Management of Takotsubo Syndrome: A Comprehensive Review

Takotsubo syndrome (TTS), also known as Takotsubo cardiomyopathy, is a transient left ventricular wall dysfunction that is often triggered by physical or emotional stressors. Although TTS is a rare disease with a prevalence of only 0.5% to 0.9% in the general population, it is often misdiagnosed as acute coronary syndrome. A diagnosis of TTS can be made using Mayo diagnostic criteria. The initial management of TTS includes dual antiplatelet therapy, anticoagulants, beta-blockers, angiotensin-converting enzyme inhibitors or aldosterone receptor blockers, and statins. Treatment is usually provided for up to three months and has a good safety profile. For TTS with complications such as cardiogenic shock, management depends on left ventricular outflow tract obstruction (LVOTO). In patients without LVOTO, inotropic agents can be used to maintain pressure, while inotropic agents are contraindicated in patients with LVOTO. In TTS with thromboembolism, heparin should be started, and patients should be bridged to warfarin for up to three months to prevent systemic emboli. Our comprehensive review discussed the management in detail, derived from the most recent literature from observational studies, systematic review, and meta-analyses.


Introduction And Background
Takotsubo syndrome (TTS), also commonly known as Takotsubo cardiomyopathy or apical ballooning syndrome, is characterized by transient left ventricular (LV) wall dysfunction triggered by physical or emotional factors with similar presentation features as acute coronary syndrome (ACS) [1]. TTS accounts for 0.02% of the inpatient admission in the United States [2]. The prevalence of TTS in the general population, mimicking ST-segment elevation myocardial infarction (STEMI), is estimated to be 0.5% to 0.9%, with a higher prevalence in women in their sixth decade of life. Indeed, 2% to 3% of STEMI presentations in women turn out to be TTS every year [2][3][4].
As the clinical presentation of TTS is often indistinguishable from ACS, it is a diagnosis of exclusion once true ACS is ruled out with coronary angiography. According to Luscher and Templin et al., TTS and ACS commonly present with chest pain and dyspnea on exertion [1,5]. However, most cases of TTS have an identifiable risk factor of physical or emotional stress that can differentiate it from ACS. To date, there is no noninvasive test that can confirm the diagnosis of TTS. The definitive diagnostic tool to differentiate TTS from ACS is coronary angiogram. Furthermore, an LV angiogram has classic features which include apical rounding, followed by basal and mid-ventricular contraction. Upon establishing the diagnosis, continuous telemetry monitoring and repeated echocardiograms are essential to identify complications of TTS. Some of the complications of severe TTS that can affect ionotropic function include acute heart failure, LV outflow tract obstruction (LVOTO), cardiogenic shock, and the presence of LV thrombus. Other complications of TTS can include rhythm abnormalities such as atrial fibrillation, ventricular fibrillation, atrioventricular block, and cardiac arrest [5]. Our review discusses current management approaches for TTS during the acute and long-term phases of the disease.

PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses
Our review of TTS is divided into a short discussion about diagnosis and an extended discussion about management. The extended discussion is divided into TTS with and without complications.

Diagnosis of TTS
The diagnosis of TTS should be based on differentials in patients with ACS symptoms such as chest pain or dyspnea on exertion with positive cardiac biomarkers, including troponin, particularly when echocardiographic and clinical manifestations do not fit the pattern of ACS [21]. A careful history review of physical or emotional stressors should be taken. However, TTS can present without any inciting emotional or physical stressors. A diagnosis of TTS is met if the patient meets all four Mayo Clinic criteria; these can be helpful in its diagnosis (  A diagnosis of TTS should also be considered if wall motion defects do not correlate with an obstructed coronary artery. The exception is a percentage of patients that have concurrent obstructed coronary artery disease (CAD) and TTS; per the International Takotsubo Registry, this subset included 15.3% of TTS cases [5]. Thus, a diagnosis of TTS that includes an electrocardiogram and troponin results can resemble ACS.

Diagnostic Imaging
Coronary angiogram is useful for diagnosing TTS. Serial LV systolic function assessment can be done with serial echocardiograms, a one-time assessment with coronary ventriculography, and then cardiac magnetic resonance imaging. It is imperative to suspect TTS during the evaluation of ACS. The approach detailed in Figure 2 should be considered for TTS diagnosis during the evaluation of ACS.  Detection of wall defects on echocardiography or LV ventriculography suggests a review of the following wall defect patterns (Table 3) [5,[24][25][26].

