive review paper on
all aspects of TTS [1]; the
reader is also prompted to engage in free-association about the content of the
present communication, so that his/her experience retains the format of self brain
storming. Such an exercise is characterized by “jumping” on issues pertaining
to therapy while reading about diagnosis, or diverting from diagnosis to the pathophysiology
of a disease entity. Finally, for maximal benefit the reader is encouraged to
study the 2 referenced papers [1,3], before reading what follows.
A non-all-inclusive list of arguments
and counterarguments about TTS
1] Although
it is stated that TTS accounts for ~2-3% of suspected acute coronary syndromes
(ACS), association of the former with myriads of comorbidities and consideration
of milder “focal” morphological variants at imaging, TTS is a highly
underdiagnosed illness.
2] The belief that ~90% of patients with TTS are women is currently challenged
by the frequent encounter of male patients, particularly in association with a
large variety of medical and surgical comorbidities, and other physical
stresses.
3] Pediatric cases of TTS are being
frequently reported in the literature; this reality has been obscured by the recruiting
of patients ≥18 years old with TTS in the leading registries.
4] Diagnostic criteria of TTS have initially excluded patients with coronary
artery disease (CAD) at coronary
angiography (CANG), acute myocardial infarction (AMI), pheochromocytoma/paraganglioma,
and spontaneous coronary artery dissection (SCAD), subsequently partially corrected
in the revised criteria; along
this line one wonders why we cannot also accept myocarditis, as a comorbidity
of TTS.
5] The currently prevailing notion is
that we need controlled randomized trials, specifically designed for the
management of TTS, which nowadays
consists of supportive therapies designed for patients with CAD, ACS,
and heart failure (HF). It is conceivable that TTS is a form of segmental
myocardial stunning, not unlike the one seen in ACS, AMI,
following a relatively brief episode of variant (i.e., Prinzmetal’s) angina, and/or catecholamine-induced
cardiomyocyte toxicity. Accordingly, our contemporary pharmacological
and device-based armamentarium may be adequate for the management of patients
with TTS.
6] It may be of value to consider that the diagnosis of TTS is often made with
considerable delay (particularly in “secondary TTS”), and thus by the time TTS
is the established diagnosis, the innate healing process is already underway.
7] The issue of “stress” in TTS should be viewed in the context of the ideas of
Hans Selye, the Father of stress field, who emphasized the concept of “nonspecificity”
and thus a stereotyped body stress response to the
emotional/physical/negative/positive stresses of life. Along this line of thought the differentiation
of physical vs. emotional stresses may be meaningless, because none of the
above is devoid of the other. Also, the notion that for 30% of the patients
with TTS no stress triggers can be identified may not be correct, considering
that “stress” is a very subjective/personal matter, often not communicated to
others by the sufferer.
8] Work by
Hans Selye revealed that stress in general has a profound effect on the
gastrointestinal system, the thymus gland, and the spleen, expressed as
shrinkage of these organs, and an increase in the volume of adrenals. Along
this line of thought it may be of value to evaluate by imaging, changes in the
volumes of thymus, spleen, and adrenals, as indices of the intensity of the
stress that led to TTS.
9] Although TTS is associated with older and/or postmenopausal women, younger women are often afflicted in
the setting of pregnancy, perinatal period comorbidities, malignancies, chemotherapy,
SCAD, and gynecological/neurological/psychiatric maladies.
10] Microvascular dysfunction, nitrosative stress, metabolic dysregulation, catecholamine-induced
lipotoxicity, myocardial and systemic inflammation, oxidative stress, among others, are often cited as
triggers/pathogenetic mechanisms of TTS. It is conceivable that many of the
above may constitute epiphenomena, following TTS’ emergence. An indication of
this is the occurrence of TTS in some otherwise healthy individuals and even
adolescents and very young children, not expected to harbor these predisposing
traits. Also, C-reactive protein (an
index of systemic inflammation) is normal/mildly elevated in patients with TTS
at admission, and its subsequent elevation suggests that it represents a
consequence of TTS. Finally, something needing evaluation is whether all these
purported triggers of TTS are/are not also present in patients with ACS
and AMI, and to what degree.
11]
It has been theorized that TTS is either a protective cardiocirculatory phenomenon [1] to
avert fatal ventricular arrhythmias or a maladaptive response to stress;
however, it could be both to varying degrees in different patients.
12]
The abrupt onset of TTS may imply that it may be due to a transient segmental
coronary vasospasm of some epicardial vessels, or rather their corresponding
coronary microvasculature and/or regional cardiomyocyte catecholamine
toxicity due to an unbridled autonomic sympathetic nervous system (ASNS) seethe
with norepinephrine spillover, and induced outpouring of epinephrine by the
adrenals [1,3].
13] In spite of TTS’ reputed formal description in 1990, as a transient
segmental myocardiac mechanical systolic hypokinesis/akinesis/dyskinesis, in
the absence of obstructive CAD, it has always been with us and the animal
kingdom, shown in experimental laboratory work and in the clinical domain
before 1990, and connected to high adrenergic states or infusion of
catecholamines.
14] One wonders whether a large proportion of what is currently called AMI with
nonobstructive CAD (MINOCA) are not
cases of TTS, particularly in MINOCA without detectable persisting regional wall motion abnormalities (RWMA) or late gadolinium enhancement (LGE), in follow-up
testing with cardiac magnetic resonance imaging (cMRI).
15]
Persisting RWMA, evidence of regional myocardial necrosis, and ventricular
aneurysm, should not be considered incompatible with
TTS. Indeed, such occurrences may point to unusually persisting pathogenetic
actions of what has precipitated TTS, which may/may not represent anything
different from the state of stunned myocardium seen in ACS or AMI.
16] Persisting LGE should not be considered incompatible with TTS. Indeed,
there are reported cases of TTS with persisting electrocardiogram (ECG)
ST-segment elevation, akinetic/dyskinetic myocardial regions, full left
ventricular (LV) transmural scars, associated with interventricular and left
ventricular (LV) free wall rupture, and death.
