key: cord-0729267-1dyjtdhw
authors: Chang, Amanda; Wang, Yi Grace; Jayanna, Manju B.; Wu, Xiaodong; Cadaret, Linda M.; Liu, Kan
title: Mortality Correlates in Takotsubo Syndrome Patients during the COVID-19 Pandemic
date: 2021-09-29
journal: Mayo Clin Proc Innov Qual Outcomes
DOI: 10.1016/j.mayocpiqo.2021.09.008
sha: c03fc57149a24555d995860f79389ad7b55e8702
doc_id: 729267
cord_uid: 1dyjtdhw

We completed a systematic review of published Takotsubo syndrome (TTS) cases during COVID-19 pandemic and performed clustering and feature importance analysis, and statistical testing for independence on the demographic, clinical and imaging parameters. Compared with the data before the COVID-19 pandemic, TTS was increasingly diagnosed in physical stress (mostly COVID-19 pneumonia)-triggered male patients without psychiatric/neurologic disorders, warranting further investigation to establish new reference criteria to improve diagnostic specificity. In clustering analysis, the gender and in-patient mortality primarily contributed to the automated classification of the TTS. Both the gender and in-patient mortality showed significant correlations with COVID-19 infection/pneumonia. There is effect modification of gender on outcomes in patients with COVID-19 infection and TTS, with male patients having significantly worse inpatient mortality. Meanwhile, significantly more male TTS patients were classified as “high-risk” following InterTAK prognostic scores, suggestive of male COVID-19/TTS survivors will likely have worse long-term outcome.

The nature of the coronavirus disease 2019 (COVID-19) pandemic has increased physical and mental stress burden to an unprecedentedly large population of people (1) . While Takotsubo syndrome (TTS) has been increasingly reported during the COVID-19 pandemic, its presentation appears to diverge from the traditional archetype (2, 3) . Evidence is mounting that increased mortality rates are associated with patients with TTS and COVID-19 infection (4, 5) . In the present study, we completed a systematic review of published TTS cases during COVID-19 pandemic, and performed clustering and feature importance analysis on the demographic, clinical, and imaging parameters, aiming to characterize clinical/imaging features and identify mortality correlates.

We completed a systematic review of 123 TTS patients from 44 published case reports, 9 case series and 3 observational cross-sectional/cohort studies from April 1, 2020 to August 20, 2021 (PubMed). The authors, geographical, and demographic information were screened to confirm the onsets of TTS within COVID-19 pandemic time frame and avoid duplication (Supplemental table) . The COVID-19 infection was clarified to either be only positive for polymerase chain reaction test or have clinical and imaging evidence of pneumonia. In order to investigate the underlying intrinsic data structure, incorporate all features comprehensively, and elucidate factors contributing to categorization, we performed clustering analysis which categorizes objects into different groups so that objects in the same group are more similar than those in other groups. This method does not rely on manual selection of the grouping criterion and leads to objective output (6, 7) . In the present study, clustering analysis on the demographic, clinical, imaging, and inpatient mortality data of 59 patients with complete entries of all variables classified patients into two distinct groups. Given the clustering results, we applied feature importance analysis to find the most relevant feature(s) to the grouping. In other words, it is used to identify which feature(s) are most useful to determine the given grouping results. We validated the significance of the results by J o u r n a l P r e -p r o o f traditional statistical testing for independence (Fisher's exact test) for the same demographic, clinical, and imaging data of the studied patients.

The mean age of TTS patients was 67.3±14.0 years old, with 31.7% males. Figure 2A ). Overall 80.0% of mortality happened in either "very high risk" or "high risk" group predicted by their InterTAK diagnostic scores (8) . The male and female TTS patients also showed different risk distribution patterns following their InterTAK prognostic scores (8) ; there are significant gender differences in long-term prognosis prediction with regard to the risk groups (P = 0.03) ( Figure 2B ).

TTS and acute myocardial infarction (AMI) have distinctive pathophysiology and management strategies (9) (10) (11) . During the COVID-19 pandemic, TTS was increasingly found in patients diagnosed as AMI (12) .

