COVID-19 With Stress Cardiomyopathy Mortality and Outcomes Among Patients Hospitalized in the United States: A Propensity Matched Analysis Using the National Inpatient Sample Database

Abstract

Takotsubo syndrome (stress cardiomyopathy) has become a well-known complication of COVID-19 infections, with limited large-scale studies evaluating outcomes. We used the National Inpatient Sample (NIS) database to compare COVID-19 patients with and without stress cardiomyopathy. A total of 1,659,040 patients were included in the study: COVID-19 with stress cardiomyopathy (n = 1665, 0.1%) and COVID-19 without stress cardiomyopathy (n = 1657, 375, and 99.9%). The primary outcome was in-hospital mortality, with secondary analysis with propensity matching performed to confirm results from traditional multivariate analysis. COVID-19 patients with stress cardiomyopathy had significantly increased in-hospital mortality compared to COVID-19 patients without stress cardiomyopathy (32.8% vs 14.6%, adjusted OR [aOR]: 2.3 [95% CI, 1.2-4.5], P = 0.01) along with significantly increased mechanical ventilation and vasopressor support, hospitalization charge, acute kidney injury requiring hemodialysis, cardiogenic shock, and cardiac arrest. These results emphasize the need for more research to reduce worse outcomes with COVID-19-related stress cardiomyopathy patients.

Introduction

Severe Acute Respiratory Virus Syndrome Coronavirus 2 (SARS-CoV-2) is the virus underlying the Coronavirus-19 (COVID-19) pandemic, which has affected millions of people around the world since it was first detected in Wuhan, China in December of 2019.^{1 , 2} While COVID-19 primarily has respiratory manifestations, it is a multi-organ disease with known cardiovascular complications, including stress cardiomyopathy, pericarditis, myocarditis, myocardial infarction, congestive heart failure, and arrhythmias.³ Cardiovascular involvement is appreciated in 20%-30% of COVID-19 patients and is associated with increased morbidity and mortality.^{4 , 5} Stress cardiomyopathy (Takotsubo Syndrome), specifically, has been associated with worse clinical outcomes in COVID-19 patients⁶; however, large-scale studies evaluating outcomes are limited.

The association between stress cardiomyopathy and COVID-19 infection has been noted in several studies in light of its increased incidence during the pandemic.6, 7, 8, 9 Stress cardiomyopathy, which is part of Takotsubo syndrome and is also known as apical ballooning syndrome or broken heart syndrome, refers to an acute, segmental ventricular dysfunction typically in a non-coronary arterial distribution commonly observed after severe physical or emotional distress.⁶ The pathophysiology underlying stress cardiomyopathy among hospitalized COVID-19 patients is not well characterized; it is hypothesized to stem from a catecholamine surge in response to a COVID-19 mediated cytokine storm.9, 10, 11, 12 The intense overstimulation of myocardial tissue by epinephrine, norepinephrine, and dopamine results in myocardial stunning and injury thereby reducing cardiac contractility.13, 14, 15 There is also a possible contribution from psychosocial and economic stressors driven by the global pandemic.

The objective of our study was to assess clinical outcomes of stress cardiomyopathy among hospitalized COVID-19 patients during the early pandemic by utilizing data from the National Inpatient Sample (NIS) database.¹⁶ We did this by comparing outcomes between a cohort of COVID-19 patients with stress cardiomyopathy and a cohort of COVID-19 patients without stress cardiomyopathy. Our primary outcome was in-hospital mortality. Secondary outcomes included length of stay (LOS), cost of hospitalization, cardiac arrest, progression to acute decompensated heart failure, mechanical ventilatory dependence, cardiogenic shock, vasopressor and inotrope use, acute kidney injury (AKI) requiring renal replacement therapy, and disposition at discharge.

Methods

This retrospective study utilized the Agency for Healthcare and Research and Quality (AHRQ) sponsored NIS Healthcare Cost Utilization Project (HCUP) database, which is an all-payer database that approximates a 20% stratified sample of discharges from US community hospitals.¹⁶ Specifically, this analysis used the 2020 NIS dataset, which included hospitalization from January 1, 2020, to December 31, 2020, and was made available to the public in October of 2022. The NIS database contains data regarding in-hospital outcomes, procedures, and other discharge-related information.

