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Takotsubo syndrome (TS) (also known as apical ballooning syndrome) is an acute heart failure condition characterised by acute but rapidly reversible left ventricular (LV) dysfunction with distinct wall motion abnormalities subtending more than one coronary artery territory.1–3 The prevalence of TS is 1.0–2.5% in patients presenting with an acute coronary syndrome (ACS), and 12% in women presenting with an apparent anterior ST-elevation myocardial infarction (STEMI).4–6 The condition tends to occur in postmenopausal women after a stressful event. The aetiology of TS remains unknown but is likely to be complex with evidence for a role of the brain-heart axis in its pathogenesis.7,8 Since the initial report by Japanese cardiologists 25 years ago, TS has been increasingly recognised internationally.

We have previously reported the clinical characteristics and outcomes of 100 patients with TS in the Auckland region.9 Christchurch has reported 21 cases of TS triggered by the February 2011 Christchurch earthquake.10 However, data on the characteristics between hospitals for homogeneity/heterogeneity in the presentation of TS patients and their outcomes in New Zealand are still lacking. Therefore, this study aims to describe the clinical features and outcomes of patients with TS in a large New Zealand cohort.

Methods

Study population

The study population was prospectively identified between January 2006 and June 2018 from the three major public hospitals in the Auckland region (Middlemore Hospital, Auckland City Hospital and North Shore Hospital) and Christchurch Hospital except Dunedin Hospital where the study population was retrospectively identified. Only patients who underwent angiography (either cardiac CT angiography or invasive coronary angiography) were included in the study.

TS was initially defined using the diagnostic criteria proposed by the Mayo Clinic group11 until 2018 when the International Takotsubo Diagnostic Criteria (InterTAK Diagnostic Criteria)12 was being proposed.

Patients’ data including baseline characteristics, triggering factors (categorised as emotional or physical), cardiovascular risk factors, psychiatric illnesses, electrocardiography (ECG), echocardiography and angiography data were obtained at the time of the index admission.

In-hospital outcomes

We recorded in-hospital complications, including acute pulmonary oedema, cardiogenic shock, use of invasive or non-invasive ventilation or intra-aortic balloon pump insertion and death. A composite endpoint was defined which included at least one of the above complications.

Late follow-up data was obtained by reviewing the medical records of each patient.

Post-discharge outcomes

The primary outcome was post-discharge mortality in those patients discharged alive. Each death was classified as due to a cardiac or non-cardiac cause. We also report rehospitalisation for recurrence of TS, obtained by reviewing the medical records of each patient, or telephone interview with patients’ general practitioners. Recurrent TS was defined using the Mayo Clinic/InterTAK Diagnostic criteria, except that in most cases coronary angiography was not repeated.

The study was approved by the Health and Disability Ethics Committees as a clinical Audit (NTX/11/EXP/288).

Statistical analysis

Categorical data were summarised as frequency and percentage while continuous data were reported as mean and standard deviation (SD), or median and inter-quartile range (IQR). Comparison of categorical data between groups was performed by Chi-square test or Fisher exact test where appropriate. For continuous data, comparison between groups were performed by the non-parametric Kruskal-Wallis test due to data were not normally distributed.

Log-rank tests were used to compare the Kaplan-Meier estimates of event rates of all-cause mortality and TS recurrence for the whole cohort.

All P-values reported were two tailed and P-value <0.05 was considered significant. Data were analysed using SAS statistical package, version 9.4 (SAS Institute, Cary, NC). Survival plots were created using RStudio version 1.1.442.

Results

Total cohort

Patients characteristics (Table 1)

Of the 632 consecutive patients with TS included in this study, 606 (95.9%) were women and the mean age at presentation was 65.0+11.1 years. More than 80% were European, 10% were Maori, 4% were Pacific Islanders and 3.5% were Asian. Almost half of the patients had hypertension. Only 8.5% patients were known to have prior cardiovascular diseases.

Table 1: Clinical characteristics of Takotsubo patients.

ACH, Auckland City Hospital; MMH, Middlemore Hospital; NSH, Northshore Hospital; CVD, cardiovascular disease.

12.7% and 11.7% of patients had a prior history of depression or anxiety, and 12.2% and 4.3% were taking antidepressants/antipsychotics or benzodiazepines on admission.

Clinical presentation (Table 2)

The predominant symptom on admission was chest pain (80.2%), followed by dyspnoea (19%). 6.3% patients presented with new atrial arrhythmia (atrial fibrillation, n=34) and 2.5% patients presented with ventricular arrhythmias (ventricular tachycardia, n=8). Seventy-three patients had radiological evidence of pulmonary oedema on admission. A stressful trigger (defined as an unusual emotional or physical stress occurring before symptom onset) was identified in 73.7% patients. Emotional triggers were more frequent than physical triggers (62.9% and 37.1%, respectively). In 26.3% of patients, TS occurred without any evident trigger.

Table 2: Clinical presentation.

Values are n (%) unless otherwise stated.
*P-value excluded missing category
ACH, Auckland City Hospital; MMH, Middlemore Hospital; NSH, Northshore Hospital; CVD, cardiovascular disease IABP, intra-aortic balloon pump; CPAP, continuous positive airway pressure.

One-third of patients had ST-segment elevation on their admission ECG. ST-depression occurred only in 3.3% of patients with TS. More than half of the patients with TS had a significant reduction in left ventricular (LV) systolic function either on transthoracic echocardiography or left ventriculogram during the acute phase: 17.4% had low-normal LV function, 27.5% had mild LV impairment, and 55.1% had moderate/severe LV systolic impairment. Apical TS was identified in 84.7% of patients, whereas the midventricular form was found in 7.7%, and basal and focal forms were diagnosed in 2.4% and 5.3%, respectively. Right ventricular involvement was seen in only 17.1% of patients with TS. All patients underwent either invasive coronary angiography (n=603) or CT coronary angiography (n=29) during the acute admission: 55.5% of patients had normal coronary arteries.

On admission, 15.2% of the patients were taking beta-blockers, and 30.7% were taking either angiotensin-converting-enzyme inhibitors or angiotensin-receptor blockers. The rates of use of these two classes of drugs had increased at discharge (to 74.8% and 67.4%, respectively, Table 3).

Table 3: Medications on admission and on discharge.

ACH, Auckland City Hospital; MMH, Middlemore Hospital; NSH, Northshore Hospital; NOAC, non-vitamin K antagonist oral anticoagulants; ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blockers.
† Discharge medication for those patients discharged alive from index admission.

Of the 626 patients discharged alive, 91.4% underwent follow-up transthoracic echocardiography. Three died before having a follow-up transthoracic echocardiography. Eight percent of patients did not attend the follow-up echocardiography appointment. The median time of recovery imaging was 56 days (range 2–2,256 days, mean 105+198 days) from the day of index hospitalisation. Ninety-three percent of those who had echo (534/572) had full recovery of wall motion abnormalities and left ventricular function on echocardiography. One patient had worsening left ventricular function as a result of embolisation of ventricular thrombus into coronary artery. The remaining patients had persistent regional wall motion abnormalities and impaired left ventricular function but all had improved markedly compared to baseline studies.

In-hospital outcomes (Table 2)

During the index hospitalisation, 12% of patients had radiological evidence of pulmonary oedema on admission. Thirty patients were intubated, of whom three required intra-aortic balloon pump (IABP) insertion. Eight patients required continuous positive pressure airway (CPAP) ventilation. Fifteen patients with TS (2.4%) were in cardiogenic shock during the index admission. Six patients (1.0%) died during the index admission. Ninety-two patients (14.6%) had at least one of the in-hospital complications (defined as acute pulmonary oedema, cardiogenic shock, use of invasive or non-invasive ventilation or intra-aortic balloon pump insertion, or death).

