Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621000635864
Ethics application status
Approved
Date submitted
12/04/2021
Date registered
27/05/2021
Date last updated
10/05/2024
Date data sharing statement initially provided
27/05/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Unravelling the Mechanisms Underpinning the Broken Heart Syndrome
Scientific title
Takotsubo cardiomyopathy: Truly a syndrome of cardiac catecholamine excess? Understanding the effects on cardiac sympathetic nerve activity.
Secondary ID [1] 303777 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Takotsubo Syndrome 321278 0
Condition category
Condition code
Cardiovascular 319055 319055 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
This study aims to (1) comprehensively assess the level of cardiac sympathetic nerve activity in patients presenting with Takotsubo syndrome (TS) in the acute phase (days 1-3 after presentation) and at 3 months of follow-up; (2) to investigate whether cardiac adrenaline co-transmission plays a pathophysiologic role in TS; and (3) to evaluate the temporal changes in indices of myocardial contractility between the acute phase (days 1-3 after presentation) and at
3-month follow-up.

All patients will undergo the following assessments at these time points:
Pathology (cardiac enzymes, full blood count, blood glucose, kidney function & hormone profile): Baseline and 6 months.
Electrocardiogram: Baseline and 6 months
Transthoracic echocardiography: Baseline and 6 months
Coronary angiography and ventriculography: Baseline
Cardiac catheterisation: Within 1-3 days of presentation
18-FDG-PET/CT scan: Baseline and 6 months
Cardiac MRI: Within 1-3 days of presentation
Microneurography: Within 1-3 days of presentation and 6 months
Quality of Life Questionnaires: Baseline and 6 months.
Intervention code [1] 320085 0
Not applicable
Comparator / control treatment
Patients who present with symptoms of Takotsubo Syndrome, but who are later confirmed not to have the condition will be invited to undergo testing as per the study protocol and to serve as a comparator group.
Control group
Active

Outcomes
Primary outcome [1] 327143 0
Cardiac sympathetic nerve activity in patients presenting with Takotsubo Syndrome will be assessed following infusion of tritium labelled adrenaline during the diagnostic coronary angiogram. Cardiac catheterisation of the coronary sinus will be performed and blood samples collected for measurement of adrenaline/noradrenaline spillover.
Timepoint [1] 327143 0
Once at the acute (days 1 to 7 after presentation) and peri-acute phase (~4 weeks after presentation).
Secondary outcome [1] 393951 0
Cardiac arendaline co-transmission will be assessed via central sympathetic outflow innervating the peripheral vascular bed, measured using microneurography. This involves percutaneous insertion of a tungsten microelectrode in the motor fibre of the right peroneal nerve to measure continuous spontaneous sympathetic nerve activity. When combined with the cardiac spillover measurements (measured as the primary outcome), this will allow determination of cardiac adrenaline co-transmission.
Timepoint [1] 393951 0
Once at the acute (days 1 to 3 after presentation) and once at the peri-acute phase (~4 weeks after presentation).
Secondary outcome [2] 395457 0
Temporal changes in indices of myocardial contractility as assessed by cardiac MRI and associated pathology of cardiac biomarkers.
Timepoint [2] 395457 0
Once at the acute (days 1 to 3 after presentation), once at the peri-acute phase (~4 weeks after presentation) and once at the long-term (6 months).
Secondary outcome [3] 395700 0
Quality of Life will be assessed through use of validated quality of life questionnaires. These include:
SF-36
BDII
STAI Form Y-1
STAI Form X-2
Timepoint [3] 395700 0
Once at baseline (within 1-3 days of presentation) and once at 3 months after presentation.

Eligibility
Key inclusion criteria
Patients presenting with symptoms indicative of Takotsubo Syndrome per diagnostic criteria, including acute cardiac chest pain and/or shortness of breath will have routine investigations including ECG, high sensitivity troponin levels, BNP/NT pro-BNP and trans thoracic echocardiogram. Those who fulfil the inclusion criteria of (1) typical clinical symptoms, (2) relevant electrographic changes and cardiac biomarker profile consistent with Takotsubo Syndrome and (3) relevant echocardiographic characteristics, will be enrolled in the study. Diagnosis criteria is per HF Association diagnostic criteria and includes:
(1) transient regional wall motion abnormalities of LV or right ventricle myocardium which are frequently but not always preceded by a stressful trigger;
(2) the regional wall motion abnormalities usually extend beyond a single epicardial vascular distribution and often results in circumferential dysfunction of the ventricular segment
involved;
(3) the absence of culprit atherosclerotic CAD including acute plaque rupture, thrombus
formation and coronary dissection or other pathological conditions to explain the pattern of temporary LV dysfunction observed (e.g. hypertrophic cardiomyopathy, viral myocarditis);
(4) new and reversible electrocardiography (ECG) abnormalities (ST-segment elevation, ST-depression, LBBB, T-wave inversion and/or QTc prolongation) during the acute phase (less than 3 months);
(5) significantly elevated BNP or NT-proBNP during the acute phase;
(6) positive but relatively small elevation in cardiac troponin measured with a conventional assay (i.e. troponin negative levels is possible);
(7) recovery of ventricular systolic dysfunction on cardiac imaging at follow-up (after 3 months).
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
In ~25% of patients, significant coronary artery disease will be detected and account for their symptoms. If a coronary artery stenosis is detected during coronary angiography, percutaneous coronary interventions if required, will be performed as deemed appropriate by
the treating physician and management and follow up arranged as per standard guidelines. If deemed safe by the interventional cardiologist, these patients may still undergo cardiac NA/A spillover assessment and will serve as a “control group” for those with Takotsubo Syndrome. If not, they will be excluded from the study.

