Over the last several years after its initial recognition [1], some attempts have
been made to artificially reproduce transient takotsubo syndrome (TTS), a complex
and persistently unknown human pathology, by using animal models [2-5]. But, to make
experiments be meaningful, can any of these attempts reproduce the essential and distinguishing
features of human TTS? This update of the current discussion attempts to clarify what
this new entity consists of, what published early experiments meant, and then to suggest
new animal models that could better duplicate similar dysfunctional behavior.
Firstly, it is important to emphasize that indeed, experimental animal models can
potentially be key tools for investigating a novel and obscure human disease, but
only if some distinctive features of the model faithfully correspond to those of the
human disease (its nature, its pathophysiological mechanisms, its appearance on imaging,
and its clinical course). When dealing with a model of a human disease that is still
nebulous in its essence and that has a wide spectrum of clinical presentations, it
is important to start by carefully describing our best current understanding of the
disease under study. Attempts to develop relevant animal models should initially focus
on basic anomalies in clinical presentations and reproduce similar phenotypic features.
What is Transient Takotsubo Cardiomyopathy?
Summarizing a current characterization of the essential features of TTS, we propose
the following items [6-8].
Human TTS is most frequently characterized by de novo, sudden-onset transient apical
ballooning (dyskinesia), usually affecting 35-50% of the left ventricle (LV) (causing
the ejection fraction to drop from 60-70% to 20-50%) and accompanied simultaneously
by hyperfunction of the remnant segments of the LV. Most cases (99%) involve a discrete
symmetrical (circumferential) territory along the longitudinal axis of the LV, independent
of any single coronary branch territory. Additionally, identifying TTS forms usually
requires that no critical coronary atherosclerotic stenosis be recognized by angiography
(that could explain the LV dysfunction) [6-9].
The typical clinical history of TTS includes some variable and nonspecific human conditions,
events, or morbid insults that may have triggered its onset, but many different clinical
conditions can coexist with TTS and may or may not be intrinsic to its genesis; also,
in 30-40% of cases, patients have no recognized pre-existent condition [6-9]. Typically,
the events that are claimed to precede/precipitate TTS episodes occurred on multiple
prior occasions before a given TTS episode or were chronic, and they may eventually
worsen during TTS (like stress) or reoccur after the episode, without concomitant
TTS recurrence [6-9].
TTS resolves spontaneously and completely over a few days in 90% of cases [6-9], and
mostly it occurs only once in a person’s lifetime (enabling what seems a sort of “automatic
vaccination,” rarely previously observed in medicine) [10].
Temporary, evolutionary and transient ST-T electrocardiographic changes usually occur
[5-9]. Q-wave changes rarely appear.
Commonly, inconsistency is reported between the extent of the initial area of LV akinesia
or dyskinesia (the apparent extent of the myocardial injury) and the peak elevation
of serum cardiac enzyme levels, in comparison to an equivalent area of a typical acute
myocardial infarction [10, 11].
The usual end-result of a TTS event is essentially a quick return of intact regional
myocardial function in a few days in the absence of any recanalization intervention,
suggesting that TTS is a myocardial stunning episode (temporary dysfunction that does
not cause permanent scarring [6-9].
Hospital mortality is relatively low (about 2-5%); however, it is likely that mortality
mainly occurs during the first hour(s) after the onset of symptoms, usually in an
extra-hospital environment, and therefore is significantly underreported [11-13].
This notion is supported by the fact that autopsy studies commonly do not reveal myocardial
histologic changes typical of myocardial infarction [11, 12].
Although several claims have been made in the literature about the frequent occurrence
of triggering or causative factors at the onset of TTS [12], recurrent and reliable
causes of TTS have not been identified (“anything goes” [14]). One putative cause
of TTS is stress (hence the term “stress cardiomyopathy”). The physiological correlates
of stress have never been quantified by any measurable method. Mental upsets are frequent
in the life of any human being, but the association between the severity of such stress
and catecholamine levels (an elevated serum level is the claimed mechanism), initially
claimed by Wittstein and colleagues [15], has never been confirmed. Currently, catecholamine
serum levels (a potential measure of stress severity) are rarely measured in clinical
settings, evidence that this marker is no longer considered clinically relevant, but
“catecholamine cardiomyopathy” is another term in popular use, even though the concept
is unconfirmed.