All patients 18 years of age and older and admitted to the hospital with COVID-19 infection were included in this study. Patients were then divided into 2 cohorts based on the presence of stress cardiomyopathy. International classification of diseases 10th – clinical modification (ICD-10-CM) codes were used to retrieve patient samples with comorbid conditions, and ICD-10 procedure codes were used to identify inpatient procedures. A detailed code summary is provided in Supplemental Table 1. Patients who were under the age of 18 years or were transferred out of the index hospital were excluded from our study.

Baseline Characteristics

• 1.Patient-related: age, race, sex, insurance status, mean income based on zip code, medical comorbidities, and Elixhauser Comorbidity Index.¹⁷
• 2.Hospital-related: geographic division, teaching status, and size.

Study Outcomes

The primary outcome was in-hospital mortality. Secondary outcomes included length of stay, cost of hospitalization, incidence of cardiac arrest, progression to acute decompensated heart failure, mechanical ventilatory dependence, incidence of cardiogenic shock, vasopressor and inotrope dependence, mechanical circulatory support (LVAD or pVAD or ECMO), acute kidney injury (AKI) requiring renal replacement therapy, incidence of left ventricular thrombus, and disposition at discharge.

Statistical Methods

Descriptive statistics were used to summarize continuous and categorical variables. Continuous variables were summarized as mean ± SD; categorical data as number and percentage. Univariate analyses for between-group comparisons used the Rao-Scott Chi-square test for categorical variables (eg sex and risk factors) and weighted simple linear regression for continuous variables (eg age). On an unmatched sample, univariate regression was used to identify independent variables (P ≤ 0.2), which were utilized to build a multivariate regression model. As our control group (COVID-19 patients without stress cardiomyopathy) had a significantly larger sample than the test group (COVID-19 patients with stress cardiomyopathy) we conducted a secondary analysis with propensity score matching (PSM) to confirm the results obtained by traditional multivariate analysis. Baseline demographic data (age, race, sex, mean income, and insurance status) were matched using a 1:1 nearest neighbor propensity score with a 0.05 caliper width. On matched cohorts, a secondary multivariate regression model was built as described above. All analysis was performed using Stata 90 software version 17.0 (Stata Corporation, College Station, TX, U.S.A.). P-values of less than 0.05 were considered statistically significant.

Results

Baseline Characteristics

A total of 1,659,040 patients were hospitalized with COVID-19 infection between January 1, 2020 and December 31, 2020. Of these, 1665 (0.1%) patients had concomitant stress cardiomyopathy. We found that among COVID-19 patients, stress cardiomyopathy was more prevalent among females (62.2% vs 47.9%, P < 0.001), Caucasians (59.9% vs 50.9%, P = 0.03), Asians (4.9% vs 3.3%, P = 0.03), patients ages 50-69 years (38.4% vs 37.2%, P < 0.001), and patients ages 70 years and older (52.9% vs 41.0%, P < 0.001). COVID-19 patients with stress cardiomyopathy were more likely to have household incomes between 50,000 and 64,999 USD (29.1% vs 27.2%, P = 0.01), between 65,000 and 85,999 USD (25.7% vs 22.2%, P = 0.01), and greater than 86,000 USD (19.9% vs 16.5%, P = 0.01) as well as a higher proportion of Medicare beneficiaries (65.2% vs 53.2%, P = 0.000) when compared to COVID-19 patients without stress cardiomyopathy (Table 1 ). While there was variability in the geographic distribution of patients, most COVID-19 patients, both with and without stress cardiomyopathy, were admitted to urban teaching hospitals (80.5% and 71.5%, respectively, P = 0.002). The baseline characteristics of both study cohorts are outlined in Table 1.

Table 1.

