With interest we read the review article by Sharma et al. about SARS-CoV-2 associated Takotsubo syndrome (TTS) in 27 patients [1]. It was found that TTS was complicated by cardiogenic shock, atrial fibrillation, heart failure, or supra-ventricular tachycardia in 12 patients and that 29 patients were discharged, three remained hospitalised, and four died [1]. It was concluded that high-risk patients with COVID-19 should be screened for TTS and that optimal treatment of TTS should include antiplatelet medication, statins, and beta-blockers [1].  We have the following comments and concerns. 

We do not agree with the notion that the review by Sharma et al, is the first ever systematic review about SARS-CoV-2 associated TTS. In a recent review article about the same topic 38 patients with SARS-CoV-2 associated TTS have been published as per the end of September 2020 [2]. A shortcoming of the study by Sharma et al. in this respect is that the time-point until which the search for articles was carried out was not provided. 

Missing in the review by Sharma et al. are the triggers of TTS in each of the 27 included patients. In one third of the cases TTS is triggered by psychological stress, in one third by physical stress, and in one third the cause remains elusive. Thus, we should be informed which triggers were responsible for the occurrence of TTS in each of the 27 patients.

Since autonomic cardiac denervation has been implicated in the pathogenesis of TTS, we should be told how many of the 27 included patients had autonomic neuropathy. Since one third of the patients had diabetes it and since diabetic neuropathy is frequently associated with affection of the autonomic fibers, it is conceivable that autonomic neuropathy played a pathophysiological role in the development of TTS, at least in patients with a history of diabetes in this respect it would be interesting to know the HbA1c vales of all 27 included patients. 

Since COVID-19 is frequently managed therapeutically with drugs that are potentially neurotoxic, such as chloroquine, hydro-chloroquine, azithromycin, lopinavir/ritonavir, tocilizumab, steroids, interferon-alpha, umifenovir, or favipiravir [3], we should be told which anti-COVID-19 drugs the 27 included patient received and it should be discussed if toxic neuropathy including autonomic fibers could has played a pathophysiological role in the development of TTS.

Since almost 10% of the included patients had a psychiatric illness, we should be told in how many of the 27 patients an acute psychosis was present or how many experienced an acute anxiety syndrome. Anxiety or psychosis should be considered as triggers of TTS.

Since COVID-19 can be complicated by multisystem disease, including the heart, we should be told how any of the 27 patients developed cardiac involvement in addition to TTS. Of particular interest is myocarditis, which has been repeatedly reported as a complication of COVID-19 and may be even implicated in the development of TTS. In this respect we should know in how many patients TTS was diagnosed upon echocardiography, in how many patients by cardiac MRI, and in how many patients by ventriculography. Among those undergoing cardiac MRI it would be interesting to know how many received contrast medium to see how often myocardial gadolinium enhancement, suggesting myocarditis, was found. We should be told if cardiac abnormalities in addition to TTS were attributable to TTS or rather due to cardiac complications of the viral infection.

We do not consent with the conclusions. Since the pathogenesis of TTS is non-vascular (coronary angiography is per definition normal), it is not comprehensible  why  TTS  patients should receive statins or antiplatelet drugs. Since TTS is associated with wall motion abnormalities, systolic dysfunction and occasionally ventricular arrhythmias [4], rather anticoagulation than antiplatelet treatment should be considered.   

Since onset of TTS may precede the onset of COVID-19 we should be told in how many of the 27 patients TTS occurred before clinical manifestations of COVID-19.

Overall, given the fact that the prevalence/incidence of TSS has not increased since the outbreak of the pandemic, a causal relation between COVID-19 and TTS is rather unlikely. Conceivable, however, is that psychosocial or physical stress due to the viral infection can secondarily trigger TTS. Premorbid conditions, such as autonomic neuropathy, cardiomyopathy, or myocarditis should be considered as pathophysiological contributors to the development of TTS.