Apical
The most common type of pattern of wall defect found in the TTS International Takotsubo Registry. There is significant LV systolic apical ballooning with mid/apical hypokinesia and often basal hyperkinesia.

Midventricular
The second most common pattern of wall defect found in the International Takotsubo Registry. There is LV hypokinesia/wall defect only in LV mid-ventricular region with apical sparing.

Basal
The third most common type of pattern of wall defect found in the International Takotsubo Registry. There is basal hypokinesia of LV with sparing of mid-ventricular and apical region.

Focal
The fourth most common type of pattern of wall defect found in International Takotsubo Registry. In this type, isolated anterolateral segment dysfunction of LV is found.

Global
In rare circumstances, TTS patients can have global hypokinesia.

Cardiac Magnetic Resonance
Cardiac magnetic resonance can highlight the absence of late gadolinium enhancement in TTS as compared to the presence of late gadolinium enhancement seen in transmural or subendocardial regions in myocardial infarction [25].

General Management
The management of TTS is generally conservative and focused on emotional or physical stress relief. However, in some cases, acute complications such as heart failure and shock develop, and intensive management is required. The management of heart failure and shock is similar to that in the general guidelines of their management in non-TTS cases except in the presence of LVOTO. In cases of LVOTO, caution should be taken in preventing volume depletion or with vasodilatory medications. Generally, the duration of treatment of TTS ranges from three months to one year depending on expert opinion. In a study by Fazio et al., it was found that TTS treatment of more than three months did not add any significant change to survival and should be avoided [16].
The management of TTS is divided into TTS without complications and TTS with complications. These complications include hypotension and cardiogenic shock with heart failure or LVOTO, cardiac arrhythmias, and thromboembolism.

TTS without Complications
After a comprehensive assessment, if patients are hemodynamically stable with no other signs of complications such as acute heart failure, arrhythmia, or thromboembolism, they should be admitted to cardiology for further monitoring. In a study by Yeyehd et al., the acute and postdischarge management of TTS with dual antiplatelet therapy (DAPT) including aspirin and clopidogrel, anticoagulation such as low molecular weight heparin or fondaparinux, betablockers, statins, angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs), and psychological stress relief management helped to lower inpatient mortality and recurrence of TTS [8]. Furthermore, a study by Yeyehd et al. indicated that DAPT should be discontinued at discharge if TTS is certain [8]. A further review also revealed a study by Dias et al. indicating that single antiplatelet therapy or DAPT are independently helpful in lowering major adverse cardiovascular events/complications in TTS patients [19]. In a study by Templin et al. ACE/ARBs were associated with improved survival at one-year follow-up in patients with and without heart failure in TTS [5]. A study by Regnante et al. showed that the use of ACE inhibitors before the onset of TTS prevented cardiogenic shock, arrhythmias, and death [15]. A meta-analysis by Santoro et al. reviewed three-year follow-up data and concluded that aspirin, statin, beta-blocker, and ACE/ARBs do not reduce the recurrence of TTS [13].

