Assessing the Role of High-Dose β-Agonists Use in Triggering Takotsubo Syndrome During Asthma Exacerbation


Danish Abbasi, MD1*; Saif Faiek, MD2*; Waqas J Siddiqui, MD3; Angel Lopez-Candales, MD4

Perm J 2022;26:21.062 • E-pub: 04/05/2022 •

Volume 26, Issue 1

Corresponding Author
Saif Faiek, MD

Author Affiliations
1Division of Cardiovascular Medicine, The University of Arkansas for Medical Sciences, Little Rock, AR, USA

2Division of Pulmonary and Critical Care Medicine, Southern Illinois University, Springfield, IL, USA

3Department of Cardiovascular Medicine, Mayo Clinic School of Health Sciences, Orange Park, FL, USA

4Cardiovascular Medicine Division, Truman Medical Center, University of Missouri-Kansas City, MO, USA

*These authors contributed equally to this work.

Author Contributions:
All of the authors participated in writing and proofreading this review article.

Conflicts of Interest: None declared
Funding: None declared

Copyright Information
© 2022 The Permanente Federation. All rights reserved.


A surge in catecholamine levels has been postulated as a potential mechanism causing cardiomyopathy, particularly Takotsubo Syndrome (TTS). Consequently, repeated exposure to β1/β2 agonists could contribute to the development of TTS in patients with asthma during periods of intense exacerbation.

Even when no guidelines have been proposed for the identification and management of asthmatic patients who might develop TTS, recurrent asthma exacerbation requiring prolonged use of β1/β2 agonists have the potential of triggering life-threatening arrhythmias and increasing hospital deaths.

We conducted a PubMed search for published case reports, experimental studies, animal studies, and review articles examining TTS documentation among patients with asthma. We encountered 45 articles, of which 21 were case reports that were reviewed separately for age, sex, diagnosis, recurrence, electrocardiogram findings, echo results, and mortality.

Based on our review, it appears as if the use of high doses of β-agonists may predispose patients with asthma to cardiac events that might be preventable if physicians are aware of this association and become more judicious in their use of β-agonists. A standardized identification and treatment protocol would certainly be most helpful.


Clinical data have shown that asthma, chronic obstructive pulmonary disease (COPD), and interstitial lung disease are all associated with a higher incidence of cardiovascular diseases through a host of different pathophysiological mechanisms.15

Acute, severe asthma is also known to alter cardiovascular function during episodes of exacerbation.6 Most notably, decreased systemic venous return and rapid right ventricular filling shifts the interventricular septum toward the left ventricle (LV), which may lead to left ventricular diastolic dysfunction and incomplete filling. Pulmonary artery pressure may also be increased owing to lung hyperinflation, causing increased right ventricular afterload. In addition, sinus tachycardia can occur as a result of anxiety and hypoxemia. The use of β-agonists can further aggravate this tachycardia.

Takotsubo Syndrome (TTS) has been recognized more recently as a reversible form of stress-induced cardiomyopathy that is characterized by an acute and transient wall motion abnormality associated with reduced left ventricular systolic and diastolic dysfunction often related to an emotional or physical stressful event without evidence of obstructive epicardial coronary artery disease.7

One of the recognized risk factors for TTS is asthma that is mainly due to β-agonist use, as well as the use of epinephrine, and requires intubation with mechanical assisted ventilation.8,9

Even when the etiology of TTS in patients with asthma has not been well characterized, a potential link that has been suggested is the interaction of high levels of neuropeptide Y in these patients.10 Therefore, this review intends to analyze published literature regarding the documentation of TTS incidence and recurrence during asthma exacerbations.


TTS (also known as Takotsubo cardiomyopathy, stress-induced cardiomyopathy, broken heart syndrome, or apical ballooning syndrome) is characterized by transient systolic dysfunction of the LV in the absence of obstructive coronary artery disease. The term “Takotsubo” is taken from the Japanese name for an Octopus trap. It was first described in 1990, and since then it has been increasingly recognized. Stress cardiomyopathy occurs in approximately 1% to 2% of patients with suspected coronary artery syndrome and presenting with elevated troponin levels.11 TTS is more common in elderly populations, especially women. A review of 1750 patients from the International Takotsubo registry by Templin et al showed an overwhelming preponderance of the female sex (89.8%). The patients’ mean age in this study was 66.8 years; however, in Japan TTS mainly affects men following physical stress.12

Even when TTS pathophysiology has not been clearly elucidated, acute coronary syndrome presentation preceded by some form of profound predisposing stressors in patients without epicardial luminal stenosis on coronary angiography at the time of initial evaluation has been considered as a typical clinical scenario.