COVID-19 and stress cardiomyopathy - unmatched patient-level characteristics

Characteristics	COVID 19 patients with stress cardiomyopathy	COVID 19 patients without stress cardiomyopathy	P value
N = 1,659,040	N = 1665 (0.001)	N = 1,657,375 (99.89%)
SEX (Female)	62.16%	47.93%	<0.001
Mean age years (SD)			<0.001
Male	63.52 (14.4)	63.42 (16.29)
Female	71.34 (12.1)	63.05 (18.85)
AGE GROUPS			<0.001
≥18-29	1.2%	4.94%
30-49	7.51%	16.81%
50-69	38.44%	37.23%
≥70	52.85%	41.01%
RACE			0.027
Caucasians	59.94%	50.9%
African American	12.54%	19.06%
Hispanics	19.88%	21.47%
Asian or Pacific Islander	4.89%	3.25%
Native American	-	1.03%
Others	2.75%	4.29%
MEDIAN HOUSEHOLD INCOME			0.009
<49,999$	25.38%	34.13%
50,000 – 64,999$	29.05%	27.2%
65,000 – 85,999$	25.69%	22.16%
>86,000$	19.88%	16.52%
INSURANCE STATUS			<0.001
Medicare	65.2%	53.22%
Medicaid	10.97%	15.16%
Private	21.32%	27.65%
Self-pay	2.51%	3.96%
HOSPITAL DIVISION			<0.001
New England	7.81%	3.79%
Middle Atlantic	15.02%	14.61%
East North Central	19.52%	15.54%
West North Central	9.91%	6.74%
South Atlantic	17.12%	20.08%
East South Central	2.4%	6.72%
West South Central	7.51%	14.33%
Mountain	7.21%	6.91%
Pacific	13.51%	11.29%
HOSPITAL BEDSIZE			0.001
Small	18.92%	24.33%
Medium	24.02%	28.99%
Large	57.06%	46.67%
HOSPTAL TEACHING STATUS			0.002
Rural	6.31%	9.81%
Urban nonteaching	13.21%	18.66%
Urban teaching	80.48%	71.53%

COVID-19 patients with stress cardiomyopathy were more likely to have pre-existing chronic pulmonary disease (31.5% vs 22.0%, P < 0.001), metastatic cancer (2.4% vs 1.1%, P = 0.02), coronary artery disease (31.2% vs 17.9%, P < 0.001), and remote myocardial infarction (8.1% vs 4.2%, P < 0.001) when compared to COVID-19 patients without stress cardiomyopathy. COVID-19 patients with stress cardiomyopathy also had less pre-existing hypertension (28.5% vs 38.1%, P < 0.001), obesity (20.7% vs 25.6%, P = 0.048), obstructive sleep apnea (4.8% vs 8.2%, P = 0.02), and remote coronary artery bypass grafting (1.5% vs 3.5%, P = 0.048) when compared to COVID-19 patients without stress cardiomyopathy. There was no significant differences with respect to alcohol use, smoking, and incidence of diabetes mellitus, chronic kidney disease, or remote percutaneous coronary interventions between the 2 cohorts (Supplemental Table 2).

After propensity-matching for patient age, sex, race, and mean income there were 1540 patients in each cohort of COVID-19 patients (with stress cardiomyopathy and without stress cardiomyopathy). The baseline characteristics for the propensity-matched cohorts are included in Table 2 .

Table 2.

COVID-19 and stress cardiomyopathy propensity 1:1 matched patient-level characteristics

Characteristics	COVID 19 patients with stress cardiomyopathy	COVID 19 patients without stress cardiomyopathy	P value
N = 3080	N = 1540	N = 1540
SEX (Female)	64.61%	64.61%	1.0
Mean age years (SD)	68.95 (7.01)	68.94 (7.0)	0.990
AGE GROUPS			1
≥18-29	0.65%	0.65%
30-49	7.14%	7.14%
50-69	37.99%	37.99%
≥70	54.22%	54.22%
RACE			0.999
Caucasians	61.36%	61.36%
African American	12.34%	12.34%
Hispanics	19.48%	19.81%
Asian or Pacific Islander	4.55%	4.22%
Native American	2.27%	2.27%
MEDIAN HOUSEHOLD INCOME			0.999
<49,999$	25%	25%
50,000 – 64,999$	29.22%	29.22%
65,000 – 85,999$	25.32%	25%
>86,000$	20.45%	20.78%
INSURANCE STATUS			0.999
Medicare	64.94%	65.26%
Medicaid	10.71%	10.71%
Private	21.75%	21.43%
Self-pay	2.6%	2.6%
HOSPITAL DIVISION			<0.001
New England	7.79%	85.06%
Middle Atlantic	15.91%	12.99%
East North Central	18.83%	0.97%
West North Central	10.39%	-
South Atlantic	17.21%	0.32%
East South Central	2.6%	0.32%
West South Central	6.49%	-
Mountain	7.14%	-
Pacific	13.64%	0.32%
HOSPITAL BEDSIZE			<0.001
Small	19.48%	34.42%
Medium	24.35%	35.06%
Large	56.17%	30.52%
HOSPTAL TEACHING STATUS			0.079
Rural	6.17%	3.9%
Urban non-teaching	13.96%	8.12%
Urban teaching	79.87%	87.99%

In-hospital Mortality

After propensity-matching for patient age, sex, race, and mean income, we found that the in-hospital mortality was significantly higher among COVID-19 patients with stress cardiomyopathy in comparison to COVID-19 patients without stress cardiomyopathy (32.8% vs 14.6%, aOR: 2.3, 95% CI: 1.2-4.5, P = 0.01) (Table 3 ).