17] Considering the association with emotional stress
(both negative and positive), physicians may consider
proactively prescribing anxiolytics and β-blockers for patients both
experiencing, or possibly expected to experience, emotional stress (i.e.,
bereavement, reunions).
18] The occasional emergence of TTS in the setting of anesthesia, surgery, and
invasive procedures (e.g. ablation of atrial fibrillation [AF]), should prompt physicians
to consider proactively initiating intravenous infusions of short half-life β-blockers for patients suffering hypertension,
angina, ventricular arrhythmias or AF. Such infusions could be terminated
in response to HF, bradycardia or heart blocks with impunity, due to the short
half life (i.e., 3-9 min) of the employed β-blockers.
19] Recurrence of TTS is underdiagnosed if one considers that many patients
evaluated for their index TTS episodes, have already suffered previously TTS with clinical episodes
erroneously attributed to AMI, ACS, or CAD, or at follow-up many years after an
index TTS episode.
20] The recent seemingly increasing rate of TTS
triggered by physical stress may be due to the increasing recognition of TTS
associated with other comorbidities (i.e., “secondary TTS”).
21] The recent seemingly increasing age of patients suffering TTS may be a
reflection of the increasing human lifespan.
22] Changes
in the incidence/prevalence of TTS as reflected in the reported literature is
partially influenced by publication biases (i.e., "file drawer problem"), the nonpublication of many
cases of TTS), that are continuously changing.
23] A seemingly increasing rate of the midventricular variant of TTS may be
partially due to the “looseness”
in including in reports of this variant the “apical/midventricular” combination phenotype.
24] Delving in the consequences of episodes of proven variant (Prinzmetal’s)
angina (e.g., troponin release, RWMA at imaging, and their persistence), might
be instrumental in deciphering the pathophysiology of TTS. I am referring
herein to episodes lasting 20-30 min, and their clinical aftermath. There are
reports of patients with angina/dyspnea episodes triggered by stress, who were
asymptomatic by the time they reached the hospital, and who showed all the
hallmarks of TTS. One wonders whether
such episodes are due to diffuse coronary vasospasm or intense
catecholamine toxicity, or both.
25] Serial uptrending vs. downtrending of high sensitivity troponin values may
suggest a different stage of the clinical course (i.e., hyperacute vs. acute) of
TTS.
26] Selective coronary epicardial and/or microvascular spasm based on
ASNS/catecholamine-mediated stimulation of β1-,
β2-, and a1-adrenergic receptors should be the subject of further contemplation, as viable
pathogenetic hypotheses of TTS. Such mechanisms are not incompatible with the
morphological TTS variants of reverse and midventricular TTS, if one assumes
that spasm could be multi-site and selective, depending on the different types
of adrenergic receptors, their topographic distribution, density, and
sensitivity to various catecholamines.
27] Dynamic
left ventricular outflow tract obstruction (LVOTO), particularly early in the
clinical course of TTS, should be considered not as an occasional complication
of the disease, but as a possible pathogenetic mechanism ushering the emergence
of TTS. Indeed, it is advisable to evaluate for LVOTO, not via the
initial formal transthoracic echocardiogram (ECHO) or CANG, but with early and
frequent implementation of point of care ECHO (POCUS), using targeted portable or even
hand-held ECHO devices, and auscultation for associated mitral regurgitation
(MR), particularly in patients with hypotension, HF, and cardiogenic shock (CS).
28] Since estrogen deficiency and the post-menopausal state are associated with
TTS, one wonders whether the use of reduced-dose estrogen supplematation may
have a role in preventing TTS recurrence.
29]
It is crucial that information is sought, recorded, and reported about the exact
time of the onset of symptoms in patients with suspected/proven TTS.
30] During the early clinical stage of proven/suspected TTS, as assessed by the
history and uptrending troponins, close monitored infusions of short-, or
ultrasort β-blockers may be of value. This is imperative in the presence of
LVOTO. Such infusions can easily be terminated without consequences, if
bradycardia, heart blocks, or signs of HF arise.
31] It may be of value to resurrect measuring catecholamines (norepinephrine, epinephrine, and
dopamine, and their metabolites in plasma and urine), as was done early after
the formal description of TTS. Uptrending or downtrending of catecholamine
values may reflect the acuteness of the TTS clinical stage, and whether the
process is acutely evolving or subsiding. In the first case one could advocate
employing intravenous short-half-life β-blockers. Also, it is
conceivable that there is an association between the rise of specific
catecholamines and the TTS morphological variants.
32]
Although one could evaluate once the peripheral ASNS state in the setting of
TTS during hospitalization with electroneuromyography, it may be advantageous
to adopt a monitoring technique of evaluating continuously or serially, the
ASNS’s cardiac input via thoracic electrical signals (i.e., a surrogate of
stellate ganglia’s neural input to the heart) by subjecting the routine electrocardiogram
(ECG)-acquired signals to a 500-1,000 Hz analysis, a technique pioneered by Dr.
Peng-Sheng Chen.
33] Heart rate variability, even deriving from short ECG recordings, should be
serially and systematically evaluated in patients admitted with TTS, during
hospitalization and at follow-up, for its diagnostic and prognostic value.
34] Pheochromocytoma
should be suspected in patients admitted with suggestive symptomatology and
eventually diagnosed with TTS. Many
such patients are diagnosed after repeated admissions, and even after
recurrent TTS.
35] All physicians, other members of medical teams, dentists, rehabilitation
and nursing home facilities, and the public at large, should be familial about the
nosogenic potential of both negative and positive (“happy heart symdrome”) stress, in precipitating
TTS.
