Edited by: Giovanni Quarta, Papa Giovanni XXIII Hospital, Italy
Reviewed by: Riccardo Liga, Pisana University Hospital, Italy; Ankush Gupta, Military Hospital Jaipur, India
This article was submitted to Cardiovascular Imaging, a section of the journal Frontiers in Cardiovascular Medicine
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Takotsubo syndrome (TTS) is an increasingly recognized condition burdened by significant acute and long-term adverse events. The availability of novel techniques expanded the knowledge on TTS and allowed a more accurate risk-stratification, potentially guiding clinical management. The present review aims to summarize the recent advances in TTS prognostic evaluation with a specific focus on novel imaging and genetic markers. Parametric deformation analysis by speckle-tracking echocardiography, as well as tissue characterization by cardiac magnetic resonance imaging T1 and T2 mapping techniques, currently appear the most clinically valuable applications. Notwithstanding, computed tomography and nuclear imaging studies provided limited but promising data. A genetic predisposition to TTS has been hypothesized, though available evidence is still not sufficient. Although a genetic predisposition appears likely, further studies are needed to fully characterize the genetic background of TTS, in order to identify genetic markers that could assist in predicting disease recurrences and help in familial screening.
Takotsubo syndrome (TTS) is an acute heart failure (HF) syndrome accounting for ~1-2% of all suspected acute coronary syndromes, it is characterized by transient systolic dysfunction (
TTS was initially perceived as a benign condition (
To date, multiple studies from several multicenter registries have led to a changing perspective and currently agree on considering TTS a not-entirely benign condition, burdened by both in-hospital and long-term mortality (
A table summarizing the major acute complications of patients with TTS.
Acute heart failure | 12-45% |
RV involvement | 18-34% |
LV outflow tract obstruction | 10-25% |
Mitral regurgitation | 14-25% |
Cardiogenic shock | 6-20% |
LV thrombus | 2-8% |
Ventricular arrhythmias | 4-9% |
In-hospital death | 1-5% |
Cardiac rupture | <1% |
Despite TTS is characterized by a substantial recovery of LV systolic function, studies with long-term follow-up have unraveled adverse outcomes, with rates of morbidity and mortality comparable to those experienced after an acute myocardial infarction (AMI). Stiermaier et al. reported a long-term mortality higher than in patients with ST-elevation AMI (
Finally, the risk of TTS recurrence is low but persistent throughout the clinical history of TTS. This is a potentially life-threatening event, presenting even several years after the first occurrence (
Over the years, several studies have investigated the usefulness of diverse tools (particularly imaging) to better define risk stratification in TTS (
A summary comparing the main diagnostic features and risk markers (established or emerging) of different imaging modalities.
- Transient circumferential wall motion abnormalities (except focal type) | - LV ejection fraction |
- Atria and ventricles deformation analysis by speckle tracking | |
- Transient circumferential wall motion abnormalities (except focal type) |
- LV ejection fraction |
- T1 and T2 mapping |
|
- Absence of culprit CAD | - CAD | - pFAI | |
– | – | - Reduced 123-I-MIBG uptake |
In the acute phase of TTS, transthoracic echocardiography (TTE) is the cornerstone of risk stratification. Several features can be identified by standard TTE that are associated with a higher risk, including low LV ejection fraction (EF) (
Novel, advanced echocardiographic techniques may provide an accurate and sensitive detection of cardiac abnormalities during both the acute and the “recovery” phase of TTS. Speckle tracking-TTE (ST-TTE) provides parametric quantification of myocardial chambers deformation. In the acute phase of TTS, assessment of LV global longitudinal strain (GLS) by ST-TTE has an important prognostic value, being associated to worse outcomes including in-hospital death and major adverse cardiovascular events (
The added value of ST-TTE is even more evident after the acute event, as LVEF usually normalize, but functional LV abnormalities might persist (
Bull-eye depicting longitudinal strain of the LV by speckle tracking echocardiography in a patient with previous TTS at 1-month follow-up after the acute event. Despite complete recovery of LVEF, longitudinal systolic function is still impaired (global longitudinal strain −13.6%).
Echocardiographic particle imaging velocimetry (E-PIV) is an emerging technique for estimating intracardiac blood flow patterns (
Amongst cardiovascular imaging techniques, cardiac magnetic resonance (CMR) is the diagnostic gold standard for assessing cardiac volumes, function (
Frames taken from cardiac magnetic resonance cine imaging. Top row, end-diastolic
Classic CMR appearance of TTS includes widespread myocardial edema in the absence of significant replacement fibrosis at late gadolinium enhancement (LGE) imaging, especially when strict criteria for identification are used (i.e., >5 standard deviation) (
In summary, standard CMR techniques can be extremely useful to establish a TTS diagnosis against other forms of MINOCA, moreover, novel tools are emerging to grant quantitative analysis and more accurate prognostic information.