Post-discharge outcomes (Figure 1 and 2, Table 4)

Six hundred and twenty-six patients were discharged alive after the index hospitalisation. The mean follow-up time was 4.9+3.4 years (median 4.4 years). 8.6% of the patients (54/626) died after hospital discharge, only one from cardiac causes. One patient developed heart failure as a result of embolisation of ventricular thrombus into coronary artery.

Figure 1: Kaplan-Meier curves showing post-discharge survival in Takotsubo patients.

Figure 2: Recurrence of Takotsubo syndrome post-discharge.

6.4% (40/626) of patients, all women, experienced recurrent TS, none of which were fatal. In 26 of the 40 patients with TS recurrence, the subsequent events involved stress triggers (physical triggers, n=5; emotional triggers, n=21). These 26 patients had their first recurrence of TS 23 days to 3,323 days after the initial event.

Comparison between hospitals

Demographic (Table 1)

The majority of TS cases were females in all hospitals and there were only minor differences in the mean age of patients. The distribution of patients by ethnicity was representative of New Zealand population without predominance of a particular ethnic group.

Cardiovascular risk factors

There were some relatively minor differences in the risk factors between the hospitals. There were more diabetes and smokers in Middlemore and Auckland whereas dyslipidaemia and hypertension were more common in Dunedin.

Psychiatric disorders

12.7% and 11.7% of patients had a prior history of depression or anxiety but this was more common in Christchurch patients (20.4% and 23.4%, respectively). The high prevalence of psychiatric disorders in Christchurch was also reflected by the fact that a substantial number of patients were taking antidepressants/antipsychotics (n=29) and benzodiazepines (n=11) on admission.

Clinical presentation (Table 2)

Chest pain was the predominant symptom on admission in all hospitals. The rates of preceding stressor, ST-elevation on admission ECG, clinical heart failure and moderate/severe LV systolic impairment were similar. The distribution of the type of TS was also similar among the hospitals.

Compared with pre-admission, there was a similar increase in prescribing of aspirin, beta-blocker, ACE inhibitors and statins on discharge in all hospitals (Table 3).

In-hospital outcomes (Table 2)

The rates of in-hospital complications among the hospitals did not differ significantly (p=0.37). The in-hospital mortality rate for TS patients is comparable among the five hospitals (p=0.73).

Post-discharge outcomes (Table 4)

There were no differences in the mortality (p=0.63) and recurrence risks (p=0.38) in TS patients after discharged among the five hospitals.

Table 4: Post-discharge outcomes.

Discussion

To our knowledge, this cohort is the largest series of TS patients published to date in Australasia and one of the largest internationally. Our series was similar to prior published series1,5,13,14 in terms of characteristics of the patient population. The distribution of patients by ethnicity was similar to that of New Zealand patient presenting with ACS without predominance of a particular ethnic group.15 There were no significant differences in the baseline demographics in TS patients among the five hospitals.

There was a high prevalence of depression and anxiety in our TS cohort. Of interest, the prevalence of depression and anxiety were higher in Christchurch. Following the major Christchurch and Kaikoura earthquakes, Christchurch Hospital has seen unprecedented case clusters of TS.10 Two extensive overviews of American TS cohorts found that anxiety and chronic stress were both associated with significantly higher odds of developing TS.16,17 Depression has also been reported to be associated with higher odds of developing TS.18 The increased prevalence of premorbid psychiatric diagnoses, particularly anxiety disorders and depression in TS patients suggests a potential link between neuropsychiatric disorders and TS. In particular, the Canterbury earthquakes had significant adverse impact on mental health, which could account for the high incidence observed.

A unique feature of TC is a preceding emotional or physical stressor, although in some cases, precipitant stressors have not been identified. Presentation was preceded by a physical or emotional stressor in two-thirds of our patients, but in the remaining third there was no identifiable pre-event stressor despite specific enquiry after the diagnosis was made. Emotional triggers were more frequent than physical triggers (62.9% and 37.1% respectively). Reassuringly, the rates of preceding stressor were similar among the five hospitals.

Patients with TS have an in-hospital mortality rate similar to that of patients with an MI.19 In addition, adverse events due to haemodynamic instability (eg, acute heart failure or cardiogenic shock) may occur in up to one-fourth of patients, even during the first hours after clinical onset. Almost 12% of our patients had pulmonary oedema at admission and there was a subset of patients who were critically ill at presentation requiring inotropic support, intubation and/or intra-aortic balloon pump. This finding was similar to the North American and European cohorts,20 illustrating the previously underestimated risk of complications during the acute phase of TS and highlights the need for concise clinical evaluation, monitoring and management. Despite the relatively high adverse events reported during the acute phase, the rates of in-hospital complications did not differ significant among the five hospitals.

Of the patients with TS discharged alive, 8.6% died during follow-up, with all but one of the 54 deaths from non-cardiac causes. This is consistent with other local and international studies which have reported that late mortality after TS is largely due to non-cardiac causes9,19,21,22 and appears to be related to the presence of comorbid disease rather than the TS event itself. Forty of our surviving patients experienced recurrent and remarkably similar TS episodes. There were no significant differences in the late mortality and recurrence rates for TS patients in our cohorts among the five hospitals, albeit with only small event rates.

There was no clear consensus about the appropriate treatment of patients with TS. New Zealand guidelines recommend routine post-discharge use of dual antiplatelet therapy, either clopidogrel or ticagrelor, statins, ACE inhibitors or ARB and beta blockers in patients without contraindications or intolerance after ACS presentations, with the aim of reducing further events.23,24 Because TS patients are frequently started on the same therapy on the basis of suspected ACS, there was marked increase in prescribing aspirin, beta-blocker, ACE inhibitors and statins on discharge among the five hospitals. To our knowledge, there are no data to support the use of particular medication regimens in patients with TS.

Study limitations

Despite prospectively capturing all patients presenting with TS in four major hospitals in New Zealand over 12 years, it is possible that some TS cases in the participating hospitals were not diagnosed, were hospitalised in other specialty departments, did not undergo catheterisation, which would imply underestimation of the true number of TS cases that occurred over the study period. However, it is likely that such cohort will continue to form an important source for research on TS in the future. In addition, we were unable to provide results of cardiac biomarkers such as troponin because of the different assays used in the different centres.

Conclusion

This study represents the largest TS cohort published to date in Australasia and also one of the largest internationally. Our clinical findings support previously published series. A subset of patients had a complicated in-hospital course but the in-hospital mortality for patients diagnosed with TS was similar among the five major hospitals. The late mortality and recurrence rates for TS patients who survived the index event also did not differ significantly among the hospitals. TS is a relatively recently described condition, its aetiology is poorly understood and it is probably still underdiagnosed.6 This cohort reassures us that TS presentations are similar across New Zealand and comparable to international experience. Establishment of this cohort will allow further investigation of this novel condition.

Summary

Abstract

Aim

Takotsubo syndrome (TS) mimics acute coronary syndrome but has a distinct pathophysiology. This study aimed to compare and contrast the clinical presentation, management and outcomes of patients with TS in five large New Zealand hospitals.

Method

We identified 632 consecutive patients presenting to the five major tertiary hospitals in New Zealand (Middlemore Hospital, Auckland City Hospital, North Shore Hospital, Christchurch Hospital and Dunedin Hospital) between January 2006 and June 2018 and obtained clinical, laboratory, electrocardiography, echocardiography, coronary angiography and long-term follow-up data.