36] The concepts of “stroke-heart syndrome”, with resultant brain-heart axis dysregulations as potential
precipitants of TTS should always be part of our diagnostic approach, when
faced with patients with structural or functional brain morbidities,
psychiatric afflictions, electroconvulsive
therapy, or any evidence of underlying stress.
37] Could
epinephrine be administered for the management of anaphylaxis in half of the
current recommended dose, with the second half administered, while the patients
are monitored in terms of their anaphylactic attack and the response to
epinephrine?
38] Occasionally patient case reports appear in the literature in which the authors
vacillate whether the patients had suffered myocarditis or TTS; in light of
frequent other various comorbidities of patients with TTS, one wonders whether
it is conceivable that myocarditis and TTS can occasionally be present
simultaneously.
39] RWMA in patients with myocarditis, and their
evolution, along with the corresponding tissue characterization at cMRI can
be used to distinguish among myocarditis, TTS, or myocarditis with TTS.
40] Although
TTS with LVOTO is associated
with MR, the latter can also be present in the absence of LVOTO, particularly
with the apical or apical/mid-ventricular TTS phenotypes resulting from a dilated
LV and mitral valve “tenting”.
41] Presence of LVOTO should be correlated with ECG changes
(either ST-segment elevation or T-wave inversion), which provide insights as to
the timing of this hemodynamic complication, since ST-segment elevation occurs
early in the clinical course, followed by T-wave inversion.
42] Time interval between inception of illness in TTS and
subsequent performance of CANG, LVAngio, ECHO, and other imaging tests should be secured and recorded in
the patients’ records.
43] The interplay among “sigmoid septum”, other LV
segmental hypertrophies, probable or definite diagnosis of hypertrophic
cardiomyopathy (HCM), LV “pseudohypertrophy”, eventually dissipating, LV
hypertrophy from long-standing hypertension, mitral valve leaflet elongation,
papillary muscle abnormalities, along with transient MR, LVOTO, in serial ECHO or cMRI, should be
explored in patients with TTS.
44] In terms of the pathophysiology of TTS, it may be of
value to explore whether LVOTO was associated with ST-segment elevation,
bespeaking of an early appearing LVOTO subsequently dissipating, a thought
that has made some to theorize that LVOTO is the pathogenetic trigger of TTS.
45] In reference to brain natriuretic peptides (BNP) in
TTS, one wonders whether these biomarkers are secreted in the absence of HF or
CS, or are merely related to LV chamber dilatation. Does BNP have any arterial or
venous vasodilating effect in TTS? Is BNP’s level related to the associated
catecholamine outpouring or hyperactivation of the ASNS? Is the BNP’s rise partially
independent of the underlying LV function in TTS?
46] Is
troponin release in TTS due to
cardiomyocyte injury, necrosis, or both? Is there a component of myocardial
necrosis in TTS? Are some cardiomyocytes necrosed and some have undergone
stunning with eventual recovery? Histological evaluation of tissue from
endomyocardial biopsies or autopsies should provide the contrast between patients
with TTS and AMI, particularly of the stunned (i.e, not necrosed), myocardial component in the latter. Can we
possibly expect some correlation between the peak troponin release and the drop
of LVEF, or the extent of LV RWMA, to grossly estimate the proportion of cardiomyocyte
necrosis in patients with TTS?
47] Should we consider serotonin as one,
additional to catecholamines, triggering factor for TTS, considering that some
patients suffer TTS in the setting of drug uptitration of selective serotonin
reuptake inhibitors?
48] Employment of
β-blockers in periprocedural settings (e.g., catheter ablation for AF), or
post-anesthesia and at peri-operative state to prevent emergence of TTS, or
manage complicated early TTS, has been advocated by some. The use of short
half-life (e.g., esmolol) or ultrashort-half-life (e.g., landiolol) could be
employed, since they can be abruptly terminated with impunity, if HF,
hypotension, or bradycardia emerge.
49] POCUS early and repeatedly implemented by many
members of the caring team, in addition to the referral for a subsequent formal
ECHO testing
is necessary for an earlier diagnosis and appropriate management of patients
with TTS. Particularly important goals should be the detection of LVOTO, MR,
worsening or improvement of LVEF, estimation of cardiac output (CO), and
changing in the TTS morphological phenotypes.
50]
Left ventricular end diastolic pressure (LVEDP), is frequently either not measured or
reported, and this needs to be corrected. There is controversy in the
literature whether LVEDP is or is not elevated in patients with TTS. In addition
estimation of LVEDP by ECHO-based established methods needs to become routine, along
with ECHO-based estimation of right atrial (RA) pressure, and CO. A calculation
of LV ventricular-arterial coupling should become routine and evaluated
serially [3], since it is different in TTS, that
in patients with ACS, AMI, HF, and CS. Such measurements are useful in the management
of patients with TTS and they may provide significant insights towards
the elucidation of its pathophysiology.
51] There
is a wide range of blood catecholamine levels in patients with TTS, partially due
to the time of measurement in connection with the onset of the illness, the
degree of catecholamine spillover resulting from the overstimulation of ASNS and/or
the secretion from the adrenal glands. Also, there is a large variation of the
kind of catecholamines (i.e., epinephrine, norepinephrine, dopamine) released
in the bloodstream. Whether other blood elevated substances like neuropeptide
Y, have a role in the pathogenesis of TTS is not clear. Variation in the levels
of blood catecholamines may also be influenced by the variation of catecholamine
reuptake; this is supported by the triggering of TTS in patients treated for
depression, in whom starting or upgrading their therapy, employing
norepinephrine, and dopamine reuptake inhibitors, triggers the disease. We
should restart measuring catecholamines in patients with TTS; one of the
benefits of such action might be the earlier diagnosis of patients with
pheochromocytoma/paraganglioma, who often are being diagnosed with great delays
and after multiple hospital admissions.
52] Triggering
of TTS, its severity, and the variation in the morphological phenotypes, may be
a function of the topography of the autonomic sympathetic and parasympathetic
innervation, the density and sensitivity of β1-, β2-, α1-
and other receptors to catecholamines, which also may be subject to continuous
neuromodulation within the brain-heart axis.
