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Cardio-Oncology

, 5:20 | Cite as

Antecedent cancer in Takotsubo syndrome predicts both cardiovascular and long-term mortality

  • Thanh H. Nguyen
  • Jeanette Stansborough
  • Gao J. Ong
  • Sven Surikow
  • Timothy J. Price
  • John D. HorowitzEmail author
Open Access
Research

Abstract

Background

Takotsubo syndrome (TTS), primarily an acute myocardial inflammatory condition engendered by catecholamine exposure, is associated with similar long-term mortality rates to those of patients with acute myocardial infarction. However, there is increasing evidence of a nexus between TTS and underlying malignancies:- many patients have antecedent cancer (A/Ca), while incremental risk of late cancer-related death has also been reported.

Purpose

To evaluate potential interactions between A/Ca among TTS patients and both early and late clinical course.

Methods

Three hundred forty-six consecutive TTS patients [aged 69 ± 13 (SD) years, males: 8.2%] were prospectively followed up for a median duration of 4.1 (IQR 2.2–6.4) years. Associations between A/Ca and severity of acute attacks, in-hospital complications and long-term death rates were sought utilising univariate analyses followed by multiple logistic regression analysis.

Results

A/Ca (present in 16.8% of patients) was associated with (i) greater elevation of hs-CRP and NT-proBNP concentrations (p = 0.01 and 0.04, respectively), (ii) more complicated in-hospital clinical course, with major adverse cardiac events (MACE) in 30.9% of patients, compared to 18.2% in non-A/Ca patients (p = 0.04). Long-term all-cause mortality rate was also greater [hazard ratio (HR) = 2.4, p = 0.0001] in A/Ca patients, with an excess cardiovascular (CVS) fatality rate (HR = 3.1, p = 0.001). On multivariate analysis, male gender, peak plasma concentrations of normetanephrine and hs-CRP, early arrhythmias and development of shock, but not A/Ca per se, were all independently associated with increased long-term mortality rate. Furthermore, patients discharged on β-adrenoceptor antagonists (βBl) or angiotensin converting enzyme inhibitors/ angiotensin receptor blockers (ACEi/ARB) had lower long-term mortality rates (β = − 0.2, p = 0.01; β = − 0.14, p = 0.05, respectively).

Conclusions

(1) A/Ca is associated with greater clinical severity of initial TTS attacks and substantially greater long-term CVS-related as well as all-cause mortality.

(2) Post-discharge therapy with either βBl or ACEi/ARB is associated with reductions in long-term mortality rates.

Overall, the current data suggest operation of substantial interactions between neoplasia and TTS, both at the level of pathogenesis and of outcomes.

Keywords

Takotsubo syndrome Antecedent cancer Cardiovascular mortality 

Abbreviations

A/Ca

Antecedent cancer

ACEi

Angiotensin converting enzyme inhibitor

ARB

Angiotensin receptor blocker

BP

Blood pressure

CVS

Cardiovascular system

hs-CRP

high sensitive C-reactive protein

LVEF

Left ventricular ejection fraction

MACE

Major adverse cardiac events

NT-proBNP

N-terminal-pro-B-type natriuretic peptide

TTS

Takotsubo syndrome

βBl

β-adrenoceptor antagonist

Introduction

Takotsubo syndrome (TTS) occurs predominantly in aging women and largely reflects acute catecholamine-induced myocardial inflammation [1]. Only approximately 4% of TTS patients die in hospital at initial presentation, but long term mortality rates are similar to those for acute myocardial infarction patients [2, 3].

The precise range of stimuli for development of attacks of TTS remains uncertain, as does the basis for predominance of female gender and advanced patient age. There is increasing evidence that inflammation of the myocardium may be triggered by Gi-biased post-receptor responses to β2-adrenoceptor agonist stimulation in susceptible individuals [4, 5], and that excessive β2-adrenoceptor [6, 7] triggered nitric oxide release may initiate nitrosative stress and thus inflammation. However, precisely why this tends to occur in aging women remains uncertain.

Recently, reports have been made from several groups, including the International InterTAK collaboration, that TTS is often associated with presence of internal malignancy at the time of presentation [8, 9, 10]. Furthermore, there is a suggestion that TTS represents a basis for increased risk of later emergence of malignancies and for fatal outcomes from those malignancies [11, 12]. Specifically, it has been suggested that a higher proportion of patients die of cancer following TTS than following acute myocardial infarction [13, 14]. Registry data [10] suggest that approximately 39% of deaths following TTS are attributed to cancer. These findings therefore suggest some commonality of pathogenesis between TTS and internal malignancies, and it has even been suggested that TTS, should be regarded as a paraneoplastic disease state [14].

If the presence of cancer were a predisposing factor for initial attacks of TTS, it might also represent a basis for increased severity of these index episodes. Furthermore, it could be argued that the continued presence of cancer might affect long-term patient outcomes, both directly and via an interaction with cardiovascular (CVS) homeostasis.

In the current study, we therefore sought to evaluate the impact of antecedent cancer (A/Ca) on short and long-term outcomes in a registry-based cohort of TTS patients who were prospectively followed up from the time of diagnosis.

The principal objective of the study was to determine the impact of A/Ca on long-term all-cause, CVS, and non-CVS mortality rates.

The results suggest that A/Ca exerts reciprocal and ongoing deleterious interactions with TTS, and that these interactions may be important in the management of such patients. Furthermore, the results point to a substantial impact of some forms of pharmacological management on long-term mortality rates following TTS.

Methods

Patient population

Screening for TTS was performed routinely on patients admitted to 3 tertiary referral hospitals in Adelaide, South Australia. The diagnosis of TTS was based upon modified Mayo Clinic Criteria [15], essentially consisting of presence of evidence of acute left ventricle (LV) regional systolic dysfunction, together with exclusion of acute myocardial infarction (AMI) by coronary angiography and/or cardiovascular magnetic resonance (CMR) [16]. The severity of acute attacks was quantitated via: (1) severity of LV dysfunction [acute LV ejection fraction (LVEF), as measured by transthoracic echocardiography], (2) clinical measures of hemodynamic changes (lowest systolic BP within the first 48 h, presence of shock), (3) extent of myocardial injury (peak troponin T concentrations), (4) inflammatory changes [peak concentrations of high sensitive C-reactive protein (hs-CRP) and N-terminal pro B-type natriuretic peptide (NT-proBNP)], and (5) markers of catecholamine release (normetanephrine and metanephrine concentrations). Patients in whom TTS emerged in the context of an acute life-threatening extracardiac disease and/or medical procedure were classified as “secondary” TTS [17].

At the time of discharge following initial admission with TTS, demographic data, including the prior diagnosis of A/Ca, patients’ medications and, where appropriate, anti-cancer treatment, were recorded.

This investigation was approved by the Institutional Ethics of Human Research Committee (Central Northern Adelaide Health Service: the Queen Elizabeth Hospital and Lyell McEwin Hospital; protocol number: 009014). Written informed consent was obtained from all participants before study entry.

Patients’ follow-up

Patients were routinely seen at 3 months, and annually thereafter. Data regarding patient outcomes were obtained both by direct follow-up and by recourse to national mortality data. Primary causes of death were categorised as documented on death certificates, while late emergence of malignancies was documented on the basis of follow-up. Recurrences of TTS were documented from both hospital admission data and via follow-up.

Major adverse cardiac events (MACE)

The objectives of the study were to determine whether A/Ca had any impact on:-
  • In-hospital course: In-hospital MACE were classified as the combination of shock, arrhythmias and death.

  • Long-term mortality rate (including both all-cause and CVS mortality rates)

Statistics

Data were analyzed using SPSS software (version 23, Chicago, Illinois, USA) and presented as mean and SD or median and interquartile range depending on data distributions.

Comparisons between TTS patients with and without A/Ca regarding markers of severity of acute attacks, were performed utilizing non-paired t-tests or Wilcoxon rank sum tests as appropriate. Comparisons of proportional data were analyzed utilizing Chi-squared or Fisher’s exact tests as appropriate.

Impact of A/Ca on mortality rates was evaluated via Kaplan-Meier analyses and a univariate Cox proportional hazards model.

Associations between markers of severity of index attacks and long-term mortality rates were sought utilising univariate analysis, followed by backwards stepwise multiple logistic regression analysis. Variables prospectively selected for these analyses (in accordance with hypotheses to be tested) were patients’ age, sex, presence of A/Ca, CVS risk factors, acute plasma concentrations of NT-proBNP, hs-CRP, normetanephrine, troponin-T, development of shock, arrhythmias, primary versus secondary TTS, TTS recurrence, and discharge medications [β-adrenoceptor antagonists (βBl) and angiotensin converting enzyme inhibitors/ angiotensin receptor blockers (ACEi/ARB)].

A p value of < 0.05 was considered significant.

Results

Patients’ characteristics

The clinical characteristics of the study population are described in Table 1.
Table 1

TTS patients’ characteristics: Entire cohort and subdivision according to previous diagnosis of A/Ca. Statistical comparisons are between A/Ca and no A/Ca subgroups

 

Entire group (n = 346)

A/Ca (n = 58)

No A/Ca (n = 288)

p

Duration of follow-up (years)

4.1 (2.2–6.4)

3.5 (1.2–5.8)

4.4 (2.3–6.8)

0.05

Age (years)

69 ± 13

74 ± 10

68 ± 14

0.001

Male: (%)

8.2

14.3

7.0

NS

Secondary TTS (%)

34

47

31

0.02

Site (Apex; %)

66.4

64.3

66.7

NS

Annual recurrence rate (%)

2.1

1.8

2.2

NS

CVS risk factors

 Hypertension (%)

56.0

54.7

57.2

NS

 Diabetes mellitus (%)

18.2

17

18.4

NS

 Dyslipidemia (%)

37.8

34.0

38.6

NS

 Current smoking (%)

9.8

9.4

9.9

NS

Markers: size of acute attacks

 Minimal systolic BP (mmHg)

97 ± 16

98 ± 15

96 ± 16

NS

 Acute LVEF (%)

46 ± 12

44 ± 13

47 ± 12

NS

 Peak NT-proBNP (ng/L)

4800 (2600–9000)

5800 (3600–10,800)

4600 (2500–8600)

0.04

 Peak normetanephrine (pmol/L)

980 (610–1400)

960 (600–1460)

980 (620–1410)

NS

 Peak metanephrine (pmol/L)

200 (200–270)

210 (200–290)

200 (200–270)

NS

 Peak hs-CRP (mg/L)

13 (6–44)

23 (8–100)

11 (6–38)

0.01

 Peak troponin T (ng/L)

400 (223–620)

310 (187–564)

400 (230–638)

NS

In-hospital complications (%)

 Arrhythmias

15.1

21.8

13.8

NS

 Shock

7.4

12.7

6.4

NS

 Mortality

3.2

8.9

2.1

0.02

 MACE

20.3

30.9

18.2

0.04

Neoplasia (%)

 A/Ca (Prior/current)

16.8

   

 Chemo/Immunotherapy

 

34.6

  

 Subsequent neo malignancy

 

6.9

  

Discharge CVS medications (%)

 ACEi/ARB

78.4

88.2

76.5

0.07

 βBl

42.6

31.3

44.7

0.09

 Statins

50.5

45.1

51.5

NS

 Aspirin

42.4

37.3

43.4

NS

Of 346 TTS patients, there were 58 with A/Ca (16.8% of the total cohort). Patients with A/Ca were significantly older that those without A/Ca [74 ± 10 vs. 68 ± 14 (SD) years, p = 0.001], but did not differ significantly from other TTS patients as regards site within the LV of hypokinesis, CVS risk factors and mean initial systolic blood pressure. A larger proportion of A/Ca patients had secondary TTS, and plasma concentrations of NT-proBNP and hs-CRP were significantly greater in A/Ca patients (p = 0.04 and 0.01, respectively).

The majority of patients were discharged on cardio-active medications. Approximately 78% received either ACEi or ARB, while 43% received βBl. Statins and aspirin were also extensively prescribed.

Approximately 35% of patients with A/Ca had received treatment with either chemotherapeutic or immunotherapeutic drugs (Table 1). In general, a substantial period of time had elapsed since the initial diagnosis of cancer:only two patients were receiving chemo/immunotherapy at the time of TTS admission. The most common internal malignancy was breast cancer, accounting for 33% of total A/Ca (Table 2). Only 3 patients had received anthracyclines and 2 trastuzumab as components of chemotherapy.
Table 2

Distribution of A/Ca and subsequent de novo malignancies within the studied cohort

Type of cancer

A/Ca

Subsequent cancera

Breast

19

1

Uterine/Cervical/endometrial

5

2

Ovarian

0

2

Prostate

5

0

Lung

7

7

Skin

7

2

Bowel

9

5

Gastric carcinoid

1

0

Esophageal

0

1

Liver

0

1

Pancreatic

0

2

Metastatic SCC tongue

1

0

Thyroid

0

1

Parotid tumor

1

0

Phaeochromocytoma

2

1

Bladder

0

1

CLL

1

1

aSubsequent cancer are de novo malignancies

Early and late clinical course

In-hospital MACE

Overall in-hospital mortality was 3.2% (Table 1) which was similar to that described in previous larger studies [2, 17]. There was a significant increase in in-hospital mortality rate in patients with A/Ca (p = 0.02). Early MACE occurred in 30.9% of patients with A/Ca, compared to 18.2% in patients with no A/Ca (p = 0.04) (Table 1). Early arrhythmias particularly tachyarrhythmias, occurred commonly: (new AF/flutter [n = 23], supraventricular tachycardia [n = 9], ventricular tachycardia/ fibrillation [n = 12]) with a non-significant excess in the A/Ca group.

Subsequent course

Median duration of follow-up was 4.1 (IQR 2.2–6.4) years and was shorter for A/Ca patients (p = 0.05), because of greater mortality rates. During follow-up, a total of 27 (7.8%) patients were diagnosed with “new” internal malignancies (Table 2). In a further 11 cases, clinical emergence of metastasis occurred among patients with A/Ca.

A total of 59 patients died during the course of the study, with 15 (25%) of deaths attributed to cancer and 30 (51%) to CVS disease states.

Impact of A/Ca on subsequent clinical course

This analysis was conducted to determine whether A/Ca might in any way predispose patients either to recurrence of TTS or to CVS death. Comparisons were made between subgroups with and without A/Ca. Hazard ratio (HR) for relative risks were derived from total subgroup data sets.

Recurrence

Recurrence of TTS occurred in 8.5% of the total cohort and 7.3% of patients with A/Ca (annual recurrence rates 1.9 and 2.1%, respectively, p = NS). No recurrences were associated with in-hospital death.

Mortality

Both long-term all-cause mortality (HR = 2.4, p = 0.0001) (Fig. 1) and CVS death rates were substantially greater (HR = 3.1, p = 0.001) in patients with A/Ca (Fig. 2).
Fig. 1

Kaplan-Meier analysis indicating increased of long-term all-cause mortality in patients with A/Ca [hazard ratio (HR) = 2.4, p = 0.0001]

Fig. 2

Kaplan-Meier analysis indicating greater CVS mortality in patients with A/Ca [hazard ratio (HR) = 3.1, p = 0.001]

Factors predictive of all-cause mortality

As shown in Fig. 3a and b, discharge prescription of ACEI/ARB or of βBl was associated with lower mortality rates (p = 0.03 and 0.01, respectively) on univariate comparisons. Interestingly, the relative impact of these forms of therapy on mortality among A/Ca patients, evaluated by Fisher’s exact test, was significantly greater for patients prescribed with ACEI/ARB (p = 0.02).
Fig. 3

Kaplan-Meier analyses: associations between discharge treatment with ACEi/ARB (a; p = 0.03) and βBl (b: p = 0.01) and long-term all-cause mortality rates

Furthermore, backwards stepwise multiple logistic regression analysis (Table 3) revealed that extent of elevation of plasma levels of normetanephrine, presence of early arrhythmias, early development of shock, male gender, as well as ACEi/ARB or βBl therapies at discharge but not A/Ca per se, were independently associated with increased long-term mortality rates.
Table 3

Predictors of long-term all-cause mortality in the entire TTS patient cohort: results of backwards stepwise multiple logistic regression analysis

Predictors

β

p

Male gender

0.15

0.04

Presence of shock during acute admission

0.15

0.04

Peak normetanephrine concentrations

0.25

0.001

Peak hs-CRP concentrations

0.13

0.09

Arrhythmias at admission

0.21

0.006

βBl at discharge

−0.2

0.01

ACEi/ARB at discharge

−0.14

0.05

ACEi/ARB Angiotensin converting enzyme inhibitors/ Angiotensin receptor blockers

Discussion

The structure and main findings of the current investigation are summarised in Fig 4.
Fig. 4

Schematic of study design and major findings

The results of this study are important because:
  • They confirm that a substantial proportion of patients with TTS have known A/Ca, and demonstrate that breast cancer is the most common association.

  • They show that TTS in association with A/Ca more often presents as secondary TTS,with associate clinical impact includingsignificantly increased in-hospital MACE rates [17]. Indeed, Cammann et al. [8] have recently reported, within the InterTAK cohort, increased in-hospital death rates in patients with A/Ca and TTS.

  • They also show that patients with A/Ca have greater risks not only of late all-cause mortality, but somewhat surprisingly, a markedly increased risk of CVS death.

  • On multivariate analyses, factors predicting long-term mortality include male gender, extent of catecholamine release (normetanephrine concentrations), acute attack hemodynamic impact (presence of shock, early arrhythmias),and extent of inflammatory activation (hs-CRP concentrations).

  • Patients discharged on ACEi/ARB or on βBl had substantially lower mortality rates, and this apparent influence of discharge medication on survival was most marked among A/Ca patients who were prescribed ACEi/ARB.

Thus, findings (2) and (3) point strongly to some substantial and ongoing interaction between the presence of cancer and the probability of CVS complications (short- and long-term) of TTS. To the best of our knowledge, this is the first time that such an association has been reported.

The results also suggest that there are reciprocal long-term interactions between CVS outcomes and presence of A/Ca, in the sense that CVS death rates were substantially elevated in patients with A/Ca. Previously, it has been observed that patients with TTS have an increased risk of long-term cancer death relative to control populations. This was not strongly suggested by the current data, but no control population was used. The data regarding excess long-term CVS mortality in A/Ca patients, were statistically robust, but no complete explanation for the finding is currently available. One possible explanation would be related to patients’ age (older for A/Ca patients) and/or comorbidities. However, patients with A/Ca had similar CVS risk profiles (with the exception of age) to those without A/Ca, and patients’ age was not an independently significant predictor of mortality.

It could be also be argued that the “main” finding might have related to greater hemodynamic impact of the acute attack in patients with A/Ca, leading putatively to greater long-term myocardial fibrosis [18] and therefore greater risk of late cardiac failure and death. Indeed, the available data (see Table 1) suggest that hemodynamic impact might have been greater in A/Ca patients, but this was not studied in detail. A recent analysis from the InterTAK group [19] also demonstrated that clinical factors associated with haemodynamic impact of TTS attacks, including hypotension, tachycardia and reduced left ventricular ejection fraction, all function as adverse long-term prognostic markers. Other recent publications [20, 21] also documented that patients with A/Ca had poor in-hospital outcomes. As a number of neoplasms may be associated with increased catecholamine production, the associated neoplasms themselves may have contributed to severity of attacks, as schematized in Fig. 5. What is unlikely is that our observations were primarily related to the impact of heart failure induced by prior chemotherapy, as only a minority of patients had received chemotherapy and only 2 were receiving concurrent chemotherapy. Therefore, although precipitation of TTS is a well-recorded complication of cancer chemotherapy, direct contributions of chemotherapy per se to emergence of TTS are likely to be relevant only to a small proportion of TTS patients.
Fig. 5

Schematic: potential signal-transduction pathways contributing to (i) shared pathogenesis between TTS and systemic malignancies and (ii) ongoing interactions between presence of malignancy and cardiovascular outcomes post TTS

Discharge prescription of either ACEi/ARB or βBl predicted low mortality risk both on univariate (Fig. 3) and on multivariate analysis (Table 3). There are theoretical reasons why ACEi/ARB treatment might reduce risk of inflammation and therefore impact of TTS [22]. Furthermore, a previous meta-analysis [23] suggested that ACEi/ARB therapy reduces risk of TTS recurrence; in the current study, the observed annual rates of recurrence were 2.2 and 1.8% for patients with and without A/Ca, respectively (p = NS). The salutary effects of βBl therapy (Fig. 3b, Table 3) were a little surprising, given the relative β1-adrenoceptor selectivity of most currently used βBl and the implication from animal studies that the signal transduction pathway for catecholamine-induced precipitation of TTS is primarily or exclusively related to β2-adrenoceptor stimulation [4, 5]. Previous clinical studies [3, 10, 24] have failed to document any benefit associated with discharge therapy including βBl, but this issue now merits re-examination. Nevertheless, in a non-randomized data set, it remains possible that discharge prescription of βBl was biased towards “less ill” patients. Interestingly, the prognostic benefit of ACEi/ARB therapy seemed to be most marked in A/Ca patients.

The study, while representing the first of its type has a number of additional limitations.

It is possible that there may have been some inaccuracies in attribution of cause of death, and also that patient pharmacotherapies at discharge might not have been properly representative of long-term treatment.

No firm conclusions can be drawn about impact on recurrence rates, given the low number of diagnosed recurrences, the possibility that some recurrences were fatal, and the extensive use of ACEi/ARB, which may have reduced likelihood of recurrence [23].

On backwards stepwise multiple logistic regression, A/Ca per se was not a significant correlate of mortality risk. The most likely theoretical explanation for this finding was that A/Ca was an indirect factor predisposing to mortality, partially via increased severity of acute TTS episodes, as evidenced by the identification of acutely elevated plasma levels of normetanephrine and hs-CRP, presence of early arrhythmias and shock, and male gender as significant multivariate correlates of mortality. Plasma normetanephrine concentrations probably relate to severity of attacks both via intensity of initial catecholamine discharge and via its autonomic consequences of persistent sympathetic activation (for example in the face of hypotension). In the event, however, patients with A/Ca differed primarily on the basis of more intense early inflammation, as characterized via hs-CRP and NT-proBNP elevation (Table 1). Furthermore, there is a possibility that measurement of other parameters, such as liver/renal function tests and white blood cell count, may have shed additional insight on determinants of prognosis.

As regards mechanisms of association with CVS mortality risk, relevant data remain very limited, and no particular type of cancer predominated. While chronic inflammation may represent a risk factor for both carcinogenesis and development of ischemic heart disease [25], the current data add little beyond that.

How, then, might an association between A/Ca and long-term CVS mortality risk have operated? One possibility is that both index and recurrent attacks are more likely to occur in patients with cancer. In the current series, there were too few recurrent episodes to be certain about this possibility. Furthermore, it remains possible that some of the late CVS deaths might have reflected arrhythmias associated with recurrence.

A second possibility would be the induction of TTS as a complication of antineoplastic therapy [26] or because of prior cardiotoxicity induced by antineoplastic drugs. If this contributed to the current findings, it would probably have been a relatively minor factor, given that only 34.5% of patients with A/Ca had received chemo/immuno therapies.

A final possibility is of a “hormone-like” effect of some cancers inducing cardiotoxicity. There is evidence that many cancers may exhibit paracrine effects [27]. In general, such effects are potentially independent of the induction of TTS, or of the mechanisms, including Gi-protein biased post-receptor β2-adrenoceptor signalling and induction of nitrosative stress [7, 28], thought to underlie the pathogenesis of TTS. Figure 5, a schematic view of potential reciprocity between TTS and cancer both at the level of initiation and progression, represents an integrated view of our current mechanistic speculation in this regard.

However, it is also known that both ovarian and breast cancers may rely crucially on induction of activity of poly (ADPribose)polymerase-1 (PARP-1) [29], which appears to play a crucial role in myocardial energy impairment in a rat model of TTS [7]. To date, there is no suggested mechanism to explain multi-organ induction of PARP-1 activity, so this possibility remains to be tested.

In conclusion, A/Ca is a common finding among patients with TTS, and is associated with a more complicated in-hospital course, and a far higher long-term mortality risk, towards which ongoing cardiac events contribute substantially. While the mechanisms underlying this evidence of close ongoing association and probable reciprocity between TTS and cancer must remain somewhat speculative at this stage, at the very least the data would suggest that A/Ca be viewed as a high risk indexation factor among TTS patients.

The further finding that treatment with ACEi/ARB or βBl appears to be protective in long-term follow-up of TTS patients cannot be regarded as a substitute for randomized clinical trials, and indeed no such trials have yet been completed. However, coupled with the results of the previous meta-analysis [17], these data add to the argument for such a study to be undertaken.

Notes

Acknowledgements

We would like to acknowledge help provided by the medical staff, nursing staff and echocardiogram technicians at the Queen Elizabeth Hospital, Lyell McEwin Hospital and Royal Adelaide Hospitals.

Authors’ contributions

All of the authors have contributed substantially to data collection and/or analysis, and all have approved the content of the manuscript.

Funding

G.J.O. was supported by a PhD scholarship through the University of Adelaide.

Ethics approval and consent to participate

This investigation was approved by the Institutional Ethics of Human Research Committee (Central Northern Adelaide Health Service: the Queen Elizabeth Hospital and Lyell McEwin Hospital; protocol number: 009014).

Consent for publication

The manuscript does not contain any individual person’s data in any form.

Competing interests

The authors declare that they have no competing interests.

References

  1. 1.
    Neil C, Nguyen TH, Kucia A, Crouch B, Sverdlov A, Chirkov Y, et al. Slowly resolving global myocardial inflammation/oedema in Tako-Tsubo cardiomyopathy: evidence from T2-weighted cardiac MRI. Heart. 2012;98(17):1278–84.CrossRefGoogle Scholar
  2. 2.
    Templin C, Ghadri JR, Diekmann J, Napp LC, Bataiosu DR, Jaguszewski M, et al. Clinical features and outcomes of Takotsubo (stress) cardiomyopathy. N Engl J Med. 2015;373(10):929–38.CrossRefGoogle Scholar
  3. 3.
    Tornvall P, Collste O, Ehrenborg E, Jarnbert-Petterson H. A case-control study of risk markers and mortality in Takotsubo stress cardiomyopathy. J Am Coll Cardiol. 2016;67(16):1931–6.CrossRefGoogle Scholar
  4. 4.
    Paur H, Wright PT, Sikkel MB, Tranter MH, Mansfield C, O'Gara P, et al. High levels of circulating epinephrine trigger apical cardiodepression in a beta2-adrenergic receptor/Gi-dependent manner: a new model of Takotsubo cardiomyopathy. Circulation. 2012;126(6):697–706.CrossRefGoogle Scholar
  5. 5.
    Shao Y, Redfors B, Scharin Tang M, Mollmann H, Troidl C, Szardien S, et al. Novel rat model reveals important roles of beta-adrenoreceptors in stress-induced cardiomyopathy. Int J Cardiol. 2013;168:1943–50.CrossRefGoogle Scholar
  6. 6.
    Conti V, Russomanno G, Corbi G, Izzo V, Vecchione C, Filippelli A. Adrenoreceptors and nitric oxide in the cardiovascular system. Front Physiol. 2013;4:321.CrossRefGoogle Scholar
  7. 7.
    Surikow SY, Nguyen TH, Stafford I, Chapman M, Chacko S, Singh K, et al. Nitrosative stress as a modulator of inflammatory change in a model of Takotsubo syndrome. JACC Basic Transl Sci. 2018;3(2):213–26.CrossRefGoogle Scholar
  8. 8.
    Cammann VL, Sarcon A, Ding KJ, Seifert B, Kato K, Di Vece D, et al. Clinical features and outcomes of patients with malignancy and Takotsubo syndrome: observations from the international Takotsubo registry. J Am Heart Assoc. 2019;8(15):e010881.CrossRefGoogle Scholar
  9. 9.
    Girardey M, Jesel L, Campia U, Messas N, Hess S, Imperiale A, et al. Impact of malignancies in the early and late time course of Takotsubo cardiomyopathy. Circ J. 2016;80(10):2192–8.CrossRefGoogle Scholar
  10. 10.
    Kim H, Senecal C, Lewis B, Prasad A, Rajiv G, Lerman LO, et al. Natural history and predictors of mortality of patients with Takotsubo syndrome. Int J Cardiol. 2018;267:22–7.CrossRefGoogle Scholar
  11. 11.
    Moller C, Stiermaier T, Graf T, Eitel C, Thiele H, Burgdorf C, et al. Prevalence and long-term prognostic impact of malignancy in patients with Takotsubo syndrome. Eur J Heart Fail. 2018;20(4):816–8.CrossRefGoogle Scholar
  12. 12.
    Sattler K, El-Battrawy I, Lang S, Zhou X, Schramm K, Tulumen E, et al. Prevalence of cancer in Takotsubo cardiomyopathy: short and long-term outcome. Int J Cardiol. 2017;238:159–65.CrossRefGoogle Scholar
  13. 13.
    Sattler K, El-Battrawy I, Gietzen T, Lang S, Zhou X, Borggrefe M, et al. Long term outcome of patients suffering from cancer and Takotsubo syndrome or myocardial infarction. QJM. 2018;111(7):473–81.CrossRefGoogle Scholar
  14. 14.
    Burgdorf C, Kurowski V, Bonnemeier H, Schunkert H, Radke PW. Long-term prognosis of the transient left ventricular dysfunction syndrome (Tako-Tsubo cardiomyopathy): focus on malignancies. Eur J Heart Fail. 2008;10(10):1015–9.CrossRefGoogle Scholar
  15. 15.
    Prasad A, Lerman A, Rihal CS. Apical ballooning syndrome (Tako-Tsubo or stress cardiomyopathy): a mimic of acute myocardial infarction. Am Heart J. 2008;155(3):408–17.CrossRefGoogle Scholar
  16. 16.
    Placido R, Cunha Lopes B, Almeida AG, Rochitte CE. The role of cardiovascular magnetic resonance in takotsubo syndrome. J Cardiovasc Magn Reson. 2016;18(1):68.CrossRefGoogle Scholar
  17. 17.
    Singh K, Carson K, Shah R, Sawhney G, Singh B, Parsaik A, et al. Meta-analysis of clinical correlates of acute mortality in takotsubo cardiomyopathy. Am J Cardiol. 2014;113(8):1420–8.CrossRefGoogle Scholar
  18. 18.
    Scally C, Rudd A, Mezincescu A, Wilson H, Srivanasan J, Horgan G, et al. Persistent long-term structural, functional, and metabolic changes after stress-induced (Takotsubo) cardiomyopathy. Circulation. 2018;137(10):1039–48.CrossRefGoogle Scholar
  19. 19.
    Wischnewsky MB, Candreva A, Bacchi B, et al. Prediction of short- and long-term mortality in takotsubo syndrome: the InterTAK prognostic score. Eur J Heart Fail. 2019. [Epub ahead of print].Google Scholar
  20. 20.
    Zaghlol R, Kashyap K, Al-Shbool G, Basyal B, Desale S, Campia U, et al. Usefulness of malignancy as a predictor of WorseIn-hospital outcomes in patients with Takotsubo cardiomyopathy. Am J Cardiol. 2019;123:995–1001.CrossRefGoogle Scholar
  21. 21.
    Brunetti ND, Tarantino N, Guastafierro F, De Gennaro L, Correale M, Stiermaier T, et al. Malignancies and outcome in Takotsubo syndrome: a meta-analysis study on cancer and stress cardiomyopathy. Heart Fail Rev. 2019;24:481–8.CrossRefGoogle Scholar
  22. 22.
    Chong CR, Chan WP, Nguyen TH, Liu S, Procter NE, Ngo DT, et al. Thioredoxin-interacting protein: pathophysiology and emerging pharmacotherapeutics in cardiovascular disease and diabetes. Cardiovasc Drugs Ther. 2014;28(4):347–60.CrossRefGoogle Scholar
  23. 23.
    Singh K, Carson K, Usmani Z, Sawhney G, Shah R, Horowitz J. Systematic review and meta-analysis of incidence and correlates of recurrence of takotsubo cardiomyopathy. Int J Cardiol. 2014;174(3):696–701.CrossRefGoogle Scholar
  24. 24.
    Sharkey SW, Windenburg DC, Lesser JR, Maron MS, Hauser RG, Lesser JN, et al. Natural history and expansive clinical profile of stress (tako-tsubo) cardiomyopathy. J Am Coll Cardiol. 2010;55(4):333–41.CrossRefGoogle Scholar
  25. 25.
    Ridker PM, MacFadyen JG, Thuren T, Everett BM, Libby P, Glynn RJ. Effect of interleukin-1beta inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial. Lancet. 2017;390(10105):1833–42.CrossRefGoogle Scholar
  26. 26.
    Desai R, Abbas SA, Goyal H, Durairaj A, Fong HK, Hung O, et al. Frequency of Takotsubo cardiomyopathy in adult patients receiving chemotherapy (from a 5-year Nationwide inpatient study). Am J Cardiol. 2019;123(4):667–73.CrossRefGoogle Scholar
  27. 27.
    Dittmer J, Leyh B. Paracrine effects of stem cells in wound healing and cancer progression (review). Int J Oncol. 2014;44(6):1789–98.CrossRefGoogle Scholar
  28. 28.
    Surikow SY, Raman B, Licari J, Singh K, Nguyen TH, Horowitz JD. Evidence of nitrosative stress within hearts of patients dying of Tako-tsubo cardiomyopathy. Int J Cardiol. 2015;189:112–4.CrossRefGoogle Scholar
  29. 29.
    Heitz F, Harter P, Ewald-Riegler N, Papsdorf M, Kommoss S, du Bois A. Poly (ADP-ribosyl) ation polymerases: mechanism and new target of anticancer therapy. Expert Rev Anticancer Ther. 2010;10(7):1125–36.CrossRefGoogle Scholar

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© The Author(s). 2019

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors and Affiliations

  • Thanh H. Nguyen
    • 1
    • 2
  • Jeanette Stansborough
    • 1
  • Gao J. Ong
    • 1
    • 2
  • Sven Surikow
    • 1
    • 2
  • Timothy J. Price
    • 2
    • 3
  • John D. Horowitz
    • 1
    • 2
    Email author
  1. 1.Cardiology Unit, Department of CardiologyThe Queen Elizabeth HospitalWoodville SouthAustralia
  2. 2.The University of AdelaideAdelaideAustralia
  3. 3.Department of Medical OncologyQueen Elizabeth HospitalWoodville SouthAustralia

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