Table 3.

In-hospital outcomes for 1:1 PS matched sample

Variable	COVID 19 with stress cardiomyopathy	COVID 19 without stress cardiomyopathy	P Value
In-hospital mortality	32.79%	14.61%	0.013
(N = 730)	Adjusted odds ratio*	2.30 (95% CI 1.19-4.45)
Vasopressor use	12.01%	5.84%	<0.001
	Adjusted odds ratio*	6.08 (95% CI 2.31-16.05)
Mechanical ventilation	45.45%	16.23%	<0.001
	Adjusted odds ratio*	3.76 (95% CI 1.95-7.25)
Acute kidney Injury on	6.17%	1.95%	0.031
Hemodialysis	Adjusted odds ratio*	3.99 (95% CI, 1.13-14.10)
Sudden Cardiac Arrest	9.09%	1.3%	0.004
	Adjusted odds ratio*	7.79 (95% CI, 1.90-31.90)
Cardiogenic Shock	15.91%	0.32%	<0.001
	Adjusted odds ratio*	63 (95% CI, 6.7-599.08)
Mechanical Circulatory	1.95%	0.32%	0.723
Support (LVAD or pVAD or ECMO)	Adjusted odds ratio*	1.31 (95% CI, 0.29-5.94)
Pulmonary Embolism	3.6%	2.8%	0.734
	Adjusted odds ratio*	1.1(0.6-2.04)
CVA	3.3%	1.3%	0.077
	Adjusted odds ratio*	1.9(0.93-3.89)
Disposition			0.045
Home/Routine	37.56%	44.71%
SNF/LTAC/Nursing home	39.59%	27.84%
Home health	21.32%	26.67%
AMA	1.52%	0.78%

AMA, against medical advice; CVA, cerebrovascular accident; ECHO, extracorporeal membrane oxygenation; LTAC, long term acute care facility; LVAD, left ventricular assist device; pVAD, percutaneous ventricular assist device; SNF, skilled nursing facility.

^⁎Adjusted for discharge quarter, elixhauser co-morbidities, hospital location, teaching status and bed size.

In-hospital Complications

COVID-19 patients with stress cardiomyopathy required more mechanical ventilation (45.5% vs 16.2%, aOR: 3.8, 95% CI: 2.0-7.3, P < 0.001) and vasopressor use (12.0% vs 5.8%, aOR: 6.1, 95% CI: 2.3-16.1, P < 0.001). This cohort also had higher incidences of acute kidney injury requiring renal replacement therapy (6.2% vs 2.0%, aOR: 4.0, 95% CI: 1.1-14.1, P = 0.03), cardiogenic shock (15.9% vs 0.3%, aOR: 63, 95% CI: 6.7-599.1, P < 0.001), and cardiac arrest (9.1% vs 1.3%, aOR: 7.8, 95% CI: 1.9-31.9, P = 0.004) when compared to COVID-19 patients without stress cardiomyopathy. There were no differences in the rates of utilization of mechanical circulatory support (2.0% vs 0.3%, aOR: 1.3, 95% CI: 0.3-5.9, P = 0.72) between the 2 cohorts (Table 3). Rates of cerebrovascular accidents (CVA) (3.3% vs 1.3%, aOR: 1.9 [95% CI, 0.9-3.9], P = 0.08) and pulmonary embolism (3.6% vs 2.8%, aOR: 1.1 [95% CI, 0.6-2.0], P = 0.73) during the same admission were not statistically significant.

In-hospital Quality Measures and Disposition

COVID-19 patients with stress cardiomyopathy had an increased length of stay (11.9 days vs 8.4 days, adjusted length of stay 7.6 days higher, P = 0.007) and increased cost of hospitalization (179,502 USD vs 58,854 USD, adjusted total charge 136,305 USD, P < 0.001) when compared to COVID-19 patients without stress cardiomyopathy.