53] TTS may
be highly underdiagnosed outside and within hospitals, particularly in its mild
and forme fruste forms, and with symptoms not so alarming for patient to seek
medical attention. Also, it is conceivable that a difficult to detect “TTS
component” may be present in patients with many other serious comorbidities.
54] It is conceivable
that some patients with unspecified non-ischemic cardiomyopathy have a “chronic
form of TTS”, resulting from many recurrent attacks of TTS; this hypothesis is
supported by the occurrence of chronic LV dysfunction in some patients with
pheochromocytoma/paraganglioma, with recurrent symptoms and multiple hospital
admissions, eventually diagnosed, sometimes retrospectively with TTS.
55] The
mean age of patients suffering TTS may stay the same, because we diagnose
progressively more younger patients, particularly male with TTS in the setting
of comorbidities, balancing the aged female victims suffering the illness; also,
this is counteracted by the increasing longevity of the population, resulting
in having octogenarians and nonagenarians presenting with TTS.
56] Atypical
(i.e., nonapical) morphological variants of TTS will be identified
progressively more frequently as imaging is improving and performed serially. Although
the diagnosis of TTS is based on the identification of LV and RV RWMAs,
literature has appeared reporting patients with TTS diagnosed on the basis of ECHO
systolic and/or diastolic dysfunction, with normal LVEF, no RWMAs, and abnormal
systolic and/or diastolic ECHO strain findings.
57] TTS may
be a component of pathology in patients admitted with a hypertensive emergency/urgency
or tachycardia-induced cardiomyopathies, when LV dysfunction is not associated
with the global hypokinetic phenotype, but with LV and/or RV RWMAs.
58] Is it
possible that high sensitivity troponin I and T provide different insights
about TTS, ACS, AMI, and thus their levels and dynamics warrant scrutiny? Is it
possible that troponin I rather than T, in patients with TTS reflects changes
in the cardiac musculature (i.e., injury/stunning vs. necrosis) due to ASNS
surge?
59] What is
the mechanistic nature of catecholamine cardiomyocyte toxicity in TTS? Is it
due to overstimulation? Could this be explored in simulated animal experiments
and cardiomyocyte cultures, comparing electrical stimulation of the peripheral
ASNS (e.g., stellate ganglia) or exposure to graded blood catecholamine
concentrations?
60] It has
been stated that LVOTO constitutes a compensatory response to the LV ballooning
in patients with TTS; of course, it is conceivable that LVOTO is due to a
primary, catecholamine-induced increase in contractility. Some have theorized
that LVOTO is a trigger for the emergence of TTS; along this line, there are
reports proposing an evaluation in animals of the consequences of a protracted
increase in the afterload on the LV response. It is relevant that patients
admitted with hypertensive emergencies, sometimes reveal transient reduction of
their LVEF; such patients should be evaluated serially with sophisticated ECHO
testing for RWMAs.
61] It is
conceivable that there is one or many different pathogenetic mechanisms leading
to TTS in general, or in its morphological variants, in particular.
62] One wonders
whether measurements of coronary flow reserve will be useful in the better
pathophysiological characterization and management of TTS; this may be the case
only if such measurements are analyzed in connection with the time interval between
the measurements an the inception of the illness, and are coupled with parallel
measurements in patients with ACS and
AMI.
63] It has
been proposed that therapies (current, or expected to be available in the
future) for microvascular dysfunction may be of value in patients with TTS; of
course, such therapies should be implemented for all patients with underlying
stunned myocardium (i.e, ACS and AMI).
64]
Irrespective of the adaptive or maladaptive nature of the mechanism(s) leading
to TTS, what is important is to protect the myocardial segments displaying systolic
hypokinesis/akinesis/dyskinesis/asynergy. Also, it is imperative that we maintain
an adequate perfusion of vital organs, while simultaneously decreasing the ASNS
surge and/or the catecholamine spillover, which exerts further stimulation of
the cardiomyocytes and exacerbates the coronary microvascular dysfunction (CMD).
65] In addition
to the guideline-directed medical pharmacological therapies for patients with
TTS, we should consider intravenous short/ultrashort half-life β-blockers,
fluid infusions, phenylephrine, sodium nitroprusside, pacemakers, cardiac
circulatory support devices, extracorporeal membrane oxygenators, with constant
switching from one to the other therapy(ies). This will require very close
monitoring of blood pressure (BP), heart rate (HR), pulse oximetry, skin
temperature, with frequent auscultation, and frequent serial POCUS.
66] When
referring to multiple plausible pathogenetic mechanisms of TTS, consideration
should be given to the possibility that some may be consequences of others.
67] The fact
that different stress triggers lead to different stress responses in different
individuals is well known, it is still puzzling as to the reasons for such
varying inter-individual susceptibility.
68] Alterations
and differences from ACS, AMI, HF, and CS in the LV ventricular-arterial coupling
(VAC) in patients with TTS [3] may explain the relatively benigner clinical
course of patients with TTS than in patients with AMI, in the presence of worse
LVEF and widespread RWMAs
69] In TTS
literature reference is made about BP, HR, LVEF, and RWMA; however we should
start measuring serially and reporting CO, RA, LA, RV systolic, and LV
diastolic pressures, as derived from high quality ECHO, with calculations of
VAC, systemic vascular resistance (SVR), and
pulmonary vascular resistance.