Results

Six hundred and thirty-two consecutive patients with TS (606 women, mean age 65.0+11.1 years) were included. An associated stressor was identified in two-thirds of patients, and emotional triggers were more frequent than physical triggers (62.9% and 37.1%, respectively). Overall, 12.7% of patient had depression and 11.7% anxiety but this was more common in patients from Christchurch Hospital (20.4% and 23.4%, respectively). The in-hospital mortality among the five hospitals ranges between 0 to 2.0%. The mean follow-up was 4.9+3.4 years (median 4.4 years). Fifty-four people died post-discharge, all but one from a non-cardiac cause. Forty patients had recurrent TS. Mortality post-discharge (p=0.63) and TS recurrence (p=0.38) did not differ significantly among the five hospitals.

Conclusion

In this large New Zealand TS cohort, the clinical characteristics and presentation were similar among the five hospitals. A subset of patients had a complicated in-hospital course, but late deaths were almost all from non-cardiac causes and recurrence was infrequent. Mortality post-discharge and recurrence was similar between the hospitals.

Author Information

Jen-Li Looi, Department of Cardiology, Middlemore Hospital, Otahuhu, Auckland; Toby Verryt, Department of Cardiology, Christchurch Hospital, Christchurch; Peter McLeod, Department of Cardiology, Dunedin Hospital, Dunedin; Christina Chan, Department of Cardiology, Dunedin Hospital, Dunedin; James Pemberton, Department of Cardiology, Dunedin Hospital, Dunedin; Mark Webster, Green Lane Cardiovascular Service, Auckland City Hospital, Auckland; Andrew To, Cardiovascular Division, North Shore Hospital, Takapuna, Auckland; Mildred Lee, Department of Cardiology, Middlemore Hospital, Otahuhu, Auckland; Andrew J Kerr, Department of Cardiology, Middlemore Hospital, Otahuhu, Auckland.

Acknowledgements

Correspondence

Jen-Li Looi, Department of Cardiology, Middlemore Hospital, Private Bag 93311, Otahuhu, Auckland.

Correspondence Email

jenli.looi@middlemore.co.nz

Competing Interests

Nil.

1. 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.

2. Ghadri JR, Cammann VL, Napp LC, Jurisic S, Diekmann J, Bataiosu DR, et al. Differences in the Clinical Profile and Outcomes of Typical and Atypical Takotsubo Syndrome: Data From the International Takotsubo Registry. JAMA Cardiol. 2016; 1(3):335–40.

3. Bossone E, Erbel R. The “takotsubo syndrome”: from legend to science. Heart Fail Clin. 2013; 9(2):xiii–xv.

4. Parodi G, Del Pace S, Carrabba N, Salvadori C, Memisha G, Simonetti I, et al. Incidence, clinical findings, and outcome of women with left ventricular apical ballooning syndrome. Am J Cardiol. 2007; 99(2):182–5.

5. Bybee KA, Prasad A, Barsness GW, Lerman A, Jaffe AS, Murphy JG, et al. Clinical characteristics and thrombolysis in myocardial infarction frame counts in women with transient left ventricular apical ballooning syndrome. Am J Cardiol. 2004; 94(3):343–6.

6. Looi JL, Verryt T, McLeod P, Chan C, Pemberton J, Webster M, et al. Incidence of Takotsubo syndrome vs acute myocardial infarction in New Zealand (ANZACS-QI 45). N Z Med J. 2020; 133(1511):90–4.

7. Samuels MA. The brain-heart connection. Circulation. 2007; 116(1):77–84.

8. Suzuki H, Matsumoto Y, Kaneta T, Sugimura K, Takahashi J, Fukumoto Y, et al. Evidence for brain activation in patients with takotsubo cardiomyopathy. Circ J. 2014; 78(1):256–8.

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11. 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.

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14. Tsuchihashi K, Ueshima K, Uchida T, Oh-mura N, Kimura K, Owa M, et al. Transient left ventricular apical ballooning without coronary artery stenosis: a novel heart syndrome mimicking acute myocardial infarction. Angina Pectoris-Myocardial Infarction Investigations in Japan. J Am Coll Cardiol. 2001; 38(1):11–8.

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Takotsubo syndrome (TS) (also known as apical ballooning syndrome) is an acute heart failure condition characterised by acute but rapidly reversible left ventricular (LV) dysfunction with distinct wall motion abnormalities subtending more than one coronary artery territory.1–3 The prevalence of TS is 1.0–2.5% in patients presenting with an acute coronary syndrome (ACS), and 12% in women presenting with an apparent anterior ST-elevation myocardial infarction (STEMI).4–6 The condition tends to occur in postmenopausal women after a stressful event. The aetiology of TS remains unknown but is likely to be complex with evidence for a role of the brain-heart axis in its pathogenesis.7,8 Since the initial report by Japanese cardiologists 25 years ago, TS has been increasingly recognised internationally.

We have previously reported the clinical characteristics and outcomes of 100 patients with TS in the Auckland region.9 Christchurch has reported 21 cases of TS triggered by the February 2011 Christchurch earthquake.10 However, data on the characteristics between hospitals for homogeneity/heterogeneity in the presentation of TS patients and their outcomes in New Zealand are still lacking. Therefore, this study aims to describe the clinical features and outcomes of patients with TS in a large New Zealand cohort.

Methods

Study population

The study population was prospectively identified between January 2006 and June 2018 from the three major public hospitals in the Auckland region (Middlemore Hospital, Auckland City Hospital and North Shore Hospital) and Christchurch Hospital except Dunedin Hospital where the study population was retrospectively identified. Only patients who underwent angiography (either cardiac CT angiography or invasive coronary angiography) were included in the study.

TS was initially defined using the diagnostic criteria proposed by the Mayo Clinic group11 until 2018 when the International Takotsubo Diagnostic Criteria (InterTAK Diagnostic Criteria)12 was being proposed.

Patients’ data including baseline characteristics, triggering factors (categorised as emotional or physical), cardiovascular risk factors, psychiatric illnesses, electrocardiography (ECG), echocardiography and angiography data were obtained at the time of the index admission.

In-hospital outcomes

We recorded in-hospital complications, including acute pulmonary oedema, cardiogenic shock, use of invasive or non-invasive ventilation or intra-aortic balloon pump insertion and death. A composite endpoint was defined which included at least one of the above complications.

Late follow-up data was obtained by reviewing the medical records of each patient.

Post-discharge outcomes

The primary outcome was post-discharge mortality in those patients discharged alive. Each death was classified as due to a cardiac or non-cardiac cause. We also report rehospitalisation for recurrence of TS, obtained by reviewing the medical records of each patient, or telephone interview with patients’ general practitioners. Recurrent TS was defined using the Mayo Clinic/InterTAK Diagnostic criteria, except that in most cases coronary angiography was not repeated.

The study was approved by the Health and Disability Ethics Committees as a clinical Audit (NTX/11/EXP/288).

Statistical analysis

Categorical data were summarised as frequency and percentage while continuous data were reported as mean and standard deviation (SD), or median and inter-quartile range (IQR). Comparison of categorical data between groups was performed by Chi-square test or Fisher exact test where appropriate. For continuous data, comparison between groups were performed by the non-parametric Kruskal-Wallis test due to data were not normally distributed.

Log-rank tests were used to compare the Kaplan-Meier estimates of event rates of all-cause mortality and TS recurrence for the whole cohort.

All P-values reported were two tailed and P-value <0.05 was considered significant. Data were analysed using SAS statistical package, version 9.4 (SAS Institute, Cary, NC). Survival plots were created using RStudio version 1.1.442.

