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\begin{document}

\title{Prevalence and Impact of Takotsubo Syndrome in Hospitalizations for
Acute Ischemic Stroke}



\author[1]{Upenkumar  Patel}%
\author[2]{Rupak Desai}%
\author[3]{MOHAMMED Faisal Uddin}%
\author[4]{Hee Kong Fong}%
\author[5]{Sandeep  Singh}%
\author[6]{Smit  Patel}%
\author[7]{Gautam  Kumar }%
\author[8]{Rajesh  Sachdeva}%
\affil[1]{Nassau University Medical Center}%
\affil[2]{Atlanta VA Medical Center}%
\affil[3]{Affiliation not available}%
\affil[4]{UC Davis Department of Medicine}%
\affil[5]{Amsterdam University Medical Centres}%
\affil[6]{Hartford Hospital}%
\affil[7]{Emory University}%
\affil[8]{Morehouse School of Medicine}%


\vspace{-1em}



  
  \date{May 15, 2024}


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\selectlanguage{english}
\begin{abstract}
Background: Takotsubo Syndrome (TTS) is characterized by acute and
reversible left ventricular dysfunction with apical ballooning arising
during acute stress situations. Acute Ischemic Stroke (AIS) is one of
the known triggers to TTS, however, the impact of TTS on in-hospital
outcomes of AIS remains unexplored. Methods: We utilized data from the
National Inpatient Sample (2007-2014) and using ICD-9-CM diagnosis codes
to identify admissions for AIS with TTS and evaluated the temporal
trends, baseline characteristics, in-hospital complications, length of
stay (LOS) and all-cause mortality. Survey multivariable logistic
regression was used to compute adjusted Odds Ratios (OR and 95\%
confidence intervals (CI). Results: An estimated 2,242 (0.4\%) TTS cases
were identified among AIS hospitalizations (N=43,92,471). The frequency
of TTS was higher in elderly, whites and females (82.2\%). After
adjustment for confounders, TTS incidence in AIS was associated with
higher odds of in-hospital complications including cardiogenic shock
(OR8.84, CI:4.07-19.17, p\textless{}0.001), cardiac arrest (OR3.17,
CI:1.57-6.42, p=0.001), and venous thromboembolism (OR1.68,
CI:1.14-2.47, p=0.008). Moreover, AIS hospitalizations with TTS showed
higher odds of developing respiratory failure (OR3.13, CI:2.42-4.05,
p\textless{}0.001) and required mechanical ventilation/intubation
(OR4.09, CI:3.14-5.32, p\textless{}0.001) more frequently compared to
non-TTS cohort. The AIS-TTS cohort had longer LOS (8.59 vs 5.22 days)
and the mortality was doubled (10.2\% vs 5.1\% p\textless{}0.001)
compared to those without TTS. Conclusion: The prevalence of TTS in AIS
remained \textasciitilde{}20 times higher than the general inpatient
population and it predisposed AIS patients to worse inpatient outcomes.
Further studies are needed to evaluate the impact of TTS on long-term
outcomes in AIS.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Takotsubo Syndrome (TTS) is a relatively reversible heart condition
characterized by left ventricular (LV) dysfunction, apical ballooning
with abnormally elevated cardiac biomarkers and ECG changes in the
absence of any obstructive coronary artery disease {[}1{]}. The precise
cause of this cardiomyopathy is not known but possible explanations
include catecholamine surge during stress, ischemia-mediated stunning of
the myocardium due to microvascular spasm, and myocarditis {[}2, 3{]}.
The TTS has been one of the well-known complications following
subarachnoid hemorrhage, occurring due to increased catecholamine
release following intracranial hemorrhage {[}4, 5{]}. The overall
prognosis of TTS most of the time is favorable, however, certain
clinical conditions carry higher risk and may have poorer outcomes
{[}6{]}. Therefore, recognition and management of such clinical
conditions that might predispose the patients to TTS is of utmost
importance and should be an integral part of the management {[}3{]}.

With the rising prevalence of TTS in various clinical conditions,
multiple studies have reported TTS trends and outcomes in various
neurological and non-neurological clinical conditions {[}7-10{]}. The
acute cerebral events including acute ischemic stroke (AIS) are
associated with catecholamine surge and hence, can lead to TTS. However,
limited data exist on the prevalence and outcomes of TTS in AIS. This
study aims at evaluating the US nationwide estimate of the burden and
the differences in the outcomes of TTS and non-TTS in the inpatient AIS
population.

\textbf{Methods}

We queried the National Inpatient Sample (NIS) (2007 to 2014) a
nationally weighted data of all hospital discharges in the United States
to describe the frequency of various complications in AIS patients with
TTS and also to determine the predictors of all-cause in-hospital
mortality. The NIS is a part of the Healthcare Cost and Utilization
Project (HCUP) funded by the Agency for Healthcare Research and Quality
(AHRQ) {[}11{]}. This data consists of a sample from 20\% of total
hospitalizations from nonfederal US community hospitals representing
95\% of the general population in the US. The NIS contains de-identified
data; hence, our study was exempt from an institutional review board
authorization.

We used International Classification of Diseases, 9th Revision, Clinical
Modification (ICD-9-CM) to identify primary admissions for AIS (433.01,
433.11, 433.21, 433.31, 433.81, 433.91, 434.01, 434.11, 434.91 and 436)
and then using ICD-9 CM code 429.83 admissions with TTS as a secondary
discharge diagnoses were filtered.

The primary outcome of our study was to assess the prevalence, trends
and all-cause inpatient mortality in AIS cohort with TTS vs. without
TTS. Secondary outcomes included frequency of in-hospital complications
such as cardiogenic shock, venous thromboembolism, respiratory failure,
need for mechanical ventilation and healthcare resource utilization
{[}discharge disposition, mean length of stay (LOS) and hospital
charges{]} among AIS-TTS cohort as compared to AIS- non-TTS cohort.

We utilized designated weight values to produce nationally
representative estimates and survey multivariable logistic regression
models were performed after adjusting patients and hospital-level
confounders to estimate the odds and 95\% confidence intervals (CI) of
in-hospital mortality and other complications in AIS cohort with TTS as
compared to without TTS. We used SPSS v22 (IBM Corp., Armonk, NY) to
perform all statistical analyses.

\textbf{Results}

From 2007-14, 43,92,471 hospitalizations with AIS were identified, of
which, 2242 (0.4\%) had TTS. An increasing trend in prevalence of TTS
was seen from 2007 with the highest number of cases recorded in 2014
(n=1081). Higher proportion of AIS-TTS cohort consisted of elderly (.65)
(69.8\%), white (77.5\%) females (82.2\%).

AIS-TTS cohort showed higher prevalence of comorbidities including
congestive heart failure (37.5\% vs 14\%; p\textless{}0.001), coronary
atherosclerosis (32.2\% vs 25.7\%; p\textless{}0.001), previous
myocardial infarction (10.4\% vs 6.4\%; p\textless{}0.001), valvular
disease (14.1\% vs 10\%; p\textless{}0.001), alcohol abuse(6.5\% vs
3.9\%; p\textless{}0.001), deficiency anemias (20.2\% vs 11.5\%;
p\textless{}0.001), rheumatoid arthritis/collagen vascular diseases
(4.2\% vs 2.4\%; p\textless{}0.001, chronic pulmonary disease (20.8\% vs
14.9\%; p\textless{}0.001), coagulopathy(6.2\% vs 4.8\%;
p\textless{}0.001), fluid and electrolytes disorders (37.4\% vs 19.9\%;
p\textless{}0.001) and hypothyroidism (14.3\% vs 12.5\%;
p\textless{}0.001) as compared to AIS patients without TTS.

All-cause in-hospital mortality in AIS patients with TTS was double than
patients without TTS (10.2\% vs 5.1\%; p\textless{}0.001). Moreover, AIS
hospitalizations were associated with higher odds of cardiogenic shock
(OR 8.84, CI:4.07-19.17; p\textless{}0.001), cardiac arrest (OR 3.17,
CI:1.57-6.42; p=0.001), respiratory failure (OR 3.13, CI:2.42-4.05;
p\textless{}0.001), venous thromboembolism (OR 1.68, CI:1.14-2.47;
p=0.008), and need for intubation/mechanical ventilation (OR 4.09,
CI:3.14-5.32; p\textless{}0.001) among AIS patients with TTS.

Mean LOS was higher among AIS-TTS cohort as compared to non-TTS cohort
(8.59\selectlanguage{ngerman}±10.03 vs 5.22±6.24; p\textless{}0.001). AIS patients with TTS
required chronic care and step down to the Skilled Nursing Facility
(SNF), Intermediate Care Facility (ICF) more frequently compared to
non-TTS patients (53.8\% vs 42.9\%). In addition, mean hospital charges
were higher among AIS-TTS cohort (\$85,854 vs \$37,924).

\textbf{Discussion}

To the best of our knowledge, this is the first study demonstrating the
prevalence, temporal trends and impact of TTS in patients with AIS. In
this nationally representative sample of hospitalizations with AIS, we
demonstrate an estimated 0.4\% of TTS cases from 2007-14 which were
associated with higher all-cause mortality, adverse hospital-related
complications and longer LOS as compared to AIS patients without TTS.
This rate is nearly 20 times higher than the TTS rate reported in the
general inpatient population (0.02\%). Previous analyses studying TTS in
AIS have either been single-center studies or case reports {[}12-15{]}.

There has been an increasing trend in the prevalence of TTS with AIS
from 2007-2014, with the highest number of cases recorded during 2014
(N=1081). The highest proportion of TTS cases among AIS were recorded
among elderly \textgreater{}65 years (69.8\%) and female (82.2\%)
patients. A study by Jung et al. of 23 AIS patients reported similar
findings of increasing rates of TTS among the elderly with a mean age of
70.7±13.9 years consisting predominantly of females (73.9\%) {[}16{]}.
Female predominance was seen in another study by Templin et al {[}17{]}.
Consistent with our study findings, a study by Murugiah et al. reported
white patients representing almost 90.2\% of the total TTS population
{[}18{]}.

The baseline characteristics and comorbidities could define prognosis in
AIS patients with TTS. We observed a significantly higher prevalence of
congestive heart failure, chronic pulmonary disease, coagulopathy, fluid
and electrolytes disorders, hypothyroidism, obesity, previous myocardial
infarction, depression and coronary atherosclerosis among AIS patients
with TTS. In one study by Brinjikji et al. reported the higher
prevalence of chronic cardiovascular morbidities among TTS patients
{[}19{]}. These data could help better risk stratify patients at risk of
TTS with AIS.

In our study, we observed higher odds of developing adverse events
during AIS hospitalizations with TTS. These included cardiogenic shock
(OR=8.84), cardiac arrest (OR=3.17), and venous thromboembolism
(OR=1.68). Moreover, the AIS-TTS cohort was at higher risk of developing
respiratory failure (OR=3.13) and requiring mechanical
ventilation/intubation (OR=4.09) more frequently. Increased risk of
cardiovascular complications in AIS-TTS cohort could be due to higher
proportion of elderly patients with underlying chronic medical illness.
Similar findings were observed in a study by Brinjikji et al, in which
higher odds of complications were seen among elderly patients with
underlying chronic cardiovascular risk factors {[}19{]}.

TTS occurrence in AIS also had a worse impact on healthcare resource
utilization. We observed frequent step down of AIS-TTS cohort to more
chronic care centers including SNF, ICF etc. In addition, we observed an
extended hospital stay of TTS cohort (8.59±10.03 vs 5.22±6.24) compared
to non-TTS cohort. This could be attributed to increased risk of
complications requiring longer stay and more advanced care. Prolonged
hospital stay among AIS-TTS cohort was also associated with more than
two times higher mean total hospital charges (\$85,854 vs \$37,924).
This further signifies the importance of identifying AIS patients early
to prevent complications and associated economic repercussions.

The all-cause inpatient mortality observed in AIS patients with TTS was
double (10.2\% vs 5.1\%) than non-TTS cohort. In addition to the added
burden of TTS-related complications, this could be explained by the
higher prevalence of chronic comorbidities, which increases risk of
in-hospital adverse events among AIS patients with TTS. In a prospective
observational study, higher mortality risk along with adverse events was
observed in older age groups {[}20{]}.

\textbf{Limitations}

Our study should be reviewed with certain limitations to our analysis.
Since we used admission-associated data rather than patient-level data
we depended on administrative diagnosis codes. Therefore, the outcomes
among the patients who were discharged cannot be defined due to limited
information of follow-up. We were also unable to account for unmeasured
confounders that could be associated with increased risk of TTS in AIS
patients and the complications occurring during hospital stay. Data on
medication records and follow-up were not available. Despite these
limitations, the benefit of using a large, multi-center, representative
sample affords a truly national perspective and preserves the validity
of associations reported.

\textbf{Conclusion}

The prevalence of TTS among admissions for AIS was 0.4\%, which is
nearly 20 times higher than the TTS rate reported in the general
inpatient population. The higher prevalence of TTS was seen in elderly,
white and female patients with AIS. The TTS occurrence was associated
with higher in-hospital mortality, cardiovascular complications and
healthcare resource utilization. Further studies are warranted to
evaluate the association and potential long-term impact of TTS in AIS
patients.

\textbf{Acknowledgement:} None

\textbf{References}

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{[}4{]} V.H. Lee, H.M. Connolly, J.R. Fulgham, E.M. Manno, R.D. Brown,
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{[}5{]} M. Shimada, J.D. Rose. Takotsubo cardiomyopathy secondary to
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{[}6{]} R. Ono, L.M. Falcão. Takotsubo cardiomyopathy systematic review:
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{[}7{]} R. Desai, S.A. Abbas, H.K. Fong, et al. Burden and impact of
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{[}11{]} HCUP-US NIS Overview.
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{[}15{]} S. Yoshimura, K. Toyoda, T. Ohara, et al. Takotsubo
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{[}16{]} J.M. Jung, J.G. Kim, J.B. Kim, et al. Takotsubo-Like Myocardial
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{[}17{]} C. Templin, J.R. Ghadri, J. Diekmann, et al. Clinical Features
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Med.} 373 (2015) 929-938. 10.1056/NEJMoa1406761

{[}18{]} K. Murugiah, Y. Wang, N.R. Desai, et al. Trends in Short- and
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(2016) 197-205. 10.1016/j.jchf.2015.09.013

{[}19{]} W. Brinjikji, A.M. El-Sayed, S. Salka. In-hospital mortality
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{[}20{]} R. Citro, F. Rigo, M. Previtali, et al. Differences in clinical
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10.1111/j.1532-5415.2011.03730.x

\textbf{Figure legends}

\textbf{Figure 1. Trends in Takotsubo Syndrome Hospitalizations}

A. Trends in Takotsubo Syndrome per 1 Million Hospitalizations for Acute
Ischemic Stroke

B. Trends in Takotsubo Syndrome per 1 Million Hospitalizations for Acute
Ischemic Stroke Stratified by Stroke

C. Trends in Takotsubo Syndrome per 1 Million Hospitalizations for Acute
Ischemic Stroke Stratified by Age

D. Trends in Takotsubo Syndrome per 1 Million Hospitalizations for Acute
Ischemic Stroke Stratified by Race/Ethnicity

\emph{Cover Letter}

Date: 03/06/2021

Dr Charles Young, Editor-in-Chief, \emph{International Journal of
Clinical Practice}

Re: Short Communication: \emph{Prevalence and Impact of Takotsubo
Syndrome in Hospitalizations for Acute Ischemic Stroke}

Dear Dr. Young,

We herewith submit a Short Communication entitled ``\emph{Prevalence and
Impact of Takotsubo Syndrome in Hospitalizations for Acute Ischemic
Stroke''} for possible publication in your esteemed journal after your
kind review.

Upcoming reports suggest Acute Ischemic Stroke is one of the known
triggers to TTS. The acute cerebral events including acute ischemic
stroke (AIS) are associated with catecholamine surge and hence, can lead
to TTS. However, limited data exist on the prevalence and outcomes of
TTS in AIS. Furthermore, the impact of TTS on in-hospital outcomes of
AIS remains unexplored. Using the National Inpatient Sample (2007-2014)
databases and relevant ICD-9 CM codes, we identified AIS and TTS-related
adult hospitalizations and assessed the frequency of TTS in AIS patients
and its impact on disposition of patients and healthcare resource
utilization in the United States.

We hope the editorial board and reviewers will find the content suitable
for \emph{International Journal of Clinical Practice.} This manuscript,
as submitted or its essence in another version is not under
consideration for publication elsewhere and will not be published
elsewhere while under consideration by \emph{International Journal of
Clinical Practice.} The authors have no commercial associations or
sources of support that might pose a conflict of interest. All authors
have made substantive contributions to the manuscript, and all authors
endorse the data and conclusions.

We have no relationships with industry to disclose.

Thank you for your consideration.

Yours sincerely,

Rupak Desai, MBBS

Division of Cardiology

Atlanta Veterans Affairs Medical Center, 1670 Clairmont Rd, Decatur, GA
30033

\textbf{Email:}rdesa30@emory.edu\textbf{Phone:} (404) 321-6111 ext. 7359\selectlanguage{english}
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