70]
Literature reports on TTS include patients with normal, mildly, moderately, and
severely elevated left ventricular end-diastolic pressures (LVEDP). Work by the
Japanese investigators, early after the formal description of TTS, revealed
normal LVEDP, in patients with TTS evaluated in the catheterization laboratory
a few hours after onset of the illness. The range of LVEDP measurements in
patients reported from large patient cohorts or registries is wide, due to the
inclusion of many patients with normal LVEDP. There is controversy whether
LVEDP is elevated in patients with TTS. It is conceivable that LVEDP is normal
or ever lower than normal early in the clinical course, with LVEDP subsequently
rising as a result of the evolution of the clinical course, complications, or
administered therapies. LVEDP frequently either is not measured, or not
reported, particularly when it is normal (publication biases). One of the
reasons that LVEDP is not available in published reports, is that LVGram does
nor routinely follow CANG, since LV function assessment by ECHO has already been
carried out. When right heart catheterization has been performed, pulmonary
capillary wedge pressure measurement may be useful as a surrogate of LVEDP,
although this should be considered with reservation, because the LV and RV VAC,
are affected to different degrees in TTS.
71] TTS is
often considered in isolation as a cardiac, instead of a
cardiovascular/cardiocirculatory, affliction. TTS is a “total-body” illness
with secondary body organs/systems dysfunction due to blood hypoperfusion
(“secondary” illness component), and direct effects of hyperfunctioning ASNS
and catecholamine outpouring on the body organs/systems (“primary” illness
component). Accordingly, various body organs/systems’ pathologies might have
triggered TTS, or have been caused by TTS. Neurogenic pulmonary edema in TTS in
not necessarily due to secondary HF or CS, but due to primary nosogenic effects
of the ASNS surge, norepinephrine spillover, and adrenal epinephrine
hypersecretion, imparted to the lungs. Also, a peripheral arterial “vascular TTS”
is probably a reality, which needs confirmation, and could be explored by
serial evaluation of LV VAC in patients with TTS.
72] Neurocardiology
is an emerging cardiology subspecialty, analogous to cardio-oncology; this
discipline examines the amphidromic pathogenetic influences of the brain-heart
axis. Notable such examples are various brain, heart, total body illnesses,
emerging in the context of what is currently dubbed “the stroke-heart”
syndrome.
73] Our
index of suspicion for an underlying TTS comorbidity should be high when evaluating
patients with all kinds of somatic
(particularly neurological) and psychiatric illnesses, in order that ECG,
biomarkers’ measurements, and ECHO are employed earlier, via a specially-designed
routinely implemented protocol.
74] Not
only chest pain and dyspnea are the presenting symptoms of TTS; patients are
occasionally presenting with other than cardiac symptoms and signs (e.g.,
gastrointestinal manifestations), or in association with a serious comorbidity,
with its expected symptoms and signs.
75] The
issue of “pseudohypertrophy” due to myocardial edema in the setting of TTS
needs careful consideration; along this line of thought, repeat imaging,
particularly based on cMRI is indicated. In addition to the phenotypes of upper
septal hypertrophy (i.e., “sigmoid septum”), possible underlying HCM (including
the apical HCM variant), should be kept in mind, to avoid false diagnoses of
TTS.
76] In
evaluating hemodynamics and considering management of patients with TTS, one
should keep in mind the complexity of its pathology with varying degrees of impaired
contractility of myocardial segments, composing a 2-compartment model,
consisting of akinetic/dyskinetic and hyperkinetic components in the apical
morphological phenotype, or 3-compartment model, with
apical and basal hyperkinesis and mid-ventricular akinesis/dyskinesis, in the
mid-ventricular variant.
77] A decreased tone of the peripheral ASNS via
neurography noted in patients with TTS in a limited experience [1], is a
counterintuitive finding, in a pathophysiological setting of a disease with a purported
enhanced ASNS, with intense norepinephrine spillover, and stimulated adrenal
epinephrine hypersecretion.
78] Stimulation of the α1-adrenergic
receptors from the ASNS/catecholamine surge is expected to increase peripheral
vasoconstriction in patients with TTS; however the decreased SVR suggests that
counteracting vasodilating effects must be at play; such influences may include
the associated β2-adrenergic stimulation, nitric oxide, endothelium-derived
hyperpolarizing factor, potassium ions, adenosine, prostacyclin PGI2,
abnormal parasympathetic influences, and the outpouring of brain natriuretic
peptides. An added complexity is that all above peripheral innate vasodilators
may be orchestrated by the ASNS and elevated catecholamines, with their varying
composition, leading to different vasodilating properties.
79] It may be of value to scrutinize the
peripheral vasoreactive consequences of the administered different
catecholamines used in animal (usually murine) TTS models; in addition serial
sampling for the innate vasodilating molecules in such experiments may be
revealing in terms of the emerging different LV VAC phenotypes (i.e.,
vasoconstriction, vasodilation, unchanged from the baseline vascular tone).
80] Some inconsistencies have surfaced in the
literature regarding LV VAC in patients with TTS, in the sense that although
initially it was felt that TTS was different from ACS/AMI, more recent studies
have observed similar hemodynamic and peripheral systemic circulatory responses
[1].
81] Since different phenotypes of
pheochromocytoma/paraganglioma exist, in terms of the specific catecholamine
hypersecretion in such patients hospitalized with or without diagnosed TTS, it should
be scrutinized as to what is the stability or change in the LV VAC during the
course of single episodes and cases or recurrent hospitalizations.
82] Sepsis is characterized by an induced global
LV dysfunction, and TTS with a global LV dysfunction has rarely been
encountered; accordingly, one could consider that all cases of sepsis-induced transient
cardiomyopathy represent a TTS phenotype.
83] A proactive approach based on specific
investigating protocols aiming to the diagnosis/management of many
medical/surgical conditions, frequently encountered as comorbidities (e.g,
cancer) in patients with TTS, may be of value.
84] The diversity in the severity of TTS cases
may be due to the complex interplay of TTS and the associated comorbidities.
85] The employment of timed Doppler/ECHO and
thoracic bioimpedance technologies serially in patients with TTS, could provide
all that is necessary for their hemodynamic characterization and its
perturbations, resulting from the underlying healing process, the consequences
of complications, the interactions with comorbidities, and the effects of
therapies.