Results

Total cohort

Patients characteristics (Table 1)

Of the 632 consecutive patients with TS included in this study, 606 (95.9%) were women and the mean age at presentation was 65.0+11.1 years. More than 80% were European, 10% were Maori, 4% were Pacific Islanders and 3.5% were Asian. Almost half of the patients had hypertension. Only 8.5% patients were known to have prior cardiovascular diseases.

Table 1: Clinical characteristics of Takotsubo patients.

ACH, Auckland City Hospital; MMH, Middlemore Hospital; NSH, Northshore Hospital; CVD, cardiovascular disease.

12.7% and 11.7% of patients had a prior history of depression or anxiety, and 12.2% and 4.3% were taking antidepressants/antipsychotics or benzodiazepines on admission.

Clinical presentation (Table 2)

The predominant symptom on admission was chest pain (80.2%), followed by dyspnoea (19%). 6.3% patients presented with new atrial arrhythmia (atrial fibrillation, n=34) and 2.5% patients presented with ventricular arrhythmias (ventricular tachycardia, n=8). Seventy-three patients had radiological evidence of pulmonary oedema on admission. A stressful trigger (defined as an unusual emotional or physical stress occurring before symptom onset) was identified in 73.7% patients. Emotional triggers were more frequent than physical triggers (62.9% and 37.1%, respectively). In 26.3% of patients, TS occurred without any evident trigger.

Table 2: Clinical presentation.

Values are n (%) unless otherwise stated.
*P-value excluded missing category
ACH, Auckland City Hospital; MMH, Middlemore Hospital; NSH, Northshore Hospital; CVD, cardiovascular disease IABP, intra-aortic balloon pump; CPAP, continuous positive airway pressure.

One-third of patients had ST-segment elevation on their admission ECG. ST-depression occurred only in 3.3% of patients with TS. More than half of the patients with TS had a significant reduction in left ventricular (LV) systolic function either on transthoracic echocardiography or left ventriculogram during the acute phase: 17.4% had low-normal LV function, 27.5% had mild LV impairment, and 55.1% had moderate/severe LV systolic impairment. Apical TS was identified in 84.7% of patients, whereas the midventricular form was found in 7.7%, and basal and focal forms were diagnosed in 2.4% and 5.3%, respectively. Right ventricular involvement was seen in only 17.1% of patients with TS. All patients underwent either invasive coronary angiography (n=603) or CT coronary angiography (n=29) during the acute admission: 55.5% of patients had normal coronary arteries.

On admission, 15.2% of the patients were taking beta-blockers, and 30.7% were taking either angiotensin-converting-enzyme inhibitors or angiotensin-receptor blockers. The rates of use of these two classes of drugs had increased at discharge (to 74.8% and 67.4%, respectively, Table 3).

Table 3: Medications on admission and on discharge.

ACH, Auckland City Hospital; MMH, Middlemore Hospital; NSH, Northshore Hospital; NOAC, non-vitamin K antagonist oral anticoagulants; ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blockers.
† Discharge medication for those patients discharged alive from index admission.

Of the 626 patients discharged alive, 91.4% underwent follow-up transthoracic echocardiography. Three died before having a follow-up transthoracic echocardiography. Eight percent of patients did not attend the follow-up echocardiography appointment. The median time of recovery imaging was 56 days (range 2–2,256 days, mean 105+198 days) from the day of index hospitalisation. Ninety-three percent of those who had echo (534/572) had full recovery of wall motion abnormalities and left ventricular function on echocardiography. One patient had worsening left ventricular function as a result of embolisation of ventricular thrombus into coronary artery. The remaining patients had persistent regional wall motion abnormalities and impaired left ventricular function but all had improved markedly compared to baseline studies.

In-hospital outcomes (Table 2)

During the index hospitalisation, 12% of patients had radiological evidence of pulmonary oedema on admission. Thirty patients were intubated, of whom three required intra-aortic balloon pump (IABP) insertion. Eight patients required continuous positive pressure airway (CPAP) ventilation. Fifteen patients with TS (2.4%) were in cardiogenic shock during the index admission. Six patients (1.0%) died during the index admission. Ninety-two patients (14.6%) had at least one of the in-hospital complications (defined as acute pulmonary oedema, cardiogenic shock, use of invasive or non-invasive ventilation or intra-aortic balloon pump insertion, or death).

Post-discharge outcomes (Figure 1 and 2, Table 4)

Six hundred and twenty-six patients were discharged alive after the index hospitalisation. The mean follow-up time was 4.9+3.4 years (median 4.4 years). 8.6% of the patients (54/626) died after hospital discharge, only one from cardiac causes. One patient developed heart failure as a result of embolisation of ventricular thrombus into coronary artery.

Figure 1: Kaplan-Meier curves showing post-discharge survival in Takotsubo patients.

Figure 2: Recurrence of Takotsubo syndrome post-discharge.

6.4% (40/626) of patients, all women, experienced recurrent TS, none of which were fatal. In 26 of the 40 patients with TS recurrence, the subsequent events involved stress triggers (physical triggers, n=5; emotional triggers, n=21). These 26 patients had their first recurrence of TS 23 days to 3,323 days after the initial event.

Comparison between hospitals

Demographic (Table 1)

The majority of TS cases were females in all hospitals and there were only minor differences in the mean age of patients. The distribution of patients by ethnicity was representative of New Zealand population without predominance of a particular ethnic group.

Cardiovascular risk factors

There were some relatively minor differences in the risk factors between the hospitals. There were more diabetes and smokers in Middlemore and Auckland whereas dyslipidaemia and hypertension were more common in Dunedin.

Psychiatric disorders

12.7% and 11.7% of patients had a prior history of depression or anxiety but this was more common in Christchurch patients (20.4% and 23.4%, respectively). The high prevalence of psychiatric disorders in Christchurch was also reflected by the fact that a substantial number of patients were taking antidepressants/antipsychotics (n=29) and benzodiazepines (n=11) on admission.

Clinical presentation (Table 2)

Chest pain was the predominant symptom on admission in all hospitals. The rates of preceding stressor, ST-elevation on admission ECG, clinical heart failure and moderate/severe LV systolic impairment were similar. The distribution of the type of TS was also similar among the hospitals.

Compared with pre-admission, there was a similar increase in prescribing of aspirin, beta-blocker, ACE inhibitors and statins on discharge in all hospitals (Table 3).

In-hospital outcomes (Table 2)

The rates of in-hospital complications among the hospitals did not differ significantly (p=0.37). The in-hospital mortality rate for TS patients is comparable among the five hospitals (p=0.73).

Post-discharge outcomes (Table 4)

There were no differences in the mortality (p=0.63) and recurrence risks (p=0.38) in TS patients after discharged among the five hospitals.

Table 4: Post-discharge outcomes.

Discussion

To our knowledge, this cohort is the largest series of TS patients published to date in Australasia and one of the largest internationally. Our series was similar to prior published series1,5,13,14 in terms of characteristics of the patient population. The distribution of patients by ethnicity was similar to that of New Zealand patient presenting with ACS without predominance of a particular ethnic group.15 There were no significant differences in the baseline demographics in TS patients among the five hospitals.

There was a high prevalence of depression and anxiety in our TS cohort. Of interest, the prevalence of depression and anxiety were higher in Christchurch. Following the major Christchurch and Kaikoura earthquakes, Christchurch Hospital has seen unprecedented case clusters of TS.10 Two extensive overviews of American TS cohorts found that anxiety and chronic stress were both associated with significantly higher odds of developing TS.16,17 Depression has also been reported to be associated with higher odds of developing TS.18 The increased prevalence of premorbid psychiatric diagnoses, particularly anxiety disorders and depression in TS patients suggests a potential link between neuropsychiatric disorders and TS. In particular, the Canterbury earthquakes had significant adverse impact on mental health, which could account for the high incidence observed.