It becomes more important than ever to effectively differentiate AMI and other "AMI-mimickers" for J o u r n a l P r e -p r o o f frontline disease triage, provider protection, and hospital capacity leverage. The updated guideline requires point-of-care ultrasound (POCUS) or bedside echocardiography to triage AMI patients suspected for COVID infection before cardiac catheterization (13) . Traditionally, TTS often happens in elderly women (particularly with psychiatric and neurologic disorders) triggered by mental stress, which forms the basis of the commonly used diagnostic score and criteria in pre-pandemic time to differentiate TTS and AMI (7) . Nonetheless, during the COVID-19 pandemic, TTS was increasingly reported in physical stress (mostly COVID-19 pneumonia)-triggered male patients without psychiatric/neurologic disorders (2, 4, Figure 1A) . Meanwhile, the atypical imaging features of TTS were frequently identified in bedside echocardiograms (2, 3, 14) . It becomes compelling to study and validate these atypical clinical and imaging phenotypes of TTS during COVID-19 pandemic across datasets from the global health resources/registries, in order to establish new reference criteria to improve diagnostic specificity and support goal-directed therapy (2, 5) .

The inpatient mortality of COVID-19 patients with TTS is much higher than its pre-pandemic mortality (10) . Although the exact pathologic role of TTS in adverse outcomes of COVID-19 patients remains poorly understood, TTS in many patients with COVID-19 infection is likely a unique illness severity marker. While not every COVID-19 infection will progress to pneumonia and systemic disorder, most of the patients with COVID-19 infection in our study (except for one symptomatic COVID patient) had associated pneumonia; this suggests that higher-risk COVID-19 patients are more likely to develop TTS compared to asymptomatic COVID-19 patients. The increased mortality could be (at least partially) attributed to a result of the inherently higher risk primary disease or the increased likelihood of concurrent systemic complications. From clustering and subsequent feature importance analysis by clustering results, gender and in-patient death principally contributed to automated classification of the TTS during COVID-19 pandemic ( Figure 1B ). Significant correlations of COVID-19 infection with both gender and inhospital mortality were also demonstrated by feature importance analysis ( Figure 1C ) and confirmed by Fisher's exact test (Table) .

The large-scale data has showed that there is no gender difference in the proportion of COVID-19 infected people. Instead, males are at a significantly higher disease severity and death rate than females (15) . Although overall COVID-19 patients with TTS presented higher in-patient mortality than COVID-19 patients without TTS (16) , our study also showed that male TTS patients had nearly 2.8-fold higher inpatient mortality compared to female TTS patients. There is effect modification of gender on outcomes in patients with COVID-19 infection and TTS, with male patients having significantly worse inpatient mortality (Figure 2A) . Moreover, following InterTAK prognostic scores (8), male and female TTS patients showed distinct future risk patterns, with significantly more males were classified in "very high risk" group ( Figure 2B ). Whether male COVID-19/TTS survivors will have more persistent myocardial injuries and worse long-term outcome needs longitudinal and prospective investigations. Nevertheless, our results highlight gender as an important TTS research variable during the COVID-19 pandemic.

The physical and mental stress has constantly increased during the COVID-19 pandemic, resulting in major neurological and psychiatric conditions even after COVID-19 infections (1, 16) . As a consequence, the increased incidence of TTS may possibly rise as a long-term sequalae (2, 5) . While the interplay between COVID-19 infection at acute presentation and potential hidden long-term effects remains a general curiosity, the investigation on TTS pathophysiology during and after COVID-19 pandemic may contribute to developing effective risk stratification and reduction strategies in future public health crisis. Since our study is limited by a relatively small sample size and incomplete data in some studied patients, further investigation on large-scale datasets is needed to validate the significance of atypical clinical phenotypes and elucidate novel prognostic makers during COVID-19 pandemic. Compared with the pre-pandemic data, TTS was significantly more frequently reported in physical stress-triggered male (37% vs. 4%; P <0.0001) patients without psychiatric/neurologic disorders (88% vs. 58%; P <0.0001). The inpatient mortality of COVID-19 patients with TTS was higher than that reported before the pandemic (23.3% vs. 4%; P < 0.0001). 

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