86] The hemodynamic consequences of
administered therapies, viewed as inappropriate in the hindsight after a
delayed diagnosis of TTS, have not been yet appreciated.
87] A protocol in the form of a list of timed
hemodynamic parameters’ measurement needs to be established, that should be
implemented in all patients with TTS, and not only for the purposes of
research.
88] Different “hemodynamic phenotypes” can be
noted in patients with TTS, on the basis of serial assessment of BP, HR, CO, SV,
SVR, systemic vascular compliance, LVEF, LV RWMA (qualitative and quantitative)
and brain natriuretic peptides.
89] Six hemodynamic phenotypes appear to be
present in patients with TTS (i.e., minor
symptoms/no complications, hypertension and/or tachycardia, HF with normal BP,
HF with low BP or CS, LVOTO without HF or CS, and LVOTO with HF or CS).
90] Management of
the different hemodynamic TTS phenotypes should be different, and should
include, supportive therapy and implementation of
“primum non nocere” = “first do no harm”, fluids infusion/diuretics,
β-blockers, levosimendan/milrinone, phenylephrine, inotropes/vasopressors, intra-aortic
balloon pump, LV/RV cardiac circulatory support
devices (e.g., Impella), and extra-corporeal
membrane oxygenators.
91] Physicians should
be quick in employing temporary electronic pacing after a brief trial of
atropine, in patients with severe bradycardia, heart block, prolonged corrected
QTc interval (particularly in patients with polymorphic ventricular
tachycardia), and LVOTO.
92] The rise of creatine kinase and troponins
and their ratio may be different in TTS and AMI; one could contemplate that
released creatine kinase reflects more cardiomyocyte necrosis, while blood
troponins suggest mixed underlying cardiomyocyte stunning and necrosis; accordingly
this may be worth exploring. However, the recent trend of checking or reporting
only on troponins, may render such an undertaking impossible.
93]
The time
interval between conversion of the ST-segment elevation to T-wave inversion may
be shorter in patients with TTS than in patients with an ST-segment elevation
AMI; thus, persistent ST-segment elevation in patients with TTS may imply that
one is dealing more than a case of stunned myocardium, destined to recover
completely, and thus partial myocardial necrosis; however, underlying
pericarditis needs also to be factored in.
94] The low
rate of emotional triggers in men shown to have suffered TTS may be because fewer
men than women admit such problems.
95] A brain
scan (e.g., cMRI or functional MRI), after electroconvulsive therapy leading to
TTS may be useful in showing which brain areas were responsible for the ASNS
activation leading to TTS.
96] The mechanism
of bradycardia at the onset of some cases of TTS, may reflect autonomic nervous
system stimulation of brain loci from which the vagus nerve emanates.
97] We
should stop referring to emotional or physical stress or its absence; there is
no emotional stress without physical stressful consequences and the other way
around. Also, patients appearing not to be under stress, need to be repeatedly
and more intensely questioned. Finally, we should start relying more on
objective evidence of stress, based on appropriate testing and relevant measurements
(e.g., heart rate variability, administration of specific established stress
testing methods, during hospitalization, and at follow-up).
98] Although
TTS occurs before and after permanent pacemaker implantation for complete heart
block, the pathogenetic mechanism of TTS in the latter cases may be due to an
ASNS hyperactivation triggered by the resulting bradycardia or asystole, and
the change in the interventricular/intraventricular conduction, engendered by the
electronic pacing. Of course, TTS could also be related to the stress imparted
by the procedure, for which this author has recommended standby short-acting
β-blocker infusions, for some patients undergoing electrophysiological procedures.
99] Like
patients with HCM, patients with TTS are not immune to other cardiac (e.g.,
AMI) and noncardiac (e.g., diabetes) illnesses.
100] It is
conceivable that some patients with TTS could reveal normal heart function at
imaging, due to a rapid recovery; indeed, such cases have been reported in the
literature.
101] It is
possible that some encountered cases of nonischemic cardiomyopathy may be due
to many recurrent episodes of TTS, with some being mild, atypical, and
self-limited.
102] Shifting
morphological LV and RV variants during the same TTS admission or at TTS
recurrence may be associated with alterations in the topography, density, type,
number, and sensitivity of β-adrenergic receptors to the released different catecholamines,
and their proportional blood composition.
103] The
rapid resolution of the ECG ST-segment elevation and the transition to the
T-wave inversion unlike what happens in the setting of ST-segment elevation
AMI, suggest that the pathogenetic mechanism of TTS is a non ischemic
condition, or due to a short phase of segmental coronary vasospasm (thus
ischemic), which has dissipated by the time the patients are under our
evaluation.
104] Scrutiny
should be exercised at CANG and LVAng to differentiate AMI, TTS, SCAD, and AMI/TTS, and SCAD/TTS phenotypic combinations.
105] It is
conceivable that the pathogenetic mechanism(s) of TTS is(are) exerted on the
myocardium over the course of 30 to 60 min, and thus its(their) detection by the time we see the patients may remain
problematic.
106] We should probably employ aggressive
antithrombotic management in patients with TTS, similar to the ones used in
ACS, AMI, or MINOCA, because of the underlying
ASNS/hyperactivation/catecholamine-induced hypercoagulability, and the LV and
RV severe RWMA. Also, vigilance should be exercised since LV thrombi may appear
at different points of hospitalization, and even after hospital discharge.
107] Whether TTS is due to one or multiple
pathogenetic mechanisms has not been as yet determined. This author favors the
1st scenario, differentiating TTS from ACS, AMI, MINOCA, and
Prinzmetal’s (variant) angina.
108] The variation
in the clinical presentation of patients with TTS, and the associated outcomes,
may be due to the time interval between onset of the illness and clinical
presentation, associated drugs taken before admission or started after
admission, with some of them being inappropriate for patients with TTS, and the
variation of the intensity of ASNS surge and types and amounts of outpouring catecholamines.