A unique feature of TC is a preceding emotional or physical stressor, although in some cases, precipitant stressors have not been identified. Presentation was preceded by a physical or emotional stressor in two-thirds of our patients, but in the remaining third there was no identifiable pre-event stressor despite specific enquiry after the diagnosis was made. Emotional triggers were more frequent than physical triggers (62.9% and 37.1% respectively). Reassuringly, the rates of preceding stressor were similar among the five hospitals.

Patients with TS have an in-hospital mortality rate similar to that of patients with an MI.19 In addition, adverse events due to haemodynamic instability (eg, acute heart failure or cardiogenic shock) may occur in up to one-fourth of patients, even during the first hours after clinical onset. Almost 12% of our patients had pulmonary oedema at admission and there was a subset of patients who were critically ill at presentation requiring inotropic support, intubation and/or intra-aortic balloon pump. This finding was similar to the North American and European cohorts,20 illustrating the previously underestimated risk of complications during the acute phase of TS and highlights the need for concise clinical evaluation, monitoring and management. Despite the relatively high adverse events reported during the acute phase, the rates of in-hospital complications did not differ significant among the five hospitals.

Of the patients with TS discharged alive, 8.6% died during follow-up, with all but one of the 54 deaths from non-cardiac causes. This is consistent with other local and international studies which have reported that late mortality after TS is largely due to non-cardiac causes9,19,21,22 and appears to be related to the presence of comorbid disease rather than the TS event itself. Forty of our surviving patients experienced recurrent and remarkably similar TS episodes. There were no significant differences in the late mortality and recurrence rates for TS patients in our cohorts among the five hospitals, albeit with only small event rates.

There was no clear consensus about the appropriate treatment of patients with TS. New Zealand guidelines recommend routine post-discharge use of dual antiplatelet therapy, either clopidogrel or ticagrelor, statins, ACE inhibitors or ARB and beta blockers in patients without contraindications or intolerance after ACS presentations, with the aim of reducing further events.23,24 Because TS patients are frequently started on the same therapy on the basis of suspected ACS, there was marked increase in prescribing aspirin, beta-blocker, ACE inhibitors and statins on discharge among the five hospitals. To our knowledge, there are no data to support the use of particular medication regimens in patients with TS.

Study limitations

Despite prospectively capturing all patients presenting with TS in four major hospitals in New Zealand over 12 years, it is possible that some TS cases in the participating hospitals were not diagnosed, were hospitalised in other specialty departments, did not undergo catheterisation, which would imply underestimation of the true number of TS cases that occurred over the study period. However, it is likely that such cohort will continue to form an important source for research on TS in the future. In addition, we were unable to provide results of cardiac biomarkers such as troponin because of the different assays used in the different centres.

Conclusion

This study represents the largest TS cohort published to date in Australasia and also one of the largest internationally. Our clinical findings support previously published series. A subset of patients had a complicated in-hospital course but the in-hospital mortality for patients diagnosed with TS was similar among the five major hospitals. The late mortality and recurrence rates for TS patients who survived the index event also did not differ significantly among the hospitals. TS is a relatively recently described condition, its aetiology is poorly understood and it is probably still underdiagnosed.6 This cohort reassures us that TS presentations are similar across New Zealand and comparable to international experience. Establishment of this cohort will allow further investigation of this novel condition.

Summary

Abstract

Aim

Takotsubo syndrome (TS) mimics acute coronary syndrome but has a distinct pathophysiology. This study aimed to compare and contrast the clinical presentation, management and outcomes of patients with TS in five large New Zealand hospitals.

Method

We identified 632 consecutive patients presenting to the five major tertiary hospitals in New Zealand (Middlemore Hospital, Auckland City Hospital, North Shore Hospital, Christchurch Hospital and Dunedin Hospital) between January 2006 and June 2018 and obtained clinical, laboratory, electrocardiography, echocardiography, coronary angiography and long-term follow-up data.

Results

Six hundred and thirty-two consecutive patients with TS (606 women, mean age 65.0+11.1 years) were included. An associated stressor was identified in two-thirds of patients, and emotional triggers were more frequent than physical triggers (62.9% and 37.1%, respectively). Overall, 12.7% of patient had depression and 11.7% anxiety but this was more common in patients from Christchurch Hospital (20.4% and 23.4%, respectively). The in-hospital mortality among the five hospitals ranges between 0 to 2.0%. The mean follow-up was 4.9+3.4 years (median 4.4 years). Fifty-four people died post-discharge, all but one from a non-cardiac cause. Forty patients had recurrent TS. Mortality post-discharge (p=0.63) and TS recurrence (p=0.38) did not differ significantly among the five hospitals.

Conclusion

In this large New Zealand TS cohort, the clinical characteristics and presentation were similar among the five hospitals. A subset of patients had a complicated in-hospital course, but late deaths were almost all from non-cardiac causes and recurrence was infrequent. Mortality post-discharge and recurrence was similar between the hospitals.

Author Information

Jen-Li Looi, Department of Cardiology, Middlemore Hospital, Otahuhu, Auckland; Toby Verryt, Department of Cardiology, Christchurch Hospital, Christchurch; Peter McLeod, Department of Cardiology, Dunedin Hospital, Dunedin; Christina Chan, Department of Cardiology, Dunedin Hospital, Dunedin; James Pemberton, Department of Cardiology, Dunedin Hospital, Dunedin; Mark Webster, Green Lane Cardiovascular Service, Auckland City Hospital, Auckland; Andrew To, Cardiovascular Division, North Shore Hospital, Takapuna, Auckland; Mildred Lee, Department of Cardiology, Middlemore Hospital, Otahuhu, Auckland; Andrew J Kerr, Department of Cardiology, Middlemore Hospital, Otahuhu, Auckland.

Acknowledgements

Correspondence

Jen-Li Looi, Department of Cardiology, Middlemore Hospital, Private Bag 93311, Otahuhu, Auckland.

Correspondence Email

jenli.looi@middlemore.co.nz

Competing Interests

Nil.

1. 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.

2. Ghadri JR, Cammann VL, Napp LC, Jurisic S, Diekmann J, Bataiosu DR, et al. Differences in the Clinical Profile and Outcomes of Typical and Atypical Takotsubo Syndrome: Data From the International Takotsubo Registry. JAMA Cardiol. 2016; 1(3):335–40.

3. Bossone E, Erbel R. The “takotsubo syndrome”: from legend to science. Heart Fail Clin. 2013; 9(2):xiii–xv.

4. Parodi G, Del Pace S, Carrabba N, Salvadori C, Memisha G, Simonetti I, et al. Incidence, clinical findings, and outcome of women with left ventricular apical ballooning syndrome. Am J Cardiol. 2007; 99(2):182–5.

5. Bybee KA, Prasad A, Barsness GW, Lerman A, Jaffe AS, Murphy JG, et al. Clinical characteristics and thrombolysis in myocardial infarction frame counts in women with transient left ventricular apical ballooning syndrome. Am J Cardiol. 2004; 94(3):343–6.

6. Looi JL, Verryt T, McLeod P, Chan C, Pemberton J, Webster M, et al. Incidence of Takotsubo syndrome vs acute myocardial infarction in New Zealand (ANZACS-QI 45). N Z Med J. 2020; 133(1511):90–4.