To facilitate diagnosis, the Mayo Clinic has proposed the following elements to be included as findings that suggest TTS: 1) new electrocardiographic abnormalities, 2) modest troponin level elevation, 3) regional wall motion abnormalities beyond a single epicardial vascular distribution, 4) transient dyskinesis of the LV midsegments, 5) no obstructive coronary artery disease or acute plaque rupture, and 6) the absence of pheochromocytoma and myocarditis.12

TTS carries a substantial disease burden. Common cardiac complications, especially during the acute phase of the disease, include cardiogenic shock, left ventricular outflow tract obstruction, left ventricular thrombus formation, and left ventricular rupture.13 A review of the national database of patients with TTS yielded an inpatient mortality rate of 4.2%. Singh et al published a meta-analysis in the American Journal of Cardiology, which showed an inpatient mortality rate of 4.5%. Both studies demonstrated an increased rate of mortality in men.14,15

Secondary TTS (triggered by physical factors, asthma, surgery, trauma, etc.) has more complications than the primary form. A study by Nunez et al published in the European Heart Journal showed that patients affected with the secondary form appear to experience more short- and long-term complications. Such patients required higher doses of inotropic agents and extended periods of mechanical ventilation support, resulting in extended hospitalization. The mortality rate was also higher in this subgroup compared with the control group.16

Role of Catecholamines in TTS

One of the most commonly proposed mechanisms accounting for TTS is catecholamine surge. Clinical observations in humans and recent experimental work on isolated rat ventricular myocytes suggest that an acute catecholamine overload is the dominant mechanism.17 Rat models support the hypothesis that circulating catecholamines are initiators of stress-induced cardiomyopathy and catecholamine-induced Takotsubo-like cardiac dysfunction in rat cardiac myocytes.18

Data from Wittstein et al showed that patients with such profound, reversible left ventricular dysfunction after sudden emotional stress have evidence of excessive sympathetic activation, with plasma catecholamine levels higher than age- and sex-matched patients from Killip class III myocardial infarction.19

The β-adrenoceptor is essential in the setting of profound catecholamine overstimulation. A study by Nef et al evaluating serial myocardial biopsies taken during the severe LV dysfunction and after functional recovery showed that during the acute phase, cellular hypertrophy with characteristic morphologic changes were seen in relation to the extreme catecholamine excess.20 Furthermore, Borchert et al studied the β-adrenergic signaling pathway and found an enhanced β-adrenergic signaling and high sensitivity to catecholamine-induced toxicity as mechanisms associated with TTS.21 In addition, in a review of 157 cases of drug-induced TTS, up to 68.2 % of the cases were catecholamine related.22

Finally, Lyon et al hypothesized that high epinephrine levels triggered intracellular signal trafficking involving a change from the Gs to the Gi protein via the b2-adrenoceptor within ventricular cardiomyocytes.23 These receptors’ density appeared more noticeably abundant in the apical myocardium, which might explain the regional apical ballooning.23 A study by Willis et al using a rat model showed that rats developed cardiac apex ischemia when treated with an acute isoproterenol overdose. Cardiac myocytes from these rats showed systolic dysfunction that was reversible at 4 weeks.24

TTS in Patients With Asthma

During asthma exacerbations, patients are exposed to severe physical stress and repeated doses of β-agonist agents, resulting in TTS-like features in these patients. In a review of 25 patients whose clinical and angiographic findings were consistent with TTS diagnosis, Constantini et al noted that 23 of the 25 patients were women and that in 5 of the patients TTS had occurred during an episode of “acute asthmatic bronchitis.” Three of these had underlying COPD. All 5 were elderly women, with a mean age of 81 ± 9 years. Coronary angiography was performed in 4 of 5 patients (1 patient refused consent), showing the absence of clinically significant epicardial luminal coronary lesions. At the same time, ventriculography confirmed the presence of apical ballooning. These results prompted these investigators to conclude severe bronchospasm during asthmatic attacks might precipitate TTS, with the possibility of linking these 2 clinical diseases.25 Most importantly, in a review assessing the prevalence of asthma among patients with documented TTS, Blotzheim et al noted that it was significantly higher when compared with age-matched patients without asthma (25% vs 7%, p = 0.012).26

