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BMJ Open Is Committed to Open Peer Review. As Part of This Commitment We Make the Peer Review History of Every Article We Publish Publicly Available BMJ Open: first published as 10.1136/bmjopen-2018-025253 on 5 May 2019. Downloaded from BMJ Open is committed to open peer review. As part of this commitment we make the peer review history of every article we publish publicly available. When an article is published we post the peer reviewers’ comments and the authors’ responses online. We also post the versions of the paper that were used during peer review. These are the versions that the peer review comments apply to. The versions of the paper that follow are the versions that were submitted during the peer review process. They are not the versions of record or the final published versions. They should not be cited or distributed as the published version of this manuscript. BMJ Open is an open access journal and the full, final, typeset and author-corrected version of record of the manuscript is available on our site with no access controls, subscription charges or pay-per-view fees (http://bmjopen.bmj.com). If you have any questions on BMJ Open’s open peer review process please email [email protected] http://bmjopen.bmj.com/ on October 2, 2021 by guest. Protected copyright. BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-025253 on 5 May 2019. Downloaded from Comparing the variants of takotsubo syndrome: an observational study of the electrocardiogram and structural changes. ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2018-025253 Article Type: Research Date Submitted by the Author: 05-Jul-2018 Complete List of Authors: Watson, George; Christchurch Hospital, Cardiology Chan, Christina; Christchurch Hospital, Cardiology Belluscio, Laura; Christchurch Hospital, Biostatistics Doudney, Kit; Canterbury District Health Board, Molecular Pathology Lacey, Cameron; Christchurch Hospital, Psychological Medicine Kennedy, Martin; University of Otago, Department of Pathology Bridgman, Paul; Christchurch Hospital, Cardiology Echocardiography < CARDIOLOGY, Heart failure < CARDIOLOGY, Keywords: Cardiomyopathy < CARDIOLOGY, Takotsubo http://bmjopen.bmj.com/ on October 2, 2021 by guest. Protected copyright. For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 9 BMJ Open 1 BMJ Open: first published as 10.1136/bmjopen-2018-025253 on 5 May 2019. Downloaded from 2 3 Comparing the variants of takotsubo syndrome: an observational study of the electrocardiogram 4 and structural changes. 5 a a b c d e a 6 Watson GM , Chan CW , Belluscio L , Doudney K , Lacey CJ , Kennedy MA , Bridgman PG * 7 8 9 10 a 11 Department of Cardiology, Christchurch Hospital, Christchurch, New Zealand 12 b Biostatistics, Christchurch Hospital, Christchurch, New Zealand 13 14 c Molecular Pathology Laboratory, Canterbury District Health Board, Christchurch, New Zealand 15 d 16 Department of PsychologicalFor peer Medicine, University review of Otago, Christchurch, only New Zealand 17 e Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch, 18 New Zealand. 19 20 21 22 * Corresponding author: Dr Paul G Bridgman, Department of Cardiology, Christchurch Hospital, 23 Christchurch, New Zealand, [email protected] 24 25 26 The authors report no conflicts of interest related to this work. 27 28 29 30 31 G Watson is a medical student and was supported by the Heart Foundation of New Zealand through 32 33 a University of Otago Summer Studentship. http://bmjopen.bmj.com/ 34 35 36 37 38 39 40 41 on October 2, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 9 1 BMJ Open: first published as 10.1136/bmjopen-2018-025253 on 5 May 2019. Downloaded from 2 3 Objectives: 4 5 In takotsubo syndrome, QTc prolongation is a measure of risk of potentially fatal arrhythmia. It is not 6 known how this risk, or derangement of other markers, differs across the echo variants of takotsubo 7 syndrome. As the region of affected myocardium is usually larger, we speculated that patients with 8 the classic apical-ballooning form of takotsubo syndrome would have more severe derangement of 9 their markers. Therefore, we sought to explore whether apical takotsubo syndrome differs from the 10 variants of the syndrome in more ways than just regional wall motion pattern. 11 12 Design: 13 14 Observational study of patients gathered from a prospective database (2010-2018) and by 15 retrospective review (2006-2009). 16 For peer review only 17 Setting: 18 The sole tertiary hospital for a region in which case clusters of takotsubo syndrome were 19 20 precipitated by large earthquakes in 2010, 2011, and 2016. 