7. Samuels MA. The brain-heart connection. Circulation. 2007; 116(1):77–84.

8. Suzuki H, Matsumoto Y, Kaneta T, Sugimura K, Takahashi J, Fukumoto Y, et al. Evidence for brain activation in patients with takotsubo cardiomyopathy. Circ J. 2014; 78(1):256–8.

9. Looi JL, Wong CW, Khan A, Webster M, Kerr AJ. Clinical characteristics and outcome of apical ballooning syndrome in Auckland, New Zealand. Heart Lung Circ. 2012; 21(3):143–9.

10. Chan C, Troughton R, Elliott J, Zarifeh J, Bridgman P. One-year follow-up of the 2011 Christchurch Earthquake stress cardiomyopathy cases. N Z Med J. 2014; 127(1396):15–22.

11. 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.

12. Ghadri JR, Wittstein IS, Prasad A, Sharkey S, Dote K, Akashi YJ, et al. International Expert Consensus Document on Takotsubo Syndrome (Part I): Clinical Characteristics, Diagnostic Criteria, and Pathophysiology. Eur Heart J. 2018; 39(22):2032–46.

13. Sharkey SW, Lesser JR, Zenovich AG, Maron MS, Lindberg J, Longe TF, et al. Acute and reversible cardiomyopathy provoked by stress in women from the United States. Circulation. 2005; 111(4):472–9.

14. Tsuchihashi K, Ueshima K, Uchida T, Oh-mura N, Kimura K, Owa M, et al. Transient left ventricular apical ballooning without coronary artery stenosis: a novel heart syndrome mimicking acute myocardial infarction. Angina Pectoris-Myocardial Infarction Investigations in Japan. J Am Coll Cardiol. 2001; 38(1):11–8.

15. Wang TKM, Grey C, Jiang Y, Jackson R, Kerr A. Trends in length of stay following acute coronary syndrome hospitalisation in New Zealand 2006–2016: ANZACS-QI 32 study. N Z Med J. 2020; 133(1508):29–42.

16. Summers MR, Lennon RJ, Prasad A. Pre-morbid psychiatric and cardiovascular diseases in apical ballooning syndrome (tako-tsubo/stress-induced cardiomyopathy): potential pre-disposing factors? J Am Coll Cardiol. 2010; 55(7):700–1.

17. Mudd JO, Kapur NK, Champion HC, Schulman SP, Wittstein IS. Patients with Stress-Induced (Takotsubo) Cardiomyopathy Have an Increased Prevalence of Mood Disorders and Antidepressant Use Compared to Patients with Acute Myocardial Infarction. Journal of Cardiac Failure. 2007; 13(6):S176.

18. Deshmukh A, Kumar G, Pant S, Rihal C, Murugiah K, Mehta JL. Prevalence of Takotsubo cardiomyopathy in the United States. Am Heart J. 2012; 164(1):66–71 e1.

19. Looi JL, Lee M, Webster MWI, To ACY, Kerr AJ. Postdischarge outcome after Takotsubo syndrome compared with patients post-ACS and those without prior CVD: ANZACS-QI 19. Open Heart. 2018; 5(2):e000918.

20. Pelliccia F, Pasceri V, Patti G, Tanzilli G, Speciale G, Gaudio C, et al. Long-Term Prognosis and Outcome Predictors in Takotsubo Syndrome: A Systematic Review and Meta-Regression Study. JACC Heart Fail. 2019; 7(2):143–54.

21. 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.

22. Elesber AA, Prasad A, Lennon RJ, Wright RS, Lerman A, Rihal CS. Four-year recurrence rate and prognosis of the apical ballooning syndrome. J Am Coll Cardiol. 2007; 50(5):448–52.

23. Non STEACSGG, the New Zealand Branch of the Cardiac Society of A, New Z. New Zealand 2012 guidelines for the management of non ST-elevation acute coronary syndromes. N Z Med J. 2012; 125(1357):122–47.

24. Group ST-EMIG, New Zealand Branch of Cardiac Society of A, New Z. ST-elevation myocardial infarction: New Zealand Management Guidelines, 2013. N Z Med J. 2013; 126(1387):127–64.

Contact diana@nzma.org.nz
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Takotsubo syndrome (TS) (also known as apical ballooning syndrome) is an acute heart failure condition characterised by acute but rapidly reversible left ventricular (LV) dysfunction with distinct wall motion abnormalities subtending more than one coronary artery territory.1–3 The prevalence of TS is 1.0–2.5% in patients presenting with an acute coronary syndrome (ACS), and 12% in women presenting with an apparent anterior ST-elevation myocardial infarction (STEMI).4–6 The condition tends to occur in postmenopausal women after a stressful event. The aetiology of TS remains unknown but is likely to be complex with evidence for a role of the brain-heart axis in its pathogenesis.7,8 Since the initial report by Japanese cardiologists 25 years ago, TS has been increasingly recognised internationally.

We have previously reported the clinical characteristics and outcomes of 100 patients with TS in the Auckland region.9 Christchurch has reported 21 cases of TS triggered by the February 2011 Christchurch earthquake.10 However, data on the characteristics between hospitals for homogeneity/heterogeneity in the presentation of TS patients and their outcomes in New Zealand are still lacking. Therefore, this study aims to describe the clinical features and outcomes of patients with TS in a large New Zealand cohort.

Methods

Study population

The study population was prospectively identified between January 2006 and June 2018 from the three major public hospitals in the Auckland region (Middlemore Hospital, Auckland City Hospital and North Shore Hospital) and Christchurch Hospital except Dunedin Hospital where the study population was retrospectively identified. Only patients who underwent angiography (either cardiac CT angiography or invasive coronary angiography) were included in the study.

TS was initially defined using the diagnostic criteria proposed by the Mayo Clinic group11 until 2018 when the International Takotsubo Diagnostic Criteria (InterTAK Diagnostic Criteria)12 was being proposed.

Patients’ data including baseline characteristics, triggering factors (categorised as emotional or physical), cardiovascular risk factors, psychiatric illnesses, electrocardiography (ECG), echocardiography and angiography data were obtained at the time of the index admission.

In-hospital outcomes

We recorded in-hospital complications, including acute pulmonary oedema, cardiogenic shock, use of invasive or non-invasive ventilation or intra-aortic balloon pump insertion and death. A composite endpoint was defined which included at least one of the above complications.

Late follow-up data was obtained by reviewing the medical records of each patient.

Post-discharge outcomes

The primary outcome was post-discharge mortality in those patients discharged alive. Each death was classified as due to a cardiac or non-cardiac cause. We also report rehospitalisation for recurrence of TS, obtained by reviewing the medical records of each patient, or telephone interview with patients’ general practitioners. Recurrent TS was defined using the Mayo Clinic/InterTAK Diagnostic criteria, except that in most cases coronary angiography was not repeated.

The study was approved by the Health and Disability Ethics Committees as a clinical Audit (NTX/11/EXP/288).

Statistical analysis

Categorical data were summarised as frequency and percentage while continuous data were reported as mean and standard deviation (SD), or median and inter-quartile range (IQR). Comparison of categorical data between groups was performed by Chi-square test or Fisher exact test where appropriate. For continuous data, comparison between groups were performed by the non-parametric Kruskal-Wallis test due to data were not normally distributed.

Log-rank tests were used to compare the Kaplan-Meier estimates of event rates of all-cause mortality and TS recurrence for the whole cohort.

All P-values reported were two tailed and P-value <0.05 was considered significant. Data were analysed using SAS statistical package, version 9.4 (SAS Institute, Cary, NC). Survival plots were created using RStudio version 1.1.442.