TTS with Complications -Hypotension and Cardiogenic Shock
For TTS patients with hypotension or shock, continuous monitoring of clinical parameters such as vital signs, mental status, urine output, and renal function should be done along with telemonitoring. Up to 5%-10% of patients with TTS can develop cardiogenic shock [5,27]. A variety of factors are associated with cardiogenic shock in TTS, including physical triggers, young age, and low LV ejection fraction. Mortality is higher in TTS with shock by roughly 10fold [28,29]. A clinical discordance is found between shock and systolic function of the left or right ventricle. This discordance can be due to the presence of LVOTO [30][31][32][33]. An urgent echocardiogram should be done in TTS with cardiogenic shock to look for LVOTO and to rule out the systolic anterior motion of the mitral valve or mitral regurgitation [31,33].
The management of hypotension or cardiogenic shock can be further divided into cases with and without LVOTO as follows.
Cardiogenic shock without LVOTO: In patients with hypotension without pulmonary congestion, cautious fluid resuscitation can be performed, even in patients with or without LVOTO. In patients with LV systolic dysfunction but without LVOTO, a trial of inotropic agents such as dopamine or dobutamine can serve as a temporary measure; however, an inotropic agent can cause mild LVOTO in these patients [34]. In moderate to severe LVOTO, pressor/inotropic agents are contraindicated. Patients with persistent hypotension or any signs of end-organ damage should be closely monitoring with pulmonary catheterization/wedge pressure and intra-aortic balloon pumps (IABP). This subset of patients requires vasopressors.
Cardiogenic shock with LVOTO: In patients with cardiogenic shock with moderate to severe LVOTO, inotropic agents should not be used because they can increase the degree of obstruction [31,34]. In a study by Ansari et al., it was reported that inotropes such as epinephrine, norepinephrine, dobutamine, and dopamine should be avoided in TTS, and that catecholamine excess can increase 30-day and long-term mortality in TTS [9]. Only Marfella et al. reported that alpha-adrenergic stimulation by alpha-lipoic therapy could increase sympathetic stimulation of the heart and show improvement of cardiac defects on 123Imetaiodobenzylguanidine myocardial scintigraphy at a 12-month follow-up in TTS patients [7].
The recommended treatment of TTS with moderate to severe LVOTO is similar to hypertrophic cardiomyopathy. The management of this subset of patients includes fluid resuscitation in the absence of pulmonary congestion [22,31]. The use of beta-blockers also plays a role in the relief of obstruction. A case-control study by Santoro et al. suggested that intravenous administration of esmolol at admission, followed by daily bisoprolol can improve LVOTO gradient and relieve obstruction [10].
In TTS with severe LVOTO, alpha agonists such as phenylephrine can help in a closely monitored setting by increasing afterload. However, phenylephrine should be used with caution as it can cause coronary vasospasm. Patients with severe/persistent hypotension not responsive to fluid resuscitation or initial measure with an intra-aortic balloon pump should be closely monitored. As IABPs can decrease afterload, this effect should be monitored closely [32,34]. A further literature review showed several case reports that demonstrated the efficacy of extracorporeal membrane oxygenation as a life-saving alternative treatment for circulatory support in TTS patients with cardiogenic shock [35][36][37].

TTS with Complications -Heart Failure
Acute heart failure (HF) in TTS is managed the same way as HF from any other illness: by oxygen, respiratory support as needed, and preload and afterload reduction. The exception to the regular management is that preload and afterload reduction therapies should be avoided in cases with LVOTO. In TTS patients with HF without LVOTO, the standard cocktail of medications for HF can be prescribed. This includes diuretics, ACE inhibitors, or ARBs [22]. Beta-blockers do not lower mortality in HF due to TTS. In an observational study of 2,672 patients by Isogai et al., beta-blockers were unable to lower 30-day in-patient mortality in 423 patients [12]. A beneficial effect of beta-blockers is a low incidence of cardiac rupture in TTS treated with beta-blocker, as reported by Kumar et al. [14]. A meta-analysis by Singh et al. concluded that ACE inhibitors prevent the recurrence of TTS, while beta-blockers do not [20].
The recommended duration of treatment is not well known, but in general, treatment with HF medication is four weeks until systolic function improves. A Mayo clinic study failed to show any survival benefits of ACE inhibitors and beta-blockers in TTS patients [38]. An observation study by Abanador-Kamper et al. reviewed all the treatment regimens for TTS patients and concluded that the benefits of heart failure cocktail medications and antithrombotic therapy is highest during the first two months of TTS, with a low side effect profile, high survival, and early recovery [11]. A case series study by Santoro et al. concluded that the use of levosimendan can improve the LV ejection fraction and has a good safety profile [18].

TTS with Complications -Thromboembolism
Ventricular thrombus is found in 1.3% of the 1,750 TTS patients in the International Takotsubo Registry [5]. The risk of LV thrombus should be evaluated by echocardiography in TTS patients with severe LV dysfunction. There are no clear guidelines for anticoagulation to prevent LV thrombus, but some reports have shown that 10 days of anticoagulation can reduce the incidence of LV thrombus in TTS patients. In patients with severe LV dysfunction and/or with LV thrombus, anticoagulation for three months until resolution of LV dysfunction to prevent systemic embolization is preferred [22][23]. A systematic review by de Gregorio found that early anticoagulation is beneficial in TTS in patients with or without thromboembolism [17]. This is also supported by an observational study by Santoro et al. that found that early heparin administration followed by warfarin for three months prevented stroke in TTS patients with and without LV thrombus [6].

Conclusions
In conclusion, we have reviewed the most recent observational studies and clinical trials to summarize the management of TTS. The initial management should include optimal medical therapy with antiplatelet medications, statins, beta-blockers, and ACE/ARBs. Pressor medications are contraindicated in TTS with LVOTO. In TTS with thromboembolism, heparin