Discussion

The major results of our study are: (1) COVID-19 patients with stress cardiomyopathy had significantly increased in-hospital mortality when compared to COVID-19 patients without stress cardiomyopathy, (2) COVID-19 patients with stress cardiomyopathy had significantly longer hospitalizations and higher rates of cardiogenic shock, cardiac arrest, acute kidney injury requiring renal replacement therapy, mechanical ventilatory dependence, vasopressor, and inotrope utilization. To our knowledge, our study is the largest analysis comparing outcomes of stress cardiomyopathy among hospitalized COVID-19 patients. In previous case-study literature, the reported prevalence of stress cardiomyopathy among COVID-19 patients is 2.2%, which is significantly higher than our reported prevalence of 0.1% among patients hospitalized in the US with COVID-19; our reported prevalence is more consistent with the general non-COVID-19 population.^{18 , 19}

We found that the in-hospital mortality of COVID-19 patients with stress cardiomyopathy both before and after propensity matching analysis was similar to previously reported inpatient mortality rates of 36.3%-40.0% in the literature.^{8 , 10 , 20} Correspondingly, COVID-19 patients with stress cardiomyopathy had an increased length of stay, higher cost of hospitalization, and a higher level of care at discharge; this cohort also had significantly increased mechanical ventilatory, vasopressor, and inotropic dependence, as well as higher incidence of cardiogenic shock, cardiac arrest, and acute kidney injury requiring hemodialysis when compared to COVID-19 patients without stress cardiomyopathy. We believe that the observed elevated inpatient morbidity and mortality and prolonged hospitalization among COVID-19 patients with stress cardiomyopathy correlates with the severity and acuity of COVID-19 infection in this cohort and was influenced by the lack of COVID-19 therapeutics and vaccinations during the early pandemic. A recently published study by Hajra et al., 2022 examined stress cardiomyopathy in COVID-19 patients and compared it to stress cardiomyopathy in non-COVID-19 patients and found that in a propensity score-matched population, stress cardiomyopathy patients with COVID-19 had a higher incidence of in-hospital mortality than stress cardiomyopathy patients without COVID-19 (33.6% vs13.6%, aOR 3.22, 95% CI: 2.19-4.72, P < 0.001).²¹ Moreover, only length of stay, incidence of sepsis, incidence of respiratory failure, and prolonged intubation were significantly higher in stress cardiomyopathy patients with COVID-19 after propensity matching. These results are notable in that they support our study implicitly – the authors did not identify any significant cardiac-specific drivers of mortality – thus the mortality of stress cardiomyopathy among COVID-19 is likely driven by the severity of COVID-19 infection rather than COVID-19 specific stress cardiomyopathy. Our study is more effectively designed at investigating this hypothesis since our control group is COVID-19 patients without stress cardiomyopathy, in comparison to the study designed by Hajra et al., 2022 which utilized a non-COVID-19 control group.

Racial disparities pertaining to the incidence of stress cardiomyopathy are understudied in current literature, particularly in COVID-19 infection. Among non-COVID-19 patients, stress cardiomyopathy has a higher incidence among African Americans when compared to Caucasians – incidence among other ethnicities is not well-characterized due to limited data.²² In contrast, we found that among hospitalized COVID-19 patients, both Caucasians and Asians have a higher incidence of stress cardiomyopathy. Our study suggests Caucasians and Asians are more likely to have COVID-19-related Takotsubo. The above disparities cannot be generalized due to insufficient data but can best be explained by socio-economic factors (ie early pandemic isolation effect leading to lack of access to health care, differences in care, etc.) that predispose populations to disadvantages.^{8 , 23 , 24}

Patients with COVID-19-related stress cardiomyopathy were predominantly males, ranging from 40.4% to 100%,^{10 , 20} in some studies while predominantly females, ranging from 66.6% to 68.6% in others.^{8 , 25} Our study correlated with those where men were the greatest affected sex. In non-COVID-19 cases, stress cardiomyopathy is classically seen among postmenopausal women; however, men can become more affected in the setting of COVID-19 infection.²⁰ The increased incidence in men is consistent with the sex distribution seen in complications from COVID-19.²⁶ Men are more likely than women to be susceptible to and experience physical stress (infection, inflammation, and other insults)²⁷ due to testosterone and its pro-inflammatory effects, which increases myocardial inflammation, unlike estrogen, which is protective and decreases inflammation.²⁸

We also found that COVID-19 patients older than 50 years of age were more likely to develop stress cardiomyopathy. This correlates with published findings that the median age of diagnosis for stress cardiomyopathy in the general population is between 66 and 72 years.^{10 , 20 , 25} This finding is likely a reflection of the susceptibility of older patients to severe COVID-19 infection.

