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The Authors' reply: In response to the valuable comments of John E Madias, we are pleased to share the results of the additional analysis on our recent study titled ‘Outcomes of catecholamine and/ or mechanical support in Takotsubo syndrome’. We hope that the journal readership finds the additional information helpful. Although the exact pathophysiological mechanisms of Takotsubo syndrome (TTS) are not completely understood, considerable evidence suggests that sympathetic stimulation is crucial to its pathogenesis. It has previously been postulated that the prevalence of diabetes mellitus (DM) in patients with TTS is lower than that in the general population. The implication of this is that DM exerts a ‘protective effect’ against the development of TTS, a phenomenon referred to as the ‘diabetes paradox’; however, DM is a risk factor for other cardiovascular diseases such as acute myocardial infarction and heart failure. We compared TTS data in our study with the data from other Japanese Registry of All Cardiac and Vascular Diseases (JROAD) studies and the Japanese Health and Nutrition Examination Survey (https://www.mhlw.go.jp/bunya/kenkou/ kenkou_eiyou_chousa.html (in Japanese)). In the cohort study of acute heart failure based on the JROAD, the mean age of patients was 81 years; 52% and 26% of patients had hypertension and diabetes, respectively. In the cohort study of acute myocardial infarction, the mean age of patients was 69 years; furthermore, 62% and 29% of patients had hypertension and diabetes, respectively. In our study, the mean age of patients with TTS was 75 years, and 42.0% and 14.1% of patients had hypertension and diabetes, respectively, suggesting that the incidence of diabetes is probably approximately half of that of other diseases. However, considering the higher prevalence of TTS among women (81% in our study) and the older mean age of the acute heart failure cohort, there are limitations to simply comparing these groups of patients with TTS. Additionally, we compared TTS data with data from the Japanese Health and Nutrition Examination Survey. The age and sex adjusted incidence of diabetes based on the Japanese Health and Nutrition data in 2016 was 17.8%; meanwhile, the incidence of diabetes was 14.1% among patients with TTS in our study, suggesting that the incidence of diabetes among patients with TTS may be lower than that in the general population. In a study that argued against the hypothesis that diabetes may have a protective effect on the development of TTS, 21.1% of patients with TTS had diabetes, which was slightly higher than the expected sexadjusted and ageadjusted rates in the general population of the participating countries (Italy and Germany). Stiermaier et al indicated that identification of diseases based on the International Classification of Diseases 10th Revision (ICD10) codes could underestimate the incidence of DM. As the ICD10 codes were also used in our study, it was considered necessary to be cautious in discussing the results. Considering that overactivation of sympathetic nerve activity plays a central role in the pathogenesis of TTS, diabetesinduced autonomic neuropathy may cause a disconnection between the brain and the heart, ameliorating or blocking the effects of unrestricted adrenergic storms on the heart and leading to the manifestation of TTS. Nevertheless, further research elucidating the protective effect of DM on the development of TTS is warranted.