Study design
Purpose
Screening
Duration
Longitudinal
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
The primary endpoint is the presumed difference in cardiac NA spillover between the Takotsubo Syndrome (TS) and the “control” group, i.e. those patients whose presentation is explained by coronary artery pathology. We expect cardiac NA spillover to be at least 30% higher than in non-TS patients (who still are likely to have some degree of compensatory cardiac sympathetic activation) in whom the correlate of symptoms is coronary artery disease. Our previous data demonstrated that cardiac NA spillover ranges between 5-12±6ng/min in healthy controls, between 12-20±10ng/min in hypertensives and around 26-32±10ng/min in heart failure. Our sample size calculations are based on a 10ng/min difference (conservative
estimate of maximum of 30ng/min in non-TS and 40ng/min in TS) in cardiac NA spillover at presentation. A sample size of 30 patients in each group would have 90% power to detect this difference at a two-sided significance level of 0.05 and an estimated standard deviation of 12ng/min. To account for an estimated 20% dropout rate (i.e. technical or sampling issues, loss to follow up) we plan to recruit a total of n=80 patients, assuming ~75% of this pre-selected cohort will have TS and 25% other pathology. The absolute number of patients will be higher in the TS group, in which we also anticipate higher variability in NA spillover compared to non-TS. This number is achievable and will allow adequate analysis of all parameters to be assessed. Within the TS group, in which we anticipate to see a reduction but not necessarily normalization of cardiac NA spillover at 4-6 weeks follow-up, inclusion of ~60 TS patients
would have 90% power to detect a decrease in cardiac NA spillover by 15ng/min at a two-sided significance level of 0.05 and an estimated standard deviation of 15ng/min. The change in variables between the two groups and the change in variables within each group will be analysed by linear mixed models analysis. The relationships between variables will be evaluated by Pearson’s and Spearman’s rank correlations. Stepwise regressions will be performed with those univariate correlations where P<0.05. Statistical significance will be accepted at a two-sided P value <0.05.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/06/2022
Actual
16/03/2023
Date of last participant enrolment
Anticipated
31/12/2024
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
80
Accrual to date
4
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 19087 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [2] 19088 0
Royal Perth Hospital - Perth
Recruitment postcode(s) [1] 33644 0
6150 - Murdoch
Recruitment postcode(s) [2] 33645 0
6000 - Perth

Funding & Sponsors
Funding source category [1] 308179 0
Charities/Societies/Foundations
Name [1] 308179 0
National Heart Foundation of Australia
Country [1] 308179 0
Australia
Funding source category [2] 308310 0
Charities/Societies/Foundations
Name [2] 308310 0
Spinnaker Health Research Foundation
Country [2] 308310 0
Australia
Primary sponsor type
Individual
Name
Prof Markus Schlaich
Address
Dobney Hypertension Centre
Medical School, University of Western Australia
Level 3, MRF Building, Rear 50 Murray Street
Perth WA 6000
Country
Australia
Secondary sponsor category [1] 309119 0
None
Name [1] 309119 0
Address [1] 309119 0
Country [1] 309119 0
Other collaborator category [1] 281730 0
Hospital
Name [1] 281730 0
Fiona Stanley Hospital
Address [1] 281730 0
Barry Marshall Parade
Murdoch WA 6150
Country [1] 281730 0
Australia
Other collaborator category [2] 281731 0
Hospital
Name [2] 281731 0
Royal Perth Hospital
Address [2] 281731 0
Wellington Street
Perth WA 6000
Country [2] 281731 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308164 0
South Metropolitan Health Service
Ethics committee address [1] 308164 0
Ethics committee country [1] 308164 0
Australia
Date submitted for ethics approval [1] 308164 0
Approval date [1] 308164 0
17/12/2020
Ethics approval number [1] 308164 0
RGS0000003437

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 109762 0
Prof Markus Schlaich
Address 109762 0
Dobney Hypertension Centre
Medical School, University of Western Australia
Level 3, Medical Research Foundation BUilding
Rear 50 Murray Street
Perth WA 6000
Country 109762 0
Australia
Phone 109762 0
+61 08 9224 0382
Fax 109762 0
Email 109762 0
[email protected]
Contact person for public queries
Name 109763 0
Markus Schlaich
Address 109763 0
Dobney Hypertension Centre
Medical School, University of Western Australia
Level 3, Medical Research Foundation BUilding
Rear 50 Murray Street
Perth WA 6000
Country 109763 0
Australia
Phone 109763 0
+61 08 9224 0382
Fax 109763 0
Email 109763 0
[email protected]
Contact person for scientific queries
Name 109764 0
Markus Schlaich
Address 109764 0
Dobney Hypertension Centre
Medical School, University of Western Australia
Level 3, Medical Research Foundation BUilding
Rear 50 Murray Street
Perth WA 6000
Country 109764 0
Australia
Phone 109764 0
+61 08 9224 0382
Fax 109764 0
Email 109764 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
All data will be de-identified prior to publication. Access to identified patient data will need to be requested via the PI and the supporting HREC committees. De-identified data will only be provided when required to by law.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.