Incidence of Stress Cardiomyopathy During the Coronavirus Disease 2019 Pandemic

Key Points Question Is psychological, social, and economic stress associated with coronavirus disease 2019 (COVID-19) associated with the incidence of stress cardiomyopathy? Findings This cohort study included 1914 patients with acute coronary syndrome to compare patients presenting during the COVID-19 pandemic with patients presenting across 4 timelines prior to the pandemic and found a significantly increased incidence of 7.8% of stress cardiomyopathy during the COVID-19 pandemic, compared with prepandemic incidences that ranged from 1.5% to 1.8%. Meaning These findings suggest that psychological, social, and economic stress related to the COVID-19 pandemic was associated with an increased incidence of stress cardiomyopathy.

Meaning These findings suggest that psychological, social, and economic stress related to the COVID-19 pandemic was associated with an increased incidence of stress cardiomyopathy.

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Introduction
The World Health Organization has declared coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2, a global pandemic. As of June 2020, nearly 8.5 million infections have been reported worldwide, resulting in approximately 450 000 deaths in more than 200 countries and territories. The effect of COVID-19 has extended beyond health care, having significant social, economic, and cultural ramifications. The global effects of the virus have been linked with increasing stress and anxiety worldwide. 1 Recently, clinicians have reported a rise in stress cardiomyopathy (also known as Takotsubo syndrome) worldwide during the COVID-19 pandemic. 2,3 This observation warrants further investigation to unravel a plausible pathogenic mechanism associated with COVID-19 causing Takotsubo syndrome-like cardiomyopathy vs a true increase in its incidence due to the associated psychological, social, and economic stress with imposed quarantine, lack of social interaction, strict physical distancing rules, and its economic consequences in people's lives. Our study investigated the incidence of stress (ie, Takotsubo) cardiomyopathy during the COVID-19 pandemic in comparison with its incidence in historical cohorts, its association with the viral infection, and related outcomes.

Methods
This cohort study was approved by the institutional review board at Cleveland Clinic. A waiver of informed consent was granted because of minimal risk exposure to patients per Cleveland Clinic policy. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

Study Population
We retrospectively analyzed the electronic medical records of all patients presenting with acute coronary syndrome (ACS) (ie, ST-segment elevation myocardial infarction, non-ST-segment elevation myocardial infarction, and unstable angina) during March 1 to April 30, 2018, January 1 to February 28, 2019, March 1 to April 30, 2019, and January 1 to February 29, 2020, as our control groups, as well as March 1 to April 30, 2020, as our study group of patients who presented during the COVID-19 pandemic. All procedures were performed at 2 hospitals in the Cleveland Clinic health system in Northeast Ohio: Cleveland Clinic Main Campus (Cleveland, Ohio) and Cleveland Clinic Akron General (Akron, Ohio). The incidence of stress cardiomyopathy was measured and compared across timelines.

Diagnostic Criteria
Stress cardiomyopathy was diagnosed in accordance with the international Takotsubo syndrome diagnostic criteria in 2014 (ie, InterTAK diagnostic criteria). 4 The criteria include transient left ventricular dysfunction presenting as apical ballooning or midventricular, basal, or focal wall-motion

JAMA Network Open | Cardiology
Incidence of Stress Cardiomyopathy During the Coronavirus Disease 2019 Pandemic anomalies; an emotional, physical, or combined trigger may precede the disease onset (but is not obligatory); neurological disorders, as well as pheochromocytoma, may serve as triggers; new electrocardiographic anomalies are present (eg, ST-segment elevation, ST-segment depression, T wave inversion, and QTc prolongation); moderate elevation in cardiac biomarker levels (eg, troponin and creatine kinase) and significant elevation of brain natriuretic peptide; no evidence of myocarditis; and significant coronary artery disease may coexist. Findings on 12-lead electrocardiography, coronary arteriography, and echocardiography were interpreted and reported by Cleveland Clinic cardiologists. Clinical outcomes recorded in patients with stress cardiomyopathy included cardiac arrhythmias, hospital length of stay, 30-day rehospitalization, and overall mortality.