Notably, in our study the only noncardiac comorbidity that COVID-19 patients with stress cardiomyopathy were more likely to have chronic pulmonary disease when compared to COVID-19 patients without stress cardiomyopathy. Comorbid pulmonary disease likely reflects the increased susceptibility of these patients to severe COVID-19 infection; there is no evidence to suggest that pulmonary disease in particular increases the risk of stress cardiomyopathy in COVID-19 or non-COVID-19 patients. In fact, current literature indicates that 29.2% of COVID-19-patients who develop stress cardiomyopathy have no known comorbidities.²⁹ With respect to the increased prevalence of baseline coronary artery disease and remote myocardial infarctions among COVID-19 patients with stress cardiomyopathy there are three possibilities:

• 1)These patients have susceptible myocardium that increases risk of stress cardiomyopathy specifically.
• 2)These patients may be at risk for other types of cardiomyopathies, particularly ischemic cardiomyopathy, and sepsis-induced cardiomyopathy.
• 3)These patients had pre-existing cardiomyopathy that was discovered incidentally during hospitalization for COVID-19 infection.

In summary, the higher prevalence of cardiac comorbidities among hospitalized COVID-19 patients with stress cardiomyopathy is not surprising, and likely lends support to the notion that in addition to physiologic stress, there may other factors contributing to the cardiomyopathy observed in these patients. Moreover, much like in the case of chronic pulmonary disease, patients with chronic cardiac disease are at increased risk of more severe COVID-19 infection.

Our group of COVID-19 patients with stress cardiomyopathy had significantly increased mechanical ventilation and vasopressor requirements, acute kidney injury requiring hemodialysis, cardiogenic shock, and sudden cardiac death compared to the COVID-19 alone cohort. These results were consistent with many articles as well as a meta-analysis of 2389 patients by Santoso et al., which suggested similar outcomes in that cardiac injury was associated with higher mortality (65%, RR: 8.0 [95% CI, 5.1-12.3], P < 0.001), higher need for intensive care unit (ICU)-level care (79%, RR: 7.9 [95% CI, 1.5-41.8], P = 0.01), and severe COVID-19 disease (RR: 13.8 [95% CI, 5.5-34.5], P < 0.001).^{8 , 30} That study, among others, suggested the severity of cardiac injury correlated with troponin elevation and inflammatory markers and thus, explains why affected patients have worse outcomes than non-Takotsubo COVID-19 patients.^{20 , 30} Additionally, reliance on cardiac enzymes and other biomarkers and clinical suspicion (regardless of cardiac history) when echocardiograms and angiography were not available for confirmatory diagnosis or when the use of such modalities was delayed due to the early pandemic isolation effect can explain worse outcomes, as well. A limitation of our study is the exclusion of lab values and imaging as NIS diagnoses are based on ICD-10 codes. History, exam, and laboratory data pertaining to takotsubo can be nonspecific, and thus, it is pertinent to recognize takotsubo early and treat patients aggressively to improve morbidity and mortality.³¹

The management of stress cardiomyopathy in COVID-19 patients can be challenging. The therapeutic approach is centered on the treatment of the underlying etiology as well as guideline-directed medical therapy for improvement of long-term outcomes as is the case with other types of heart failure. Specific treatment is based on the development of clinical heart failure (American College of Cardiology stage B vs stage C heart failure) and the degree of left ventricular dysfunction (preserved, reduced, or mildly reduced left ventricular ejection fraction [LVEF]). For patients with ACC stage B [pre-] heart failure, presumably the majority of patients in our cohort, characterized by asymptomatic LVEF less than 40%, the 2022 American Heart Association and American College of Cardiology Guidelines for the Management of Heart Failure provide a class I recommendation for the initiation of angiotensin-converting enzyme (ACE) inhibitors and beta blockers in this patient population to promote cardiac remodeling and recovery of systolic function. In the acute phase, there is no disease specific management for stress cardiomyopathy outside of volume management and potential hemodynamic support related to acute decompensated heart failure from stress cardiomyopathy. Treatment of underlying COVID-19 infection with novel therapeutics, most of which have become available after the interval of our dataset, have since shown benefit in reducing the severity of COVID-19 infection³²; it remains to be seen if antivirals such as remdesivir or glucocorticoids have any specific benefit for preventing or treating stress cardiomyopathy. Additionally, Stress cardiomyopathy has a 1% to 2% annual recurrence rate and it is controversial if beta-blockers, ACE inhibitors, or other interventions help reduce recurrence.^{7 , 33} Further investigation is warranted to determine if long COVID plays a role in the incidence of recurrent takotsubo syndrome given a reported 57% of patients experience persistent cardiac symptoms at a median follow-up of 329 days (IQR, 274-383 days).³⁴ Our study is limited in that 2020 NIS data does not include the 2021 ICD-10 code for long COVID.

Many concerns have surrounded COVID-19 vaccination with mRNA vaccines and the consequent development of cardiomyopathy.³⁵ In one systematic review and meta-analysis, 5 cases after the first mRNA dose and 4 cases after the second mRNA dose reportedly developed takotsubo syndrome out of over 1.3 billion COVID-19 administered vaccines from December 2020 to December 2021.³⁵ This study correlated with other systematic reviews of case reports in the literature and no deaths were reported following COVID-19 vaccine-associated cardiomyopathy.^{35 , 36} We hypothesize that mRNA vaccinations against COVID-19 will be beneficial in reducing the overall incidence of stress cardiomyopathy among COVID-19 patients. Two theoretical vaccine-mediated mechanisms of stress cardiomyopathy reduction among COVID-19 patients include the overall prevention of severe COVID-19 infection and accompanying acute physiologic stress by modulating host immunity and secondly, reducing emotional and mental stress by providing a sense of protection.^{33 , 37} Moreover, emergency use authorization for the Pfizer–BioNTech BNT162b2, COVID-19 mRNA vaccine was granted at the end of 2020 (December 11, 2020), and the next iteration of the NIS database in 2021 presents an opportunity to analyze the effect of the vaccine on stress cardiomyopathy incidence.

Limitations

Our study data has several limitations. This study utilized the NIS database, which may lend itself to selection bias – though the database is reported to cover more than 90% of the US inpatient population. Secondly, detection bias remains a concern, particularly as it relates to both COVID-19 infection and stress cardiomyopathy. The ICD-10 diagnosis code for COVID-19 was not developed until late 2020, which allows for the possibility that certain COVID-19 diagnoses were not captured in our dataset. Consequently, a subset of patients with COVID-19 were likely excluded from our analysis due to underdiagnosis. Likewise, COVID-19 testing remained in short supply and the NIS database does not provide lab test results to confirm COVID-19 status. This principle also applies to the diagnosis of stress cardiomyopathy and takotsubo syndrome, which was extracted from ICD-10 codes, without access to confirmatory angiographic and other clinical data. Nonetheless, we believe that our large sample size likely helps minimize the effects of these possible diagnostic errors. A third limitation of our study is that we had significantly larger control group, and the retrospective nature of this study also raises possible confounding bias. Our statistical analysis accounted for numerous demographic and clinical factors via multivariable logistic regression as well as for cohort size differences via propensity-matching.

Conclusions

We found that stress cardiomyopathy among hospitalized COVID-19 patients during the early pandemic was associated with increased in-hospital mortality, greater length of stay, and higher cost of hospitalization as well as higher incidences of cardiogenic shock, vasopressor use, mechanical ventilation, acute kidney injury requiring renal replacement therapy, and cardiac arrest when compared to COVID-19 patients without stress cardiomyopathy. Acute inpatient management includes close volume and hemodynamic monitoring with supportive measures as indicated. Long-term guideline directed medical therapy of stress cardiomyopathy is similar to other forms of ACC stage B heart failure and is centered around ACEi and beta-blocker therapy. These patients should continue to be surveilled for the development of clinical congestive heart failure and should undergo aggressive risk factor modification to prevent other types of cardiomyopathies in the outpatient setting. Vaccination is likely instrumental in reducing stress cardiomyopathy incidence among COVID-19 patients, however, further investigation is needed to confirm this hypothesis. In summary, the increased in-hospital morbidity and mortality associated with stress cardiomyopathy among COVID-19 patients warrants timely diagnosis and appropriate supportive care in the acute phase as well as guideline directed medical therapy in the long-term.