109] While CMD
is attributed to coronary vasospasm, inflammation, or endothelial dysfunction,
the role of myocardial edema is often not mentioned, although it is conceivable
that CMD may be totally or partially due to external to the vessel pressure,
compromising the coronary microvessels’ caliber.
110] To evaluate the pathogenetic role of
inflammation in TTS, the rise of neutrophils and C-reactive protein could be
followed to evaluate whether inflammation is a pathogenetic influence, or an
epiphenomenon.
111] Of
interest is that both normal and compromised coronary blood flow have been
found in experimental murine models of TTS. One wonders whether the timing of
observations or the experimental variation is at the roots of this
discrepancies. It is possible that coronary blood flow reduction in the
affected regions in TTS is an epiphenomenon, it is transit, and its of varying
duration.
112] The
role of inflammation cascade in TTS needs further exploration, it should be
characterized in more detail, and studied in terms of its course in different
patients. Also, various anti-inflammatory regimens administered as early as
possible in patients with TTS may proven influential in preventing the early
worsening or shortening of the clinical course.
113] In evaluating
the role of neurological and psychiatric pathologies in patients with TTS,
emphasis should be placed on their frequency and severity prior to the
emergence of TTS, and not after.
114] Genetic polymorphisms of the ADRB1 and ADRB2
genes encoding β1 and β2
receptors respectively based on large genomic databases and patients with TTS
need to be carried out to resolve whether the disease is due to a genetic
predisposition. However, it is conceivable that the individual predisposition
to TTS is polygenic, and multifactorial
(i.e., not only related to adrenergic receptors’ polymorphism), in terms of its
genetic underpinnings.
115] The proteomics and microRNA signatures of patients with TTS need
to be explored in large databases, preferably in different TTS registries.
116] The tolerance of patients with TTS to their severe LV dysfunction
may be partially explained by an altered LV-arterial coupling [3], which is
determined not only by the cardiac decompensation, but by the total body
alterations imparted by whatever causes TTS.
117] The
possible attribution of TTS to an estrogen deficiency should be complemented by
a study of other gender-based differences as contributors to the disease.
118] We
should evaluate whether the rapid recovery of LV function is different to the
one observed in patients with ACS, undergoing percutaneous coronary
interventions/stenting.
119] The
persistence of clinical problems in patients who have suffered TTS is currently
unexplainable; partially one wonders whether such persistent affliction may be
due to the possibility that unlike AMI affecting only the heart, TTS is a total-
body illness.
120] Are
some patients with unexplainable HF, decreased LVEF, or cardiomyopathy of
unknown variety harbor a condition due to multiple episodes of TTS, some of
them subclinical?
121] The
circumferential LV involvement in patients with TTS does not preclude an
ischemic etiology, since one could envisage ASNS-based hyperstimulation of the coronary
microvasculature, leading to transient coronary vasospasm affecting selectively
many epicardial coronary vessels and their branches.
122] Cardiomyocyte
adrenergic stimulation and/or microvascular spasm is regional, and probably territorially
shifting in the hyperacute and acute phases of TTS; perhaps the adrenergic
receptors’ functionality and even density may be dynamic, changing over time.
123] Exclusively
RV or combined LV/RV TTS involvement may be related to the topography (i.e., regionality)
of ASNS cardiac nerve distribution, adrenergic receptor density, and adrenergic
receptor expression (i.e., sensitivity}.
124] The
dominance of stunning in TTS, in contrast to a combination of necrosis and
stunning in AMI, may be due to the emergence of protective mechanisms, or the
short time duration, of the noxious operating influences, causing TTS.
125] The
current modus operandi in examining and monitoring patients with TTS is
unlikely to provide answers about its pathogenesis; patients satisfying the
InterTAK criteria of TTS in the Emergency Department should be subject to
frequent auscultation and POCUS, implemented early and frequently, by many
members of the team, and not only by the consulting cardiologists.
126] ECHO evaluation
should be extended to systolic (and diastolic) strain regional
characterization; some mild cases of TTS may be associated with normal LVEF and
only presence of diastolic dysfunction.
127] Concern
about applying different therapies designed for the management of chest pain,
HF, CS, atrial and ventricular arrhythmias in patients with TTS seems to be
unwarranted; indeed they should be implemented under close monitoring to ensure
that they are effective. Also, such therapies could be terminated if they are
found to be ineffective, or result in complications.
128] It should
be kept in mind that cardiac assist devices should be implemented more
frequently and much earlier in the management of TTS, than it is currently
practiced.
129] In
patients with TTS who have a history of previous episodes of pain or dyspnea,
which have not been evaluated, and who did not experience full recovery of
their LV function at follow-up imaging, it is conceivable that the underlying
HF or cardiomyopathy may be due to recurrent episodes of mild or even subclinical
episodes of TTS.
130] The
available risk stratification algorithms, implemented in patients with TTS need
to be revised, considering the observed change in demographics and other
clinical attributes of currently evaluated TTS cohorts and registries.
131] Perhaps
the choice of different β-blockers, in terms of their β1and β2 adrenergic receptors’ affinity
may need to be explored regarding their therapeutic effectiveness catecholamine
blood levels may provide some guidance regarding which β-blocker should be
preferred.
132] Since
RV/LV thrombi in patients with TTS occur at different time points of
hospitalization and even after discharge, the threshold for implementing
anticoagulation should be low, and imaging should be repetitive and frequent.
133] It is
advisable to use frequent manual measurements from printed recordings of the
hospital ECG monitors to detect possible QTc prolongation, even if a single ECG
lead is available from such recordings.
134] The
issue of which RV/LV cardiac circulatory device(s) should be used and in what
combination for patients with TTS and CS, and their associated complications,
as well as their therapeutic effectiveness, according to the patients’ age and gender
needs further research, and should involve very large numbers of patients.