Feature-tracking CMR (FT-CMR) is a novel technique for evaluating cardiac chambers deformation in a similar fashion as ST-TTE does for echocardiography, though basic principles behind the two techniques are quite diverse (
Recently developed CMR mapping sequences allow a parametric quantification of interstitial expansion in the myocardium, with signal intensity mainly depending on extra-cellular water (T2 mapping) as well as fibrosis and infiltration (native T1 and ECV). In TTS, marked increase of native T1 and T2 as well as ECV were observed in the acute phase (
Cardiac magnetic resonance mapping images depicting myocardial edema in the acute phase of TTS. Mid-apical circumferential edema of the left ventricle is visualized as areas of higher intensity from the T2 mapping image (white arrows in
In recovered TTS patients, native T1 has been described as persistently elevated when compared to that observed in a matched control group, even more than 1 year after the acute event (
Coronary computed tomography (CCT) is a non-invasive morphologic evaluation of the coronary tree, with an expanding role in the evaluation of patients with suspected coronary artery disease. In TTS presenting without ST-elevation at ECG, it can be reliably used in the acute phase to rule-out AMI (
When compared to matched control subjects, TTS patients were found to have increased peri-coronary fat attenuation index (pFAi), a measure associated with coronary artery inflammation (
Single photon emission computed tomography (SPECT) with 201-thallium chloride has been used to investigate myocardial perfusion in TTS with conflicting results. Some studies reported a mild reduction of perfusion limited to the dis/akinetic segments in the acute phase, while others reported normal perfusion (
However, up today, almost all nuclear imaging studies have been performed mainly for research purposes, while prognostic data are scarce. A recent study in a cohort of 90 TTS patients demonstrated that an extensive defect of 123-I-MIBG scintigraphy uptake appears to be associated with a higher rate of in-hospital complications (
Both nuclear and non-nuclear imaging modalities have been used to investigate the brain-heart axis in TTS. The precise pathophysiological mechanisms of TTS are incompletely understood but there is considerable evidence that sympathetic stimulation is central to its pathogenesis (
The response to stressors is governed by an ensemble of neural structures, such as the limbic system (the amygdala, the cingulate gyrus, the hippocampus, the insula, etc.), the ventromedial prefrontal cortex and the brainstem. Recently, increasing interest has been directed toward the involvement of the brain–heart axis in in the pathophysiology of TTS. In 2014, Suzuki et al. first documented brain activation in three patients with TTS examining cerebral blood flow with single photon-emission computed tomography (SPECT). In the acute phase, the researchers observed a marked increase in brain activity in areas linked to abnormal stress-induced sympathetic arousal (brainstem, hippocampus, and basal ganglia). Furthermore, brain activation remained to some extent in the chronic phase, after full recovery of cardiac wall motion (
Later functional magnetic resonance imaging studies demonstrated structural alterations in the limbic networks of TTS patients during the acute (
All of these studies investigated brain alterations in TTS patients after the acute event.
The study by Radfar et al. is the first to assess cerebral activity prior to the onset of TTS. The amygdala activity using [18F] fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDGPET/CT) was measured retrospectively in 104 patients who underwent clinical 18F-FDG-PET/CT imaging, including 41 who subsequently developed TTS and 63 matched controls. Patients with subsequent TTS had higher baseline amygdala activity and, among the patients who developed TTS, those with higher amygdala activity developed TTS about 2 years earlier compared with those with lower level of amygdala activity (
These neuroimaging findings demonstrate structural and functional alterations of stress-related brain networks in patients with TTS even before the acute event, suggesting long-lasting psychological stress. Chronically heightened stress-associated neural activity may hypothetically induce an individual to react to subsequent stressors with a more vigorous neurophysiological response, thus increasing TTS risk (
New neuroimaging techniques could be useful in identifying patients at high risk of TTS recurrence, suggesting a longer follow-up and the implementation of both pharmacological and non-pharmacological behavioral therapy (i.e., stress reduction).
However, additional randomized prospective trials and new interdisciplinary approaches are required to further investigate the role of the brain-heart axis in the pathogenesis and prognosis of TTS.
Table summarizing studies on TTS genetic markers.
β1 adrenergic receptor | rs1801253 | Arg389Gly | Gain of function | More frequently found in TTS patients |
β2 adrenergic receptor | rs1042714 | Gln27Glu | Resistance to downregulation | More frequently found in healthy controls |
Bcl2-associated athanogene 3 (BAG3) | rs8946 | 3' UTR | Altered cellular response to epinephrine | More frequently found in TTS patients |
Estrogen receptor 1 | rs2234693 | – | unknown | Higher risk of TTS development in carriers |
A relatively larger genome-wide association study reported findings from 96 TTS patients (
In summary, current data on the genetic features of TTS only suggest a genetic etiology of this pathological condition. However, we are becoming aware that, whereas environmental triggers and concomitant comorbidities are pivotal in TTS development, the genetic heterogeneity and a potential polygenic predisposition may also play a contributory role mainly by determining the dysregulation of the adrenergic system. Larger cohorts are required for a better evaluation of the impact of genetic background on TTS occurrence and prognosis.
Despite similar long-term outcomes, the nature of adverse events in AMI and TTS is different. Indeed, TTS is featured by mainly non-cardiovascular mortality (
Genetic investigations, rather than cardiac imaging, may play an important role in risk stratification in the particular setting of the predisposition to TTS recurrence. However, where clinical implementation of genetic testing implies a multidisciplinary approach with genetic counseling and ethical considerations (
Patients with TTS may benefit from advanced cardiovascular imaging tools offering unique information to assist in short- and mid-term risk stratification, well beyond traditional assessment of left ventricular ejection fraction. Due to the limited robust evidence, genetic evaluation does not currently provide significant advantages in guiding the clinical management. Hopefully, future studies aimed at better characterizing the genetic background of TTS may identify useful markers that could assist in predicting disease recurrences and help in familial screening.
LA and LL designed the study. LA, LL, CA, MS, and GT drafted the manuscript. All authors provided relevant comments, revised the draft, and approved the final version of the manuscript.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.