Further, in a systemic review Manfredini et al analyzed the possible association between respiratory disease and TTS. These authors concluded that exposure to high doses of β-agonists in patients with respiratory conditions placed patients at increased chance of developing TTS.27

Finally, data published by Tornvall et al, comparing risk markers and mortality rates in patients with TTS to individuals with or without coronary artery disease, revealed that the use of β-blockers was less frequent among patients with TTS and that the use of b2-adrenergic agonist agents was more common in patients with TTS.28

Recurrence of TTS During Asthma Exacerbation

Although there is a substantial amount of literature to support the idea that asthma exacerbations may place a patient at risk for developing TTS, there is a paucity of data to suggest that patients with asthma are more likely to have recurrent episodes of TTS.

According to data from the World Asthma Foundation, not only do an estimated 20 million Americans have asthma (1 in 15 Americans), but asthma prevalence has also continued to increase since the early 1980s across all age, sex, and racial groups.29

Asthma accounts for one-quarter of all emergency room visits in the US each year, with 2 million emergency room visits, more than 10 million outpatient visits, and 500,000 hospitalizations with an average length of stay of 3 days.29 Despite aggressive treatment, the rate of asthma exacerbation has remained constant.30

Despite physicians following guideline-based treatments, patients with asthma continue to experience exacerbations caused by worsening of their underlying intrinsic inflammatory process or loss of disease control. Unfortunately, the prevention of asthma exacerbations remains a crucial unmet need in asthma management.31

Regardless of these patients’ clinical presentation, signs of cardiac decompensation during an asthma exacerbation should alert clinicians to have a higher index of suspicion for the possibility of TTS recurrence, especially when we already know from previous literature that among patients with COPD, the amount of energy and oxygen needed for respiration has been associated with a rise in cardiac troponin levels.32

Patients with asthma may be more prone to recurrent TTS episodes and, if so, may be more likely to have life-threatening complications such as cardiac arrhythmias, pulmonary congestion, and hospital death.33 Vriz et al prospectively followed 55 patients with TSS and found that 6 patients had recurrences within the first year and that 2 of these patients had recurrences triggered by an asthma exacerbation.34

Based on our review, no guidelines regarding the management of recurrent TTS exists in literature. Furthermore, there are no protocols regarding the monitoring of these patients after an initial episode of TTS. Moreover, the use of β-blockers has not been found protective against recurrent episodes. In fact, a meta-analysis performed by Singh et al showed that there was no correlation between TTS recurrences and the use of β-blockers but, rather, that there was an inverse correlation with the use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers.35 This association was further supported by data published by Brunetti et al from their meta-regression analysis that confirmed that Takotsubo recurrence rates were lower among patients who were treated and compliant with either angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers.36


We performed a PubMed search for articles with TTS and asthma exacerbation. Specific search criteria included (TTS OR Takotsubo OR broken heart OR stress cardiomyopathy OR stress-induced cardiomyopathy OR reversible left OR left reversible OR transient left OR left transient OR apical balloon*) AND (asthma* OR asthma exacerbation OR β-agonist OR β-agonists OR β-agonists OR β-adrenergic).

On the basis of these search parameters, 45 articles were shortlisted. Published original research, case reports, case series, case–control studies, animal studies, and review articles were included.37

The text of 21 case reports was separately reviewed and evaluated for age, sex, use of β-agonist, underlying diagnosis of asthma vs COPD, and presenting symptoms. Cases were also assessed for an initial or recurrent episode of TTS. We also explicitly evaluated the text for any documented fatality.