Laboratory Confirmation
Testing for COVID-19 was performed using reverse transcription-polymerase chain reaction (RT-PCR), with samples collected from nasopharyngeal and throat swabs. COVID-19 testing in the study group was performed in patients meeting the previously published Cleveland Clinic COVID-19 testing criteria. 5 All patients with stress cardiomyopathy in the study group were tested for COVID-19.

Statistical Analysis
After assessing the distribution, continuous data were presented as medians and interquartile ranges (IQRs), and nominal data were presented as proportions. Continuous data across groups were compared using Kruskal-Wallis rank sum test, while categorical data were compared using Pearson χ 2 test. The rate of stress cardiomyopathy among the pandemic and prepandemic periods was modeled using a Poisson regression model adjusting for overdispersion with a scale parameter. While each of the intervals studied was a 2-month period, the number of patients presenting with ACS and undergoing coronary arteriography differed among them. Thus, the number of patients served as an offset term (log transformed). Adjusted Wald method was used to compute 95% CIs of proportions.
P values were 2-sided, and P < .05 was considered statistically significant. All statistical analyses were conducted in R statistical software version 3.6.2 (R Project for Statistical Computing). Data were analyzed from May to June 2020. pandemic were negative for COVID-19. There was a significant increase in the incidence of stress cardiomyopathy in patients presenting with ACS during the COVID-19 period, with a total of 20 patients (incidence proportion, 7.8%) compared with the pre-COVID-19 timelines, which ranged from 5 to 12 patients (incidence proportion range, 1.5%-1.8%) (Figure). Comparing the COVID-19
Adjusted rate ratios were similar in magnitude.      March-April 2020 indicates the coronavirus pandemic period; dots, proportions calculated by adjusted Wald method; error bars, 95% CIs.

Discussion
To our knowledge, this cohort study is the first study to systematically investigate the association of the incidence of stress cardiomyopathy with the psychological, social, and economic stress associated with the COVID-19 pandemic. The principal finding of our analysis provides an insight into the increasing incidence of stress cardiomyopathy during the pandemic. The incidence of stress cardiomyopathy was significantly higher in patients presenting with ACS between March 1 and April 30, 2020, compared with 4 control groups across prepandemic timelines. The incidence of stress cardiomyopathy in the control groups was similar to that reported in the literature, ranging from 1.0% to 2.0% in patients presenting with acute myocardial infarction. [6][7][8] The study group outcomes were similar to the control group with regard to mortality and 30-day rehospitalization. However, patients with stress cardiomyopathy hospitalized during the pandemic had a significantly longer hospital length of stay.
The association between stress cardiomyopathy and increasing levels of stress and anxiety has long been established. 4 The psychological, social, and economic distress accompanying the pandemic, rather than direct viral involvement and sequelae of the infection, are more likely factors associated with the increase in stress cardiomyopathy cases. This was further supported by negative COVID-19 testing results in all patients diagnosed with stress cardiomyopathy in the study group.
There may still be an association of COVID-19 with Takotsubo-like cardiomyopathy. Few patients with Takotsubo syndrome with underlying COVID-19 have been reported in the literature. 2,3 The mechanism behind this type of myocardial injury in patients with COVID-19 remains to be elucidated.

Limitations
This study has some limitations. While our study examined patients from 2 hospitals within our health system, our sample represents the population of Northeast Ohio in the US. The results should be interpreted with caution when applied to other states or countries. Further research must examine the association of COVID-19 with the incidence of stress cardiomyopathy and study any temporal or regional differences. In addition, it is plausible that patients with ACS chose to avoid visiting a hospital facility amidst a pandemic, resulting in a sampling bias. Our study is also limited by the type of COVID-19 testing performed: RT-PCR is limited in its sensitivity (79%). 9 This may have resulted in false-negative tests for our study group. However, none of the patients diagnosed with stress cardiomyopathy in the study group reported any symptoms suggestive of COVID-19-related illness.

Conclusions
This cohort study found a significant increase in the incidence of stress cardiomyopathy during the COVID-19 pandemic. In addition, no patients with stress cardiomyopathy were found to have COVID-19, suggesting an indirect, psychological, social, and economic pandemic-related stress mechanism behind the disease process.