Results

Total cohort

Patients characteristics (Table 1)

Of the 632 consecutive patients with TS included in this study, 606 (95.9%) were women and the mean age at presentation was 65.0+11.1 years. More than 80% were European, 10% were Maori, 4% were Pacific Islanders and 3.5% were Asian. Almost half of the patients had hypertension. Only 8.5% patients were known to have prior cardiovascular diseases.

Table 1: Clinical characteristics of Takotsubo patients.

ACH, Auckland City Hospital; MMH, Middlemore Hospital; NSH, Northshore Hospital; CVD, cardiovascular disease.

12.7% and 11.7% of patients had a prior history of depression or anxiety, and 12.2% and 4.3% were taking antidepressants/antipsychotics or benzodiazepines on admission.

Clinical presentation (Table 2)

The predominant symptom on admission was chest pain (80.2%), followed by dyspnoea (19%). 6.3% patients presented with new atrial arrhythmia (atrial fibrillation, n=34) and 2.5% patients presented with ventricular arrhythmias (ventricular tachycardia, n=8). Seventy-three patients had radiological evidence of pulmonary oedema on admission. A stressful trigger (defined as an unusual emotional or physical stress occurring before symptom onset) was identified in 73.7% patients. Emotional triggers were more frequent than physical triggers (62.9% and 37.1%, respectively). In 26.3% of patients, TS occurred without any evident trigger.

Table 2: Clinical presentation.

Values are n (%) unless otherwise stated.
*P-value excluded missing category
ACH, Auckland City Hospital; MMH, Middlemore Hospital; NSH, Northshore Hospital; CVD, cardiovascular disease IABP, intra-aortic balloon pump; CPAP, continuous positive airway pressure.

One-third of patients had ST-segment elevation on their admission ECG. ST-depression occurred only in 3.3% of patients with TS. More than half of the patients with TS had a significant reduction in left ventricular (LV) systolic function either on transthoracic echocardiography or left ventriculogram during the acute phase: 17.4% had low-normal LV function, 27.5% had mild LV impairment, and 55.1% had moderate/severe LV systolic impairment. Apical TS was identified in 84.7% of patients, whereas the midventricular form was found in 7.7%, and basal and focal forms were diagnosed in 2.4% and 5.3%, respectively. Right ventricular involvement was seen in only 17.1% of patients with TS. All patients underwent either invasive coronary angiography (n=603) or CT coronary angiography (n=29) during the acute admission: 55.5% of patients had normal coronary arteries.

On admission, 15.2% of the patients were taking beta-blockers, and 30.7% were taking either angiotensin-converting-enzyme inhibitors or angiotensin-receptor blockers. The rates of use of these two classes of drugs had increased at discharge (to 74.8% and 67.4%, respectively, Table 3).

Table 3: Medications on admission and on discharge.

ACH, Auckland City Hospital; MMH, Middlemore Hospital; NSH, Northshore Hospital; NOAC, non-vitamin K antagonist oral anticoagulants; ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blockers.
† Discharge medication for those patients discharged alive from index admission.

Of the 626 patients discharged alive, 91.4% underwent follow-up transthoracic echocardiography. Three died before having a follow-up transthoracic echocardiography. Eight percent of patients did not attend the follow-up echocardiography appointment. The median time of recovery imaging was 56 days (range 2–2,256 days, mean 105+198 days) from the day of index hospitalisation. Ninety-three percent of those who had echo (534/572) had full recovery of wall motion abnormalities and left ventricular function on echocardiography. One patient had worsening left ventricular function as a result of embolisation of ventricular thrombus into coronary artery. The remaining patients had persistent regional wall motion abnormalities and impaired left ventricular function but all had improved markedly compared to baseline studies.

In-hospital outcomes (Table 2)

During the index hospitalisation, 12% of patients had radiological evidence of pulmonary oedema on admission. Thirty patients were intubated, of whom three required intra-aortic balloon pump (IABP) insertion. Eight patients required continuous positive pressure airway (CPAP) ventilation. Fifteen patients with TS (2.4%) were in cardiogenic shock during the index admission. Six patients (1.0%) died during the index admission. Ninety-two patients (14.6%) had at least one of the in-hospital complications (defined as acute pulmonary oedema, cardiogenic shock, use of invasive or non-invasive ventilation or intra-aortic balloon pump insertion, or death).

Post-discharge outcomes (Figure 1 and 2, Table 4)

Six hundred and twenty-six patients were discharged alive after the index hospitalisation. The mean follow-up time was 4.9+3.4 years (median 4.4 years). 8.6% of the patients (54/626) died after hospital discharge, only one from cardiac causes. One patient developed heart failure as a result of embolisation of ventricular thrombus into coronary artery.

Figure 1: Kaplan-Meier curves showing post-discharge survival in Takotsubo patients.

Figure 2: Recurrence of Takotsubo syndrome post-discharge.

6.4% (40/626) of patients, all women, experienced recurrent TS, none of which were fatal. In 26 of the 40 patients with TS recurrence, the subsequent events involved stress triggers (physical triggers, n=5; emotional triggers, n=21). These 26 patients had their first recurrence of TS 23 days to 3,323 days after the initial event.

Comparison between hospitals

Demographic (Table 1)

The majority of TS cases were females in all hospitals and there were only minor differences in the mean age of patients. The distribution of patients by ethnicity was representative of New Zealand population without predominance of a particular ethnic group.

Cardiovascular risk factors

There were some relatively minor differences in the risk factors between the hospitals. There were more diabetes and smokers in Middlemore and Auckland whereas dyslipidaemia and hypertension were more common in Dunedin.

Psychiatric disorders

12.7% and 11.7% of patients had a prior history of depression or anxiety but this was more common in Christchurch patients (20.4% and 23.4%, respectively). The high prevalence of psychiatric disorders in Christchurch was also reflected by the fact that a substantial number of patients were taking antidepressants/antipsychotics (n=29) and benzodiazepines (n=11) on admission.

Clinical presentation (Table 2)

Chest pain was the predominant symptom on admission in all hospitals. The rates of preceding stressor, ST-elevation on admission ECG, clinical heart failure and moderate/severe LV systolic impairment were similar. The distribution of the type of TS was also similar among the hospitals.

Compared with pre-admission, there was a similar increase in prescribing of aspirin, beta-blocker, ACE inhibitors and statins on discharge in all hospitals (Table 3).

In-hospital outcomes (Table 2)

The rates of in-hospital complications among the hospitals did not differ significantly (p=0.37). The in-hospital mortality rate for TS patients is comparable among the five hospitals (p=0.73).

Post-discharge outcomes (Table 4)

There were no differences in the mortality (p=0.63) and recurrence risks (p=0.38) in TS patients after discharged among the five hospitals.

Table 4: Post-discharge outcomes.

Discussion

To our knowledge, this cohort is the largest series of TS patients published to date in Australasia and one of the largest internationally. Our series was similar to prior published series1,5,13,14 in terms of characteristics of the patient population. The distribution of patients by ethnicity was similar to that of New Zealand patient presenting with ACS without predominance of a particular ethnic group.15 There were no significant differences in the baseline demographics in TS patients among the five hospitals.

There was a high prevalence of depression and anxiety in our TS cohort. Of interest, the prevalence of depression and anxiety were higher in Christchurch. Following the major Christchurch and Kaikoura earthquakes, Christchurch Hospital has seen unprecedented case clusters of TS.10 Two extensive overviews of American TS cohorts found that anxiety and chronic stress were both associated with significantly higher odds of developing TS.16,17 Depression has also been reported to be associated with higher odds of developing TS.18 The increased prevalence of premorbid psychiatric diagnoses, particularly anxiety disorders and depression in TS patients suggests a potential link between neuropsychiatric disorders and TS. In particular, the Canterbury earthquakes had significant adverse impact on mental health, which could account for the high incidence observed.