21 Participants: 22 23 222 patients who met a modified version of the Mayo criteria for takotsubo syndrome were 24 included. All patients had digitally archived echocardiograms that were over-read by a second 25 echocardiologist blinded to the clinical report. 26 27 Primary outcome measures: 28 29 Ejection fraction, peak troponin, and QT interval. 30 31 Results: 32 Patients with the apical form of the syndrome were older (p=0.011), had a lower initial LVEF (35% vs. http://bmjopen.bmj.com/ 33 44%, p<0.0001), and a higher peak hsTnI (p=0.01) than those with variant forms. There was no 34 35 difference in the electrical abnormalities between the variants (QTc interval, HR, PR interval, QRS 36 duration, or T-wave axis). There was also no correlation between any of peak hsTnI, peak QTc, and 37 ejection fraction. QTc interval increased on day two and peaked on day three before falling steeply 38 (p<0.0001). 39 40 Conclusions: 41 on October 2, 2021 by guest. Protected copyright. 42 The variants of takotsubo syndrome differ in more ways than just their echo pattern but do not 43 differ in their electrical abnormalities. There is a dissociation between the structural and electrical 44 abnormalities. QTc peaks on day 3 and then falls steeply. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 9 BMJ Open 1 BMJ Open: first published as 10.1136/bmjopen-2018-025253 on 5 May 2019. Downloaded from 2 3 Strengths and limitations of this study 4 5 - A key strength of this study is its size – it’s one of the largest studies to date in takotsubo 6 syndrome research. 7 - The dataset is remarkably complete. The lack of missing data allows for robust comparisons 8 9 and correlations and increases confidence in our conclusions. 10 - It is a weakness of our study that we did not include late imaging results or other modalities 11 such as MRI. 12 13 - Not all patients were followed up until QTc normalised – future studies should continue 14 serial recording of ECGs for a longer period to establish the later time course. 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40 41 on October 2, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 9 1 BMJ Open: first published as 10.1136/bmjopen-2018-025253 on 5 May 2019. Downloaded from 2 3 Introduction 4 5 There is widespread interest in the interaction between the mind and the body, and it is well 6 accepted that psychological factors influence physical illnesses. The purest example of psychological 7 stress causing a potentially fatal disease is takotsubo syndrome, also known as stress 8 cardiomyopathy. In this syndrome, the stress is typically acute and severe (and therefore readily 9 identifiable) and the symptoms can develop within moments. The incidence of takotsubo syndrome 10 is increasing, but it is agreed by experts that even in the most obvious of cases, we do not 11 understand how the psychological stress triggers the heart illness.1,2 Cardiologists have reported on 12 the wide range of psychological and physical triggers that can precipitate takotsubo syndrome and 13 14 recognise that there are variants within the syndrome. 15 The variants are defined by the specific pattern of wall-motion abnormality in the left ventricle. We 16 have noted how heterogeneousFor peer the clinical reviewpresentation of the conditiononly is and that different 17 18 subsets of patients can behave in different ways. Takotsubo syndrome has an early mortality rate 3 19 comparable to that of an acute coronary syndrome. Characterising the differing subsets will be 20 important in helping us move towards improved understanding of the condition and could lead to 21 better-tailored management of patients and perhaps insights into aetiology. Therefore, we sought to 22 explore whether the echocardiographic variants of the syndrome differ in more ways than just their 23 regional wall motion pattern. 24 25 In everyday clinical practice, clinicians use left ventricular ejection fraction (LVEF) as a measure of 26 risk and the degree of troponin elevation as an indicator of myocardial loss. Less widely recognised 27 in takotsubo syndrome is that QTc interval is a measure of risk of potentially fatal arrhythmia.4 It is 28 not known if this risk varies across the echo patterns of the condition or indeed if other clinical, 29 30 biochemical, and electrical features that cardiologists deal in vary between patterns either. As the 31 region of affected myocardium is usually larger, we speculated that patients with the classic apical- 32 ballooning form of takotsubo syndrome would have more severe derangement of their markers than 33 patients with one of the variant forms.
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