135] The
diagnostic and prognostic particulars of patients with cardiac interventricular
or free wall rupture need intense research scrutiny.
136] TTS
registries should start prospectively to include detailed information
pertaining to the short-term and long-term follow-up of patients after their
discharge; this should include detailed data on all the drugs taken and their
dosages.
137] Regarding
the 6 therapeutic randomized trials under way [1], one hopes that detailed information will be secured about the time
duration between the exact onset of the illness and the start of the administered
therapy; also, laboratory information may be of value to estimate the clinical
stage of the TTS of the individual patients (e.g., ECG ST-segment elevation vs.
T-wave inversion).
138]
Adenosine may not have a therapeutic effect in patients with TTS if the CMD is
not due to vasospasm but due to external compression of the coronary
microvasculature due to myocardial edema, resulting from catecholamine-induced
cardiomyocyte toxicity.
139] Formal
assessment of CMD in a systematic fashion following CANG may be of value; if
the technology or the expertise is lacking, employment of the simultaneously
recorded ECG during and immediately following CANG may be considered (i.e., the
time duration in ms of the recovery of ECG repolarization abnormalities
resulting from coronary injections of the contrast medium or saline may be a
reflection of the functional status of
the coronary vasculature), based on work by this author.
140]
Although investigated before, the therapeutic effect of antiplatelet agents in
TTS needs to be reexplored more systematically and in large patient
cohorts.
141] There
is a possibility that the CMD associated with TTS is very early established,
and thus by the time we diagnose or manage the patients it is very late to
effectively intervene; perhaps awaiting the natural recovery, while we are supporting
the patient hemodynamically, may be the way to act.
142] The
effect of cyclosporine A (a calcineurin anti-inflammatory inhibitor) as an
agent counteracting myocardial injury and inflammation in patients with TTS is
undergoing evaluation [1];
also, colchicine may be considered for such an anti-inflammatory therapeutic
role, considering that it is currently recommended in the management of ACS, AMI,
and AF; it is conceivable that such interventions are implemented late in the
clinical course, and they may be proven ineffective (vide supra about
adenosine).
143] The
hemodynamic consequences of all the currently investigated drugs (e.g.
cyclosporine A) need to be closely investigated, while their therapeutic
effects are evaluated.
144] The
systematic employment of contrast ECHO in a serial manner for the evaluation of
the status of CMD needs to be tried and become routine.
145] Serial
high sensitivity troponin values may be useful in gauging the therapeutic
response of various currently explored drug interventions.
146] Systematic
evaluation of angiotensin converting enzyme inhibitors or angiotensin receptor
blockers, starting immediately after the diagnosis of TTS, should be evaluated.
147] N-acetylcysteine infusion to counteract the
oxidative and nitrosative stress and inflammation in patients with TTS deserves
an evaluation.
148] A problem
not yet discussed regarding the currently proposed and/or evaluated drug
therapies for patients with TTS [1] is the standardization of what is called “usual
care”, against which the pharmacological interventions will be compared. Accordingly,
it may be of value to compare the various drug interventions against different
types of “usual care”, as per carefully designed management protocols. The same
applies to the different conventional drugs, administered in addition to the
experimental drug therapies, which should be viewed as exerting possible synergistic, additive, or
counteracting effects.
149] Attention
should be directed to the nature of new cardiac and noncardiac diseases which, patients
with an index episode of TTS, suffer at their short-term and long-term
follow-up.
150] The
implementation of permanent pacemaker and/or implantable cardioverter
defibrillators, in response to various possible, present, or suspected electrophysiologic
pathologies, need to be individualized, and orchestrated by multi-disciplinary
teams.
151] The
same caution should be exerted for patients with a TTS and prolonged QTc, which
should also include clinical and laboratory exploration for many possible
present or suspected underlying congenital and acquired electrophysiologic
pathologies.
152] The
familial and genetic risk of TTS needs to become explored in depth and in large
databases of patients with TTS; accordingly, such evaluations should become an
intergral part of the data collected by TTS registries, for all recruited
patients.
153] Comparison
of what is reported in various types of articles in the World literature with
periodic reports from established TTS registries may be of value, in obtaining
a more complete and global picture of the apparent or real evolution of the TTS
pathology.
154] The
notion that TTS is associated with a reduced peripheral sympathetic tone
(involving the heart and/or other body organs and systems needs scrutiny, and
if found to be the case, has implications for the therapeutic application of
β-blockers in patients with TTS.
155] There
is no doubt that elucidation of the pathogenetic mechanism(s) leading to TTS
and the emergence of proven effective therapies for its management will be
extrapolated to the diagnosis and management of all other cardiovascular
pathologies.
Conclusions
The
above free-standing arguments and counterarguments about TTS are meant to
engage our community of professionals, caring for patients with TTS and delving
in its still elusive pathophysiology. Reading the present communication along
with the 2 referenced articles [1,3], which have acted as the impetus for its
composition, may be of some value. Understanding should be sought about the
redundancy present in these individual statements, but redundancy is an
inherent component of brain-storming or free- association. The thesis being explored
in the current piece is whether the study of the 2 referenced sources and the repeated
contemplation of the above 155 “bullet-like” statements, will increase the knowledge
and the insights that caring physicians and researchers have about this
puzzling disease. Also, it should be realized that these statements could have
been infinite in number, even when emanating from a single individual. Thus, it
is in this spirit that the concluded remarks of this piece are deliberately short,
and non referential of its content.
Conflicts of interest
None
Funding
None
References
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Omerovic
E, Redfors B. Takotsubo syndrome: pathophysiological insights and innovations
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2.
PubMed.
Takotsubo [Internet]. Bethesda (MD): National Library of Medicine (US); [cited
2026 Aug 27]. Available from:
https://pubmed.ncbi.nlm.nih.gov/?term=takotsubo
3.
Madias
JE. Ventricular-arterial coupling in Takotsubo syndrome: controversies and
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