The so-called catecholamine surge has been frequently assumed but rarely demonstrated,
and no prospective studies have ever measured catecholamine levels at the onset of
an episode of TTS. Nor have any studies used this theory to reproduce TTS experimentally
in humans by elevating serum catecholamine levels [8, 16].
Chronic catecholamine cardiomyopathy in pheochromocytoma [8, 16, 17], the ultimate
example of a spontaneous, long-term catecholamine overload with recurrent peaks, presents
clinically with recurrent episodes of chest pressure, pounding of the heart, sinus
tachycardia, hypertension, and an electrocardiographic LV strain pattern [16, 17].
In this scenario, diffuse hypertrophy and progressive chronic scarring of the myocardium
are common, as shown by magnetic resonance imaging or histologic examination [16,
17].
In some TTS cases, experimental acetylcholine (Ach) testing for endothelial dysfunction
(done shortly after an event) has been reported to reproduce chest pain, ST changes,
apical dyskinesia, and diffuse and transient regional coronary spasm with coronary
arteriography. Left ventricular echocardiographic changes also occur and are similar
to those observed in the original TTS episode [18, 19]. Apical dyskinesia and coronary
spasm are quickly and completely resolved by intracoronary nitroglycerine [18, 19].
Thus, the Ach test is recognized by some (albeit few) investigators as the only way
to reproduce TTS in human beings, and it could or should be used to test the theory
that TTS is actually the product of many alternative triggering stimuli in patients
who are transiently affected by endothelial dysfunction and a spontaneous tendency
to coronary spasm [18].
It is not currently known whether any animal species exists in which human TTS can
be replicated during Ach testing, but this can be potentially tested, for example,
in animals treated with catecholamines after endothelial dysfunction is induced by
chemotherapeutic agents, or by radiation to the heart region or acute brain pathology
(Fig. 1) [20].
Figure 1
Diagrammatic representation of the dynamic factors involved in the appearance and
disappearance of TTS features. The red line represents the variable state of endothelial
dysfunction (ED); an episode starts with borderline ED that worsens in response to
some precipitating factor, and then recovers gradually over 1 - 2 days. The blue line
indicates the appearance of severe epicardial coronary arterial spasm, which quickly
resolves, while left ventricular dysfunction appears. Spastic transient occlusion
must resolve in 15 - 60 min if no thrombosis occurs (which is rare). The blue area
represents the time course of positive Ach testing (days 2 - 5). Usually, ED recovers
to within normal limits on about day 5 (i.e., at the time of negative Ach testing)
[20]. TTS: transient takotsubo syndrome.
Also, Ach testing provides objective evidence for using calcium antagonists and nitrates,
ideally at the very onset of TTS (as is typically done in cases with recurrent TTS),
to abort a full episode.
Unfortunately, this hypothesis (spasm-related pathophysiology) seems to be foreign
to most cardiologists at present. The frequently raised objection is, “If the spastic
pathogenesis of TTS is truly systematically involved in clinical TTS, why is the test
not more frequently positive?” This question is addressed by our group’s hypothesis
that the underlying cause of the positive Ach test rapidly dissipates after an episode
of TTS (consistent with the rarity of clinical TTS recurrence when done late after
an event and the auto-vaccination concept described above) [20].
In our own experience, those rare patients who have a positive Ach test more than
1 week after a TTS episode have a high rate of TTS recurrence (or of Prinzmetal angina)
[10, 18].
Unfortunately, most of the rare reports of Ach (or ergonovine) testing in TTS do not
include the time of testing since TTS onset, or the dose, or the reason for testing,
which are fundamental limitations on interpreting the results of testing.
From our group’s admittedly limited experience in this field, we are inclined to conclude
that the best window of time for eliciting a positive response to Ach is between less
than 1 day (when the probability of a positive test is potentially 100%, but the patient
is unstable at that early time, when the worst level of cardiomyopathy is present)
to 7 days (when the probability of positive testing is less than 10%) after the onset
of TTS [18, 20].
Animal Models of Experimental Takotsubo?
As a consequence of our persistent ignorance regarding TTS etiopathogenesis, some
investigators have already attempted in recent years to duplicate some or all of the
abovementioned clinical manifestations of TTS by using animal models treated with
high doses of catecholamines or agonist drugs [2-4]. In studies involving basic animal
catecholamine experiments, mortality is high (30-80%) [2-5], suggesting that the doses
used are toxic to the point of being frequently lethal [21, 22]. Clearly, this is
a very different mortality rate than that associated with clinical TTS, as stated
above.
From the onset, one should ask a critical question: Are elevated catecholamine levels
the true cause of human TTS, or are they only a triggering factor in some patients
with endothelial dysfunction (transient abnormal vasospastic hyperreactivity that
can be demonstrated by Ach administration)? To date, animal experiments have never
produced imaging proving localized and transient myocardial ballooning dysfunction
(symmetrical dyskinesia, which is rapidly reversible) and thus cannot be considered
proof of TTS reproduction in one of its basic manifestations [21].
At the same time, it is relevant to recognize in reviewing clinical cases featuring
high levels of catecholamines (i.e., pheochromocytoma, paraganglioma), a sort of natural
experiment in a human subject that TTS is rarely observed in the years, when patients
are treated medically, before or after surgical treatment [16, 17, 22]. Evidently,
only some patients (candidates for a TTS diagnosis), and only for some portion of
their lives, develop endothelial dysfunction associated with high catecholamine levels.
These recent animal experiments instead seem to simulate a different pathology from
TTS in pheochromocytoma. The resulting cardiomyopathy more commonly seen in human
pheochromocytoma (which is chronic and only partially reversible, and accompanied
by diffuse fibrotic degeneration [17, 22]) is not TTS-related and has an essentially
different prognosis (chronically progressive and generally irreversible cardiomyopathy).
Moreover, the clinical use of inotropic agents (i.e., dobutamine) in stress testing,
or to treat hypotension or shock, only rarely triggers TTS [18]. A recent meta-analysis
[8], inspired by the controversy over the etiology of TTS, rebutted the theory of
Wittstein et al [15], suggesting instead that the catecholamine surge is not the isolated
cause, but may be more of a trigger of TTS (whereby catecholamines would be not the
minimum common denominator, but a variable, nonessential precipitating or triggering
factor).
Additionally, specific human clinical study showed recently that serum catecholamine
levels in stressful human situations are only 2 - 3 times their baseline levels, much
less than the amounts used in experimental animal models [23].
Interestingly, the association occasionally observed between TTS and acute pathology
of the central nervous system has led some to suggest the term “neurogenic stunned
myocardium,” which could be very suggestive of TTS [18]. Pilot studies in animals
have been initiated that may suggest effective reproduction of transient cardiomyopathy
in this context [24].
Finally, we would propose that studies of segmental wall-motion abnormalities use
larger animals than rats or mice, whose heart is quite small and beats too rapidly
for reliable echocardiographic evaluation (about 300 beats/min at rest, and up to
600 beats/min after a large catecholamine dose) [12].
In conclusion, we should agree that to date, animal models of TTS have been inadequate
in terms of replicating the distinguishing features of human TTS and in clarifying
the persistently mysterious etiopathogenesis of its human presentations. However,
improvements are possible, especially by inducing endothelial dysfunction in animals
before administering catecholamines. Such experiments could add to the direct evidence
related to TTS, providing an experimental basis for “endothelial dysfunction,” still
a somewhat vague entity that spontaneously and mysteriously disappears after a TTS
episode [25, 26]. The possibility that TTS is the product of microvascular pathology
[13, 19] remains an unlikely hypothesis without a solid anatomically and physiologically
demonstrable basis. Incidentally, positive Ach testings in humans show severe spastic
behavior in epicardial segments but also in the smallest coronary arteries (arterioles,
probably in the range of 0.5 mm diameter), that are currently visible by catheter
angiography [18].
In conclusion, our hypothesis is that human TTS is usually the product of both pre-existent
endothelial dysfunction (increasing during a spell) and a variable catecholamine surge
or stress (precipitating a facultative event). This knowledge creates an opportunity
to develop better animal models than the standard standalone catecholamine-based ones.