Our review showed that the average age of patients was 62.9 years of age, with a female-to-male ratio of 76%. A total of 15 of the 21 patients had asthma, whereas 4 were diagnosed with COPD, and 1 was listed as having bronchiectasis. All the patients were exposed to repeated doses of β-agonists. Six of these 21 patients were found to have recurrent episodes of TSS. All of the 6 patients with recurrent episodes were female, with an average age of 67.5 years. Three patients had an atypical presentation, 1 patient presented with syncope,38 1 with cardiac arrest,39 and 1 with apnea.40 Patients with atypical presentation experienced recurrent episodes. Furthermore, 2 of the 19 patients died upon presentation.39,40 Finally, all patients with recurrent episodes had been exposed to repeated high doses of β-agonists (Table 1).

AuthorAgeSexβ-AgonistDiagnosisRecurrencePresenting symptomFatalEchoEKG findings
Kotsiou et al41 43 F Y Asthma SOB
Katsa et al38 51 F Y COPD Y Syncope LVEF of 22% and apical ballooning PR depression in II, III, aVF
Parsa et al42 72 F Y Asthma Y SOB, chest pain substantial akinesia of apical segments ST elevation V1-V6
Khwaja et al43 UNKN F Y Asthma SOB LVEF 30% with apical akinesia and basal segment hyperkinesia ST elevation I, aVL, V2–V6,
Saito et al8 63 M Y Asthma SOB LVEF 49% apical ballooning ST elevation in V2–V6
Sharrett et al40 59 F Y COPD Y APNEA Y LVEF 25 antero apical akinesis PEA
Landefeld et al44 49 F Y COPD SOB LVEF 25-30% apical akinesia ST depression II, III, aVF
Marmoush et al45 80 F Y Asthma SOB, chest pain LVEF 60–65% apical hypokinesis and distal septum Left atrial enlargement & LBBB
Patel et al46 78 F Y Asthma SOB, chest pain LVEF 40% apical ballooning ST elevations II, III, aVF, V1 to V4
Sarkar et al47 53 M Y Asthma SOB LVEF 25% apical ballooning No changes
Salahuddin et al48 50 M Y Asthma SOB LVEF 25–30% aneurysm anteroapical, apical & inferoapical walls ST elevation in V2 3 4
Venditti et al39 81 F Y Bronchitis/bronchiecatasis Y Cardiac Arrest Y LVEF 40% mid apical akinesia ST elevation lead I , V3-6
Mendoza et al49 76 F Y COPD Y SOB LVEF 40% apical dyskinesis Diffuse prominent T wave inversions
Salemi et al50 68 F Y Asthma/COPD SOB LVEF 25% hypokinesis of the medial apical segments Intraventricular conduction disorder, diffuse T wave inversions
Rennyson et al51 68 F Y Asthma/COPD Y SOB, chest pain LVEF 15% Apical Dyskinesis ST elevation V 1 - V 4
Osuorji et al52 46 F Y Asthma SOB LVEF 10% anteroapical akinesia proximal basal hyperkinesis ST elevation I II V4 5 6
Satoh et al53 51 F Y Asthma SOB Apical Akinesis and basal hyperkinesis ST elevation in II, III, aVF, V2 -V6 .T-wave inversion in leads V3- V6
Hernández Lanchas et al54 74 F Y Asthma SOB, chest pain Apical ballooning ST elevation precordial leads
Saeki et al55 62 M Y A/C SOB Apical dyskinesia and hypersystole in the basal region of the heart ST elevation, loss of R-wave progression,
Ripa et al56 64 F Y Asthma SOB Apical akinesis
Pontillo et al9 72 M Y Asthma SOB LVEF 37% apical ballooning ST segment elevation in anterior leads

Table 1: Summary of search results

Abbreviations: aVF = arteriovenous fistula; aVL = artificial ventilation of the lungs; COPD = chronic obstructive pulmonary disease; F = female; LVEF = normal left ventricular ejection fraction; LBBB = left bundle branch block; M = male; N = no; PEA = pulseless electrical activity; SOB = shortness of breath; TSS = toxic shock syndrome; UNKN = unknown; Y = yes.


Until more data becomes available it appears that judicious use of β-agonists may prevent recurrent TTS during asthma exacerbation episodes. In addition, the use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers have also shown some protective benefit from recurrence.

We suggest that standardized monitoring and treatment protocols should be devised to assist the management of a patient afflicted with recurrent Takotsubo episodes. More importantly, prospective studies are urgently needed to assist us in treating patients with asthma who are more likely to have this cardiac complication.

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