A unique feature of TC is a preceding emotional or physical stressor, although in some cases, precipitant stressors have not been identified. Presentation was preceded by a physical or emotional stressor in two-thirds of our patients, but in the remaining third there was no identifiable pre-event stressor despite specific enquiry after the diagnosis was made. Emotional triggers were more frequent than physical triggers (62.9% and 37.1% respectively). Reassuringly, the rates of preceding stressor were similar among the five hospitals.

Patients with TS have an in-hospital mortality rate similar to that of patients with an MI.19 In addition, adverse events due to haemodynamic instability (eg, acute heart failure or cardiogenic shock) may occur in up to one-fourth of patients, even during the first hours after clinical onset. Almost 12% of our patients had pulmonary oedema at admission and there was a subset of patients who were critically ill at presentation requiring inotropic support, intubation and/or intra-aortic balloon pump. This finding was similar to the North American and European cohorts,20 illustrating the previously underestimated risk of complications during the acute phase of TS and highlights the need for concise clinical evaluation, monitoring and management. Despite the relatively high adverse events reported during the acute phase, the rates of in-hospital complications did not differ significant among the five hospitals.

Of the patients with TS discharged alive, 8.6% died during follow-up, with all but one of the 54 deaths from non-cardiac causes. This is consistent with other local and international studies which have reported that late mortality after TS is largely due to non-cardiac causes9,19,21,22 and appears to be related to the presence of comorbid disease rather than the TS event itself. Forty of our surviving patients experienced recurrent and remarkably similar TS episodes. There were no significant differences in the late mortality and recurrence rates for TS patients in our cohorts among the five hospitals, albeit with only small event rates.

There was no clear consensus about the appropriate treatment of patients with TS. New Zealand guidelines recommend routine post-discharge use of dual antiplatelet therapy, either clopidogrel or ticagrelor, statins, ACE inhibitors or ARB and beta blockers in patients without contraindications or intolerance after ACS presentations, with the aim of reducing further events.23,24 Because TS patients are frequently started on the same therapy on the basis of suspected ACS, there was marked increase in prescribing aspirin, beta-blocker, ACE inhibitors and statins on discharge among the five hospitals. To our knowledge, there are no data to support the use of particular medication regimens in patients with TS.

Study limitations

Despite prospectively capturing all patients presenting with TS in four major hospitals in New Zealand over 12 years, it is possible that some TS cases in the participating hospitals were not diagnosed, were hospitalised in other specialty departments, did not undergo catheterisation, which would imply underestimation of the true number of TS cases that occurred over the study period. However, it is likely that such cohort will continue to form an important source for research on TS in the future. In addition, we were unable to provide results of cardiac biomarkers such as troponin because of the different assays used in the different centres.

Conclusion

This study represents the largest TS cohort published to date in Australasia and also one of the largest internationally. Our clinical findings support previously published series. A subset of patients had a complicated in-hospital course but the in-hospital mortality for patients diagnosed with TS was similar among the five major hospitals. The late mortality and recurrence rates for TS patients who survived the index event also did not differ significantly among the hospitals. TS is a relatively recently described condition, its aetiology is poorly understood and it is probably still underdiagnosed.6 This cohort reassures us that TS presentations are similar across New Zealand and comparable to international experience. Establishment of this cohort will allow further investigation of this novel condition.

Summary

Abstract

Aim

Takotsubo syndrome (TS) mimics acute coronary syndrome but has a distinct pathophysiology. This study aimed to compare and contrast the clinical presentation, management and outcomes of patients with TS in five large New Zealand hospitals.

Method

We identified 632 consecutive patients presenting to the five major tertiary hospitals in New Zealand (Middlemore Hospital, Auckland City Hospital, North Shore Hospital, Christchurch Hospital and Dunedin Hospital) between January 2006 and June 2018 and obtained clinical, laboratory, electrocardiography, echocardiography, coronary angiography and long-term follow-up data.

Results

Six hundred and thirty-two consecutive patients with TS (606 women, mean age 65.0+11.1 years) were included. An associated stressor was identified in two-thirds of patients, and emotional triggers were more frequent than physical triggers (62.9% and 37.1%, respectively). Overall, 12.7% of patient had depression and 11.7% anxiety but this was more common in patients from Christchurch Hospital (20.4% and 23.4%, respectively). The in-hospital mortality among the five hospitals ranges between 0 to 2.0%. The mean follow-up was 4.9+3.4 years (median 4.4 years). Fifty-four people died post-discharge, all but one from a non-cardiac cause. Forty patients had recurrent TS. Mortality post-discharge (p=0.63) and TS recurrence (p=0.38) did not differ significantly among the five hospitals.

Conclusion

In this large New Zealand TS cohort, the clinical characteristics and presentation were similar among the five hospitals. A subset of patients had a complicated in-hospital course, but late deaths were almost all from non-cardiac causes and recurrence was infrequent. Mortality post-discharge and recurrence was similar between the hospitals.

Author Information

Jen-Li Looi, Department of Cardiology, Middlemore Hospital, Otahuhu, Auckland; Toby Verryt, Department of Cardiology, Christchurch Hospital, Christchurch; Peter McLeod, Department of Cardiology, Dunedin Hospital, Dunedin; Christina Chan, Department of Cardiology, Dunedin Hospital, Dunedin; James Pemberton, Department of Cardiology, Dunedin Hospital, Dunedin; Mark Webster, Green Lane Cardiovascular Service, Auckland City Hospital, Auckland; Andrew To, Cardiovascular Division, North Shore Hospital, Takapuna, Auckland; Mildred Lee, Department of Cardiology, Middlemore Hospital, Otahuhu, Auckland; Andrew J Kerr, Department of Cardiology, Middlemore Hospital, Otahuhu, Auckland.

Acknowledgements

Correspondence

Jen-Li Looi, Department of Cardiology, Middlemore Hospital, Private Bag 93311, Otahuhu, Auckland.

Correspondence Email

jenli.looi@middlemore.co.nz

Competing Interests

Nil.

1. 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.

2. Ghadri JR, Cammann VL, Napp LC, Jurisic S, Diekmann J, Bataiosu DR, et al. Differences in the Clinical Profile and Outcomes of Typical and Atypical Takotsubo Syndrome: Data From the International Takotsubo Registry. JAMA Cardiol. 2016; 1(3):335–40.

3. Bossone E, Erbel R. The “takotsubo syndrome”: from legend to science. Heart Fail Clin. 2013; 9(2):xiii–xv.

4. Parodi G, Del Pace S, Carrabba N, Salvadori C, Memisha G, Simonetti I, et al. Incidence, clinical findings, and outcome of women with left ventricular apical ballooning syndrome. Am J Cardiol. 2007; 99(2):182–5.

5. Bybee KA, Prasad A, Barsness GW, Lerman A, Jaffe AS, Murphy JG, et al. Clinical characteristics and thrombolysis in myocardial infarction frame counts in women with transient left ventricular apical ballooning syndrome. Am J Cardiol. 2004; 94(3):343–6.

6. Looi JL, Verryt T, McLeod P, Chan C, Pemberton J, Webster M, et al. Incidence of Takotsubo syndrome vs acute myocardial infarction in New Zealand (ANZACS-QI 45). N Z Med J. 2020; 133(1511):90–4.

7. Samuels MA. The brain-heart connection. Circulation. 